In eukaryotes, the messenger RNA (mRNA), the blueprint of a protein‐coding gene, is processed and packaged into a messenger ribonucleoprotein particle (mRNP) by mRNA‐binding proteins in the nucleus. The steps of mRNP formation – transcription, processing, packaging, and the orchestrated release of the export‐competent mRNP from the site of transcription for nuclear mRNA export – are tightly coupled to ensure a highly efficient and regulated process. The importance of highly accurate nuclear mRNP formation is illustrated (...) by the fact that mutations in components of this pathway lead to cellular inviability or to severe diseases in metazoans. We hypothesize that efficient mRNP formation is realized by a molecular mRNP packaging station, which is built by several recruitment platforms and coordinates the individual steps of mRNP formation. (shrink)

Two aspects of the chromatin repeat length (r t) are discussed: (i) Why is r t, longer for slowly dividing cells than in rapidly dividing cells?, and (ii) Why is the temporal evolution of r ta decreasing function of time (t) in mammalian cortical neurons, whereas it is an increasing function of t for granule cells around the time of birth? These questions are discussed in terms of a hypothesis which assumes a correlation between deoxyribonucleic acid (DNA) packaging, transcription, (...) and replication. (shrink)

How eukaryotic genomes are packaged into compact cylindrical chromosomes in preparation for cell divisions has remained one of the major unsolved questions of cell biology. Novel approaches to study the topology of DNA helices inside the nuclei of intact cells, paired with computational modeling and precise biomechanical measurements of isolated chromosomes, have advanced our understanding of mitotic chromosome architecture. In this Review Essay, we discuss – in light of these recent insights – the role of chromatin architecture and the functions (...) and possible mechanisms of SMC protein complexes and other molecular machines in the formation of mitotic chromosomes. Based on the information available, we propose a stepwise model of mitotic chromosome condensation that envisions the sequential generation of intra‐chromosomal linkages by condensin complexes in the context of cohesin‐mediated inter‐chromosomal linkages, assisted by topoisomerase II. The described scenario results in rod‐shaped metaphase chromosomes ready for their segregation to the cell poles. (shrink)

The eukaryotic genome is packaged into a periodic nucleoprotein structure termed chromatin. The repeating unit of chromatin, the nucleosome, consists of DNA that is wound nearly two times around an octamer of histone proteins. To facilitate DNA‐directed processes in chromatin, it is often necessary to rearrange or to mobilize the nucleosomes. This remodeling of the nucleosomes is achieved by the action of chromatin‐remodeling complexes, which are a family of ATP‐dependent molecular machines. Chromatin‐remodeling factors share a related ATPase subunit and (...) participate in transcriptional regulation, DNA repair, homologous recombination and chromatin assembly. In this review, we provide an overview of chromatin‐remodeling enzymes and discuss two possible mechanisms by which these factors might act to reorganize nucleosome structure. BioEssays 25:1192–1200, 2003. © 2003 Wiley Periodicals, Inc. (shrink)

The rapidly changing field of genetics affects society through advances in health-care and through implications of genetic research. This study addresses the impacts of new genetic discoveries and technologies on different segments of today's society. The book begins with a chapter on genetic complexity, and subsequent chapters discuss moral and ethical questions arising from today's genetics from the perspectives of health care professionals, the media, the general public, special interest groups and commercial interests.

A possible atomic mechanism underlying the Re- and Ru-induced strengthening effects on the n - n ' interface in Ni-based single-crystal superalloys has been investigated using the DMol3 molecular orbital package based on density functional theory. The calculation of bonding properties has been performed on a cluster designed to model Re and Ru strengthening effects within the interface. The stronger Re--Ni bonds are formed mainly as a result of d- hybridization, while the Ni--Ni bonding become weaker accompanying the Re (...) substitution. The vertical and horizontal bond orders for a local environmental cluster are proposed and developed for the description of the strengthening effect on the n - n ' interface, with larger bond order values achieving better effect. Results show that both Re and Ru significantly strengthen the interface. It is also shown that the strengthening effect of Re is better than that of Ru, and this is explained in terms of the charge transfer of electrons between orbitals of Ru atom according to Mulliken population analysis. The calculation results provide a basis for understanding the atomic mechanism of Re- and Ru-induced n - n ' interfacial strengthening. (shrink)

Six years ago, the Singer lab published a landmark paper which described how individual mRNA particles cross the nuclear pore complex in mammalian tissue culture cells. This involved the simultaneous imaging of mRNAs, each labeled by a large number of tethered fluorescent proteins and fluorescently tagged nuclear pore components. Now two groups have applied this technique to the budding yeast Saccharomyces cerevisiae. Their results indicate that in the course of nuclear export, mRNAs likely engage complexes that are present on either (...) side of the pore and that these interactions are modulated by proteins present in the messenger ribonucleoprotein (mRNP) complex. These findings lend support to the notion that just before and/or after the completion of nuclear export, mRNPs undergo one or more maturation steps that prepare the packaged mRNAs for translation. These results represent new and exciting insights into the mechanism of mRNA nuclear export. (shrink)

Eukaryotic genomes are packaged into nucleosomal chromatin, and genomic activity requires the precise localization of transcription factors, histone modifications and nucleosomes. Classic work described the progressive reassembly and maturation of bulk chromatin behind replication forks. More recent proteomics has detailed the molecular machines that accompany the replicative polymerase to promote rapid histone deposition onto the newly replicated DNA. However, localized chromatin features are transiently obliterated by DNA replication every S phase of the cell cycle. Genomic strategies now observe the (...) rebuilding of locus‐specific chromatin features, and reveal surprising delays in transcription factor binding behind replication forks. This implies that transient chromatin disorganization during replication is a central juncture for targeted transcription factor binding within genomes. We propose that transient occlusion of regulatory elements by disorganized nucleosomes during chromatin maturation enforces specificity of factor binding. (shrink)

Recent findings indicate that substantial cross‐talk may exist between transcriptional and post‐transcriptional processes. Firstly, there are suggestions that specific promoters influence the post‐transcriptional fate of transcripts, pointing to communication between protein complexes assembled on DNA and nascent pre‐mRNA. Secondly, an increasing number of proteins appear to be multifunctional, participating in transcriptional and post‐transcriptional events. The classic example is TFIIIA, required for both the transcription of 5S rRNA genes and the packaging of 5S rRNA. TFIIIA is now joined by the (...) Y‐box proteins, which bind DNA (transcription activation and repression) and RNA (mRNA packaging). Furthermore, the tumour suppressor WT1, at first thought to be a typical transcription factor, may also be involved in splicing; conversely, hnRNP K, a bona fide pre‐mRNA‐binding protein, appears to be a transcription factor. Other examples of multifunctional proteins are mentioned: notably PTB, Sxl, La and PU.1. It is now reasonable to assert that some proteins, which were first identified as transcription factors, could just as easily have been identified as splicing factors, hnRNP, mRNP proteins and vice versa. It is no longer appropriate to view gene expression as a series of compartmentalised processes; instead, multifunctional proteins are likely to co‐ordinate different steps of gene expression. (shrink)

Computational reproducibility possesses its own dynamics and narratives of crisis. Alongside the difficulties of computing as an ubiquitous yet complex scientific activity, computational reproducibility suffers from a naive expectancy of total reproducibility and a moral imperative to embrace the principles of free software as a non-negotiable epistemic virtue. We argue that the epistemic issues at stake in actual practices of computational reproducibility are best unveiled by focusing on software as a pivotal concept, one that is surprisingly often overlooked in accounts (...) of reproducibility issues. Software is not only about designing and coding but also about maintaining, supporting, distributing, licensing, and governance; it is not only about developers but also about users. We focus on openness debates among computational chemists involved in molecular modeling software packages as empirical grounding for our argument. We then identify and analyse four epistemic characteristics as key to the role of software in computational reproducibility. (shrink)

Reproduced with the kind permission of the author. Currently available in the collection I Looked Alive . © 2010 The Brooklyn Rail/Black Square Editions | ISBN 978-1934029-07-7 Originally published 2003 Four Walls Eight Windows. continent. 1.1 (2011): 43-51. Introduction Ben Segal What interests me is instigated language, language dishabituated from its ordinary doings, language startled by itself. I don't know where that sort of interest locates me, or leaves me, but a lot of the books I see in the stores (...) seem to lack language entirely. Gary Lutz (2006). This issue of continent.'s fiction section features a reprint of “This Is Nice of You” from the first edition of Gary Lutz's collection I Looked Alive . That book was originally released by Four Walls Eight Windows in 2003 and has since been reissued in 2010 by The Brooklyn Rail/Black Square Editions. Calamari Press has also reissued Lutz's Stories in the Worst Way (originally published by Knopf, largely forgotten and dismissed, and then re-issued by the too-short-lived 3rd Bed). “This Is Nice of You” was edited for the re-issue of I Looked Alive and, as the original book is out of print, the earlier version of the story has been hard to come by for some time. This initial version is a bit longer than the new version—Lutz is a master of tightening down his texts to their most linguistically intensified cores—but it is in no way sloppy. It is a great privilege for continent. to be able to make available rare texts of (first) aesthetic and (second) scholarly value. For those readers unfamiliar with Gary Lutz, I believe this story will serve as a worthy introduction. Like Raymond Carver, Diane Williams, Christine Schutt, and so many other important twentieth century and contemporary short story writers, Lutz studied with and was edited by Gordon Lish. This connection is apparent in his attention to sound and the sentence as compositional unit, but Lutz's is a unique voice. “This Is Nice of You” bears Lutz's trademark torqued and turning syntax, his sexed-but-nameless characters, his rendering of the human body and its emissions as utterly discomfiting. Lutz's preoccupations with the mundane raise ordinariness, via startling language and observation, to grandiosity and grotesquery. In the fall of 2008, Lutz delivered a lecture entitled “The Sentence is a Lonely Place” to writing students at Columbia University. The lecture was later printed in The Believer (and is linked below). In it, he spoke about the importance of the sentence as a compositional unit, as even the distinguishing formal characteristic of prose. Specifically, Lutz explained that, from Lish, he had developed a "poetics of the sentence." Accordingly, Lutz constructs his stories at the level of the sentence, paying extreme attention to the material of words- their letters and their sounds- and the way they abut one another and interact on this material level even before they are employed in the service of traditional aims of fiction like meaning or story. Lutz often uses a(n almost constraint-related) technique called consecution. Letters or sounds from one word are carried forward into the following, producing drama and movement in the language itself at a level entirely apart from that of plot. For example, you can see how the 't's in the first sentence of “This Is Nice of You” repeat fast and hard through met and then soften into the 'th's of brothers and they. This close attention to the specific material and characteristic conditions of prose means that Gary Lutz's work always involves both a happening in language and of language. “This Is Nice of You” has a richness and depth that is hidden not in symbolism or obscure reference but on the surface of the page, in the language of every sentence. FURTHER READING Lutz, Gary. “ The Sentence Is a Lonely Place. ” The Believer January, 2009. Web. Short stories and excerpts at Web del Sol . Web. Taylor, Justin. “ An Interview with Gary Lutz .” Bookslut. July, 2006. Web. THIS IS NICE OF YOU [156] [1] I was a man dropping already well through my forties, filthy with myself, when, taking a turn at the toilets one afternoon, I met two brothers-they said they were brothers-who swore they had a sister, a schoolteacher, an officer of instruction at the county college, a whirlwind midlife turmoil of everything already put to ruin, who had gone off from a new marriage in an old car, an upkept and ennobling sedan, but had returned now to the apartment and [157] was living there alone with the little runoff there was from the marriage-some outcurved appliances, apparently, and low-posted furniture promoting its own mystery but becoming figurable in certain concentrations of TV light-and, above all, a telephone (on a pedestal, they insisted), the handpiece of which she gripped in lieu of exercise, or in fury, and I thus let out my little, reliable cry that I was in fact a student of the telephone, that it was a debasing apparatus in the main, with its meager economy of bells and tones, and the intimacy of the mouthpiece that sent your breath, tiny aftervapors of it, back toward your lips, so that regardless of the party accepting the outgoing products of your voice, you were, at most, in a further, rivaling exchange with yourself alone, and this is what must have brought the two of them around, the men who proclaimed brotherhood with the woman, because they offered me her phone number, put it at my disposal on a piece of paper one of them had already committed it to, a tearing from a menu, and the looks the men were now giving me had deletions in them, already, of my exact, beanpole shape and size. So off I went to a pay phone, the nearest canopied one I could find. The woman answered after the second ring and said she needed a lift right that very moment into the little, unlevel city close by. She was idling in the doorway of the building when I pulled up in front, and I helped her into the car, then got back in myself. I had always had a way of not having to look at people that nonetheless brought them to me in full, and so I still am certain of the susceptive and impressible comp-[158]lexion, the shimmer on the mouth, a lipstick of low brilliance, a difficulty around the eyes, the hair short and rayed out exclamation ally, skin bagged up over the elbow bone, conflict even in how her arms stayed at her sides—in sum, a spinal loveliness for me, an off-blonde quantity with shadowed, thumbworn hollows that put me out of as much as I might have ever known of women before. I set the two of us into the narrow traffic, and I remember telling her, by way of explaining the little burden which I had shifted, by now, from the shelf of the dashboard and onto my lap, that when you lived in filth, as I then did, a daily newspaper came to count for a lot, although instead of the thick-supplemented local paper I bought a trimmer one from a backlying town—not, of course, for any affluences of native data it carried, but as an article of house ware: a rough immaculacy in four lank sections, a set of fresh, hygienic surfaces to come between the table, say, and whatever I had going for me at the table, if the table was where I was going forward—because what else so cheap comes so clean and far-spreading? The woman told me that her own trouble with paper was that through a modest hole, no larger than a quarter, that had been drilled a foot or so above the floor (the standard height, she had reasoned, of legitimate electrical outlets), and by means of which her faculty office had at last gained communication with the roomier but unoccupied office next door, more and more often shot a single sheet of paper, plain copier paper she had rolled just barely into a tube, [159] so that after landing on the floor of the neighboring office the paper would preserve little if any of the curl, and there would be nothing written or typed on it, of course, and it was always a blank sheet that had been ageing on her desk for some time and had already been moved around, or advanced, from station to station on the desktop, coming into further creaselets and crimps and other infirmities—paper, in short, still too bare and unfraught to be thrown responsibly and forgettably away, and yet too seasoned and beset with irritations of the surface (a molelike blemish, say, or what looked like a tiny hair, an eyelash, sunk into it, or frecklings, or notational pressings of a fingernail), too wrought, in sum, for the paper to be appointed to any secure curricular purpose. Her office, she claimed, was in fact full of such paper, much-handled and singularized sheets of it by the loose, functionless hundred. I had to get it across to the woman that I myself no longer had an office, or any other place to divide me reliably from everybody else, and that for much of the daylight I thus appeared to be among people because I kept putting myself where people came together into even closer-fitting assortments, the viewing areas and showrooms and rotundas and such: I took in the lean-to look of the women, the tongues coming and going in what the men kept thinking of to say—whole families of low knees for me to bark my shins against during the crowded and involving way out. At home afterward, in the one room where my life was packed down, I would keep my nose stuck in the safehold of the phone [160] book, where the names of people suffered reduction to mere episodes of the alphabet and underwent humbling declensions down every column (Lail, Lain, Laine, Lainerd), and he names of streets, of the towns and townships, got docked in crude, heedless abbreviations (the vowels almost always the first to get poked out), and I would run my eyes over the telephone numbers themselves, each sequence of digits another fallible run of the infinite. I thus corrected my feelings for people and assembled myself emotionally into whatever else I had at hand—the obligating arms of the clothes hangers, usually, or the keen-angled understructure, the guardian legginess, of the ironing board. The woman said that in her case, though, it was more a matter of making slow circuits of the classroom where she had to put across the Emporial Sciences, retail theory and methods, to heat-giving and suggestive young women, some of them world cruelties already. There was the cooing of empty stomachs in the hour just before lunch, and the braying and fizzle of loaded stomachs in the low hours of the afternoon. She would recite her notes in a voice barely loyal to anyone octave, a tiny alluvium of slaver hardening at the corners of her mouth on the days she gave the glassy lozenges a slow, warming suck, and she would take lowering notice of how whatever she said succumbed at once to freak spellings and razzing paraphrase in the big, dividered notebooks; and because in midafternoon light the world looked as thorough, as filled in, as it was ever going to get, a better way to set about ruining her eyes was to review how hair had [161] established itself on the arms of the young women, because almost every arm had brought across itself a welcome and diversifying shadow. On one girl it would be a fine, driftless haze afloat above the white of the arm, never seeming to touch down on the skin itself. (An atmosphere, at most, of chestnut brown.) On another, it was as if copper wire, the narrowmost lengthlets of it, had been stuck into the fleshy batter of the thick, freckled forearms. On a third: a field of it–wheat-colored, thin-spun. On a fourth; a differencing, darkish updrift that shaded off as it approached the inner bend of the elbow, then re-emerged at the base of the upper arm as whiskery fringe. On others it was a brassy or rust-colored frizz, or it was as coarse as cornsilk, or it looked fussed on, as if the arm had been slowly stroked with charcoal. But here the woman broke off, or I may well have made an interruption of my own—I think I must have asked whether she was hungry, and she said if I was, and so on one of the lesser streets I parked the car and led her down into a belowstairs eating house I still remembered. Sandwiches were presently lowered in front of us. I watched her remove the festooned toothpick from hers and then play her fingers over the toasted planes before she took a fond first bite. "This is nice of you," she said. I must have looked at her in the way I then had of getting people to speak so they would not seem to be dwelling any longer on my features, because if on the well-set face the mouth and eyes are said to seem frozen in elegant orbit about the til) of the nose, then mine was a face that behold-[162]ers, regarders, could not help trying to round off with greater success, to goad the particulars of it back into the arcs they had wandered away from—the mouth, for instance, having been pursed and pinched suchwise that it seemed resident more on one side of the face than the other—and there were other signs of original strife to be busied with (slapdash eyebrows unbunched, it appeared, from reserves of hair elsewhere on my person; a showing of adult acne, a shrivelly little relevance of it, confined to the declivity of my nose); and so to be polite, the woman thus sank her gaze into her sandwich, and told me, in a voice lowered accordingly, that, one late-childhood summer, she had devoted herself to collecting postage stamps: it was a tongue-involving sideline to early-arriving puberty, and she liked having to lick the pale, gummed hinges instead of the sticky backs of the stamps themselves before entering everything into the hosting album; and once, during some foul weather between her and a brother (the older, thrown-over one, who had already made a habit of fooling the underside of his arm across the top of hers and calling her "pussified"), she reached for the shoe box in which she had let duplicate stamps accumulate—Spanish ones, mostly, of a fading orange—and sent the box slooshing through the lower air so that the stamps showered onto the brother's bare legs with a full, delicate harm. The woman was now touching up the surface of her iced tea with tiny activities, initiatives, of the longspun spoon. I myself was good at getting my touch onto things, although in a way that seemed to mix up the motive atoms inside [163] them, but I was satisfied that for the moment my sandwich, the unbitten-at half of it, was displayable and fit and local to my plate. The woman went on to say that, as a child, she had been bundled off, many an afternoon, to the slope-ceilinged quarters of a bachelor uncle who, when speaking of anybody not immediately present, could not bring himself to use the person's name but instead would say "an acquaintance of mine in ..." and then mention the name of some lapsed homeland, or little-loved rural orchestra, or backset building about to come down; and it was never a riddle, this device of his (not once could the girl have been expected to identify any of the subjects), and no matter how often and aloud he insisted that particularizing persons any further—bringing even a first name down upon anyone of them—would have been indecent, he claimed, much like doing things to people while they slept, the girl accepted all of the uncle's prim and extravagant evasion for what he surely must have intended it to be: a neat, protective trick to space the world out a little further in her favor, to scatter the population so that wherever her hand might at last come down, it would have to be on herself alone. And here I could sense that the woman wanted from my mouth an account of as much as I myself might have ever managed of attachment, so I told her I had once owned a house (a rising, really, of much-fingered, handwrought architecture that amounted to a little family of rooms above garages: a boxlike building with a rattly thorax of downspouts [164] and drainpipes and an unfolded but full-toned fire escape), and I had had for a time a boarder, a student, a high-colored, loose-packed representative of declining girlhood, hung with necklaces and barrettes, a girl of precise but shifting leanings and inclinations; and the afternoon she had come round to ask after the room, I stood in the entranceway, handshaken and asweat, and from what would later be my memory of the girl, I made off with, first, how every pore of her nose seemed to be sheltering within itself a tiny dark seedlet, a grain of something immediately, enormously valuable. And an almost lipless mouth (just a slit, practically), the teeth inside looking wet, watered-it was my life's chore, at that instant, to keep from sending the back of my thumb blotterlike across the line of them (I was later to learn she drank everything cold and through the narrowest of straws). And her hair: it was tea-colored hair she had, long and reachful, an unstopped downcome of it. Tall for a girl, but she managed to stay out of much of her height and put herself across as somebody backward, or behind. I must have told the girl, as best I could, that I of course had a wife, a full-faced, imperishable partner, though for the moment she was gone otherwhere in the marriage, and here the woman, my present companion, my tablemate, whose feet were now parked, in parallel, on the grade of my upper leg, interrupted to say that her husband, too, had been such a liar, and what could I bring up by way of reply other than that a lie is a truth struck through with other, further truth, or that a lie is the present multiplied by the past or that a lie [165] is an outcry of borrowed hope? The woman gave me an allowed look of disgust, her eyes lowered but still popular with me, and on I went with what had now become the girl of my story. For there had been a great, gainful carpet in the room I put the girl into, a matty expanse of coarse, grabby piles, an engrossing affair that took things into itself and held them tight, misered them, and I of course insisted that the girl not bother herself with its upkeep, that I enjoyed weekly access to a prestigious, upstanding vacuum cleaner; but no sooner was the girl out of the house each morning than I would withdraw from my room, where time was unportionable, and loose myself into the ticktock impertinence of the girl's room and get down on my knees, and, going after the carpet first with my fingers, then with a forceps, and finally by unspooling lengths of clear package-sealing tape and pressing them against the tufts in neat rectangles to catch what I might have missed, I brought vast tracts of the carpet to depletion, recovering not simply the girlinesses, the girleries, one would expect (buttons, straight pins, downed jewelry), but flirtier personalia in the form, say, of a stray confetto brought into the world when a page had been wrung with out caution from a spiral-bound notebook, or some pleated paper shells of the chocolates she required, or one of the bargain antihistamines she took to get her naps going, or a trash-bag tie ragged enough to show the kinked line of the wire within (this I would get wound around my finger), or a cough drop enwrapped like a bonbon (I would undo the [166] wings of the wrapper and have to decide whether to suck the drop all down or begin chewing it midway)—I became the following, the public, that these things, these off-faIlings, had come to have; but mostly there was hair, afloat above the uppermost pushings of the fabric of the carpet an almost continuous haziness of loose hairs of all lengths and sources, and I would have to set them out on a fresh sheet of paper and assort them according to the regions of the body they had taken their departure from, and in no time I had nest-like filiations of broken filaments and smaller involvements of the hairs that made me think of hooks, of barbs, of treble clefs, and each pile required a separate envelope, to be filed in a separate shoe box for every sector of the body until, I hoped, the boxes themselves would no longer be enough and I would have raised something semblable, brought up something equal in volume to the comprehensive girl herself. And her wastebasket! For every bit of rubbish, every dreariment she tossed into the thing, I would, in secret, deposit a reciprocal discard of my own, matching a spotted, confessory tissue of hers with a lurid throwaway after my own heart–the cardboard substructions of a fresh parcel of underwear, maybe, or tearings from pantyhose I now and again pressed against a span of my forearm to work onto it the complications of female shading I otherwise made do, choosily, without. I thus built the two of us up together in her trash! One afternoon-it was another of those lifeful, unsam-[167]pled days on which the world humors us each a little differently to keep us nicely on our last legs—I discovered in the wastebasket an inch-deep textbook of hers, a paperback with a celery-colored cover that had come partly unglued, and this dilapidation I paired off, naturally, with a name-your baby guide to whose pages, during my recurrent turnings of them, in bed or at table, I had contributed dried produces of my person, a chemical splendor entirely mine. This coupling sent a sudden spigoty thrill from me that forced an unbuckling and an unzipping and a cleanup with a handkerchief I then ventured responsively into the wastebasket as well. It was in the bathroom afterward that I found a suds-clouded puddle on the unlevel floor of the tub, a little undrained remainder, rimmed with offscum, of the girl's prolonged early-morning soak, and this was as much as I needed to get on my hands; I pressed them flat against the wet porcelain, then flapped them around in the air, and that was when I noticed it—in the amphitheater of the toilet bowl, an orange-yellow tint, or value, to the waters. When the girl arrived home that evening, I told her, of course, that I had discovered fresh, unforeseen trouble within the tank of thelet (a misalignment of the trip lever, a waywardness of the float ball, a ulation of the lift wires, kinks and defects, really, throughout the entire system) and that in fine it was an apparatus now operable only by means of advanced and strenuous equilibrial manipulations that it would be unseemly, inhospitable, of me to pre-[168]sume to burd to burden her with–so that from here on out, following any leak or evacuation she need merely lower the lid and then, before quitting the room, ring the handbell that had been placed on the would seeeverythinghing else. But the bell never rang, not even once, and from my window the next morning I watched the girl carry from the house a little plastic bag distended balloonishly, much like those bags you will remember having seen in the hands of children bearing homeward their solitary carnival-prize goldfish. In fact, I never ran across the likes of the girl again. The man who came to collect her things-not the father, apparently, but an advocate, an upholder-l found to be dull-eared and lax in his speech, and the better part of his face seemed to have already begun making tiny, rotational departures from whatever it was that the eyes, themselves impressively mobile, were just that moment having to take in. (Was there a lamp in the house that was not that night slopping its wattage over everything?) I guess I was waiting for the man to take a laggard, last-minute interest in me, and by now I was pushing everything out into the paired first person–it was, I said, “Our night shot,” and I began including the two of us in whatever it might be doing out, the expected sprinkles and such—but he was no friendship buff, and he paid no heed to my telling him that the only dress of hers I'd ever twidged myself into even part of the way had been the simplest of them all, a large-buttoned wonder of depthless blue, and then only on the principle that one naturally fits whatever one has into whatever somebody else [169] had first, or how else would the world keep getting any taller with people? The man just went about the removal of the girl's things without having to be reminded too noticeably, I guess, of how every dick hangs by a thread. My listener, though, had by this time brought about some becoming slowings of her arm—it was an arm inclinable to langorous diagonals and magicianly swoops through the air above the tabletop—but it no longer was involving itself with her plate, so I suggested we shove off, I made payment for the food, and on our way to the car, and then in the car as I took to following her pointings, the directional tilts of her head, she said that you naturally kept putting more and more of yourself into another person, at first wondering how much she can take, how much of you is accumulable and how much she can hold, and you're letting things out, disbursing yourself, and you've soon got things set up in her, and room is being made for even more of you, and if you bring this off with enough people, even two or three, what you've got is at first a comfort, because you can pass yourself along and move a little more widely through the world and leave it to these others to man your grievances, your disappointments; and what brought this to mind, the woman said, was a term of financial hardship she had contrived for herself a few years back, an unpaid leave of absence from scrupling letter grades onto quiz papers (propped-up As, and upended Bs made to look, rather, like fannies; all As and Bs, no Cs or anything lower, the difference between an A and a B having less to do with the accuracy of whatever facts might [170] have been impounded in provided for an answer than with anything recallable about the way the enrollee ad conformed her body to the confining perpendiculars of her chair and the navel-level writing surface that projected from it, or the way there might one day have been an unignorable blush on the instep of a once-moseying foot, disburdened of its shoe, that had got itself trapped in the grillwork of that cagelike involvement, intended for books, that was welded to, or otherwise schemed into, the underworks of the chair)—this had been a duration, in short, of controlled difficulty when the misexpenditure of even a twenty-dollar bill had set her thrilling, gloating, over everything she would miss out on, and one afternoon she had made an engagement for a haircut, just a trim, and very early in the session the haircutter, a woman ill-defined in the face but otherwise full of conspicuities of emotion, set down the prevailing scissors and pressed the flat of a lukewarm hand against the woman's cheek, held it there for a good minute or longer, while the other hand eventually found its way into a drawer, a shallow treasury of slender specialty scissors, one pair of which the cutter withdrew and began routing deductively through the woman's hair, the other hand staying put on the cheek, longer and longer, and the woman went home and for afterward the bathtub was now a more likely destination than any of the upright furniture, and it got easier to fill the tub with further clarifying volumes than to clear space on the difficult heights of the sofa, and she was hardly claiming to have become a cleaner [171] person in result—she in fact would often discover, voyaging about her body, a browned, fractionary detail of a larger crepe of toilet tissue that must have got itself stuck in some assy crevice and was impossible to get plucked out of the revolving suds—she was saying only that she spent more and more of her time thus immersed, ill off in water, and the haircutter had surely had a hand in it, the woman was doing some of the cutter's life now, coming into some of its wrong, because you sometimes have to look to somebody else's life to get dimensions set back even part of the way around your own, and it should not have to be any less your own life when it comes from somebody else, and you could surely fudge a society out of anyone available person and get this person doubling for the many, so that in the little run of things perpetuable from one person to the next, every loose moment stood to become a complete, active finality. But by now this was a new day, with only an hour or so off it already, and the place the woman had made me bring us to, the man's place, with a promise that the man was elsewhere—this was on a little offshoot of a street, a stewy efficiency apartment the color had long ago gone out of; and when, once in bed, still clothed, I found among the sheets and blankets a spoiling pair of the man's underpants, one of the leg openings of which was puckered into an avid, sloppy mouth, I held myself accountable for redisposing the fabric until I got a befitting featurelessness back onto it; but all the while, I am sure I had to make myself go over again in my mind that if the body is the porter of as many organs of affec-[172]tion as there might one day turn out to be, then the idea was to let the thing carry you to where you would otherwise never have any reason to arrive, because I listened for the unmelodiof the the thede ofthe woman's zipper, and then the woman made me put myself out of my own clothes, the attritional corduroys and overshirt, and got herself up at last onto the topic not of the man whose apartment it was (because his story was scarcely the story of how the boy who decides he is half a girl no sooner starts to worry about where the other half might than he gets careless with where he rests his eyes, or what he gives even the feeblest of fingerholds to, and anything, even a crumbly triangle of pie offered on a saucer instead of on a pie plate proper, comes in easy, ready, wronging answer), but of her husband, and how, no more than a couple of months into the marriage, he had begun snugging away in his undershorts a little source of chanc, reliable frictions to nudge him onward through the workday—anything company-keeping that could be counted on not to slide out of the elasticky leg holes: a half-dollar packet of chocolate tittles, maybe, that was barely noticeable in the baggy surround of the widecut trousers so popular at the time. For by now the woman had at last brought what is usually called the other mouth to within only inches of my lips, but it is not a mouth, obviously, although I let myself go along with the goodwill behind the comparison, the way I will remain loyal to anything deliberately and faithfully misunderstood, and I fussed my tongue against the vital trifles hung inside of her, as much of the curtailed finery as I could find, [173] and gave the whole insimplicity of it a slow-circling, examinational lick, until I was taking a sudden tepid downwash on the tongue. It was a familiar, latrine in dribble that must have tasted, no doubt, like trouble just starting out.p [1] Editor's Note: Original pagination from first edition print denoted with bracketed page numbers. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Adjusting Laboratory Practices to the Challenges of WartimeOksana Sulaieva, Anna Shcherbakova, and Oleksandr DudinFunding. Oksana Sulaieva, MD, PhD is supported by the Loyola University Chicago–Ukrainian Catholic University Bioethics Fellowship Program, funded by the National Institutes of Health Fogarty International Center (D43TW011506).After 500 days of the unjust war initiated by the Russians, we look back to reflect on the challenges our medical laboratory faced during these early days. On the (...) morning of February 24th, we were awakened by the dreadful roar of sirens, the sound of which filled us with adrenaline and anxiety. Although our team had considered the risks of Russian military aggression and thus updated our emergency plan at the beginning of 2022, the first day of the war revealed that nobody was truly ready for the bombing, air alarms, tanks on the streets of towns and cities, violence and murders of civilians. That morning the city’s transportation system collapsed, and the flow of cars cluttered all the roads as people were trying to leave the city and escape the upcoming atrocities and death. Serious and disquieted people hurried along the streets—some people rushed to shelters, and others went to the military registration and enlistment offices to fight against Russian aggressors for the life, independence, and sovereignty of Ukraine.We hurried to work, committed to performing our duties. Our medical laboratory serves more than 750 hospitals in Ukraine. Despite fear and uncertainty, we walked to the lab, taking our children and alarm case1 with documents and essential things. Months later, people asked us why we went to the laboratory instead of leaving the city or even the country. At that moment, our [End Page 155] professional duties were an anchor linking us to each other against fear and panic. Our responsibility to provide patients and physicians with the results of blood testing, pathology, and molecular reports outweighed our fears of the war. We had to complete the testing of all the samples delivered to the laboratory to provide our customers—who include children, pregnant women, diabetic and cancer patients—with data essential for identifying accurate diagnoses and effective treatments. So we spent the first days of the war in the laboratory. At the same time, we had obligations and responsibilities to our staff as well. We had to consider how to manage our employees’ protection along with continuous laboratory services provided under endless air alarms and bombings. Many healthcare facilities in eastern regions and around Kyiv were affected by missiles or completely destroyed. Of our sixty laboratory offices around Ukraine, ten were damaged or abandoned due to occupation. Several of our fleet cars were also damaged and riddled with bullets. Many employees in the regional offices in Melitopol, Kherson, Mariupol, Chernihiv, and in suburbs of Kyiv such as Bucha and Irpin lost their homes as a result of massive military operations or occupation. Dozens of our employees joined the Ukrainian armed forces to defend civilians and fight against aggressors. Many others became volunteers, involved in blood donation, medical care for the wounded, cooking, and serving the troops. And still, we had to continue our work and protect our staff at the same time. We also helped each other by sharing our goods, medication, homes, cars, warmth, and support. Some pathologists stayed at the workplace for several days moving between pathology stations, microscopes and shelters, and sleeping on the floor but continuing to work.Our main challenge was the regular terroristic attacks on healthcare facilities situated far away from the front line, which in fact, violated international humanitarian law regarding respect for human rights during armed conflicts. During the first weeks of the war, the magnitude of military aggression, massive bombing, and air attacks undermined the healthcare system and endangered laboratory staff and patients. We prioritized protective measures. Some of our laboratory staff and facilities were evacuated from Kyiv to Lviv in western Ukraine. The partial relocation of our laboratory to Lviv was also driven by the displacement of several million Ukrainians to the western part of the country.We were able to arrange relatively safe accommodations for our laboratory employees and their families in Lviv. Under strikes and alarms, our... (shrink)

Genomic function is dictated by a combination of DNA sequence and the molecular mechanisms controlling access to genetic information. Access to DNA can be determined by the interpretation of covalent modifications that influence the packaging of DNA into chromatin, including DNA methylation and histone modifications. These modifications are believed to be forms of “epigenetic codes” that exist in discernable combinations that reflect cellular phenotype. Although DNA methylation is known to play important roles in gene regulation and genomic function, (...) its contribution to the encoding of epigenetic information is just beginning to emerge. Here we discuss paradigms associated with the various components of DNA methylation/demethylation and recent advances in the understanding of its dynamic regulation in the genome, integrating these mechanisms into a framework to explain how DNA methylation could contribute to epigenetic codes. (shrink)

The secretory pathway delivers proteins synthesized at the rough endoplasmic reticulum (RER) to various subcellular locations via the Golgi apparatus. Currently, efforts are focused on understanding the molecular machineries driving individual processes at the RER and Golgi that package, modify and transport proteins. However, studies are routinely performed using non‐dividing cells. This obscures the critical issue of how the secretory pathway is affected by cell division. Indeed, several studies have indicated that protein trafficking is down‐regulated during mitosis. Moreover, the (...) RER and Golgi apparatus exhibit gross reorganization in mitosis. Here I provide a relatively neglected perspective of how the mitotic cyclin‐dependent kinase (CDK1) could regulate various stages of the secretory pathway. I highlight several aspects of the mitotic control of protein trafficking that remain unresolved and suggest that further studies on how the mitotic CDK1 influences the secretory pathway are necessary to obtain a deeper understanding of protein transport. (shrink)

Local differences in chromatin organisation may profoundly affect the activity of eukaryotic genomes. Regulation at the level of DNA packaging requires the targeting of structural proteins and histone‐modifying enzymes to specific sites and their stable or dynamic interaction with the nucleosomal fiber. The “chromodomain”, a domain shared by many regulators of chromatin structure, has long been suspected to serve as a module mediating chromatin interactions in a variety of different protein contexts. However, recent functional analyses of a number of (...) different chromodomains revealed an unexpected diversity of interaction targets, including histones, DNA and even RNA. The chromodomains of today seem to have evolved from a common ancestral fold to fulfill various functions in different molecular contexts. Combining information gained from recent functional and structural studies of chromodomains with a bioinformatic classification of their structure could lead to the definition of sequence motifs with predictive quality for chromodomain function. BioEssays 26:133–140, 2004. © 2004 Wiley Periodicals, Inc. (shrink)

Although bone development during embryogenesis and bone repair after injury have a number of features which appear similar, they are distinctly different processes which involve separate controlling elements and cuing parameters. Repair of bone is influenced by bioactive factors which reside in bone itself; some of these factors are not present when embryonic mesenchymal cells first differentiate. For example, a bone protein which induces the conversion of mesenchymal cells into cartilage cells is not present in the embryo at the site (...) where cartilage first differentiates into the anlagen for future bone. Ultimately, the sequence of cellular and molecular events which controls the success of bone repair is dependent on the prior embryologic and developmental packaging of bioactive factors into bone and the release of these factors at a bone break site. The success of the reparative events depends not only upon the release of these bone‐derived factors but also on systemic factors and the identity and numbers of responding cells at the repair site. (shrink)

Summary Sexual communication in most species of fireflies is a male±female dialogue of precisely timed flashes of bioluminescent light. The biochemical reactions underlying firefly bioluminescence have been known for 30 years and are now exploited in biomedical assays and other commercial applications. Several aspects of flash regulation are also understood: flash rhythm is controlled by a central pattern generator, and individual flashes are neurally triggered, with octopamine serving as the transmitter. The molecular oxygen needed by the biochemical reactants is (...) delivered by a network of tracheal arborizations extending throughout the light organ (lantern).However, the actual means by which oxygen quickly reaches the reactants packaged within specialized photocytes and the specific event(s) triggered by neural action have not been identified; termination of axons away from the photocytes has exacerbated the latter problem. A recent paper(1) by a consortium of cell and evolutionary biologists, however, reports that nitric oxide (NO), manufactured and released in response to neuronal discharge, is the missing link by which neural action in the firefly lantern yields a sudden flash of light. BioEssays 23:992±995, 2001. ß 2001 John Wiley & Sons, Inc. (shrink)

Two groups of plant viruses have DNA in their genomes. One group, the caulimoviruses, are non‐integrating retroviruses that package dsDNA in virions. The other group, the geminiviruses, package small circular ssDNA and include the only DNA viruses known with bipartite genomes. The regulation of transcription of these viruses is not well characterized, but recent work is beginning to yield interesting results. Regulatory sequences from these viruses function in cells of species that are not hosts of the virus and are finding (...) use in constitutive expression of chimeric genes in transformed plants. Development of vectors based on plant viruses requires further characterization at the molecular level of viral life cycles. (shrink)

Implicit God-like and ghost-in-the-machine metaphors underlie much current thinking about genomes. Although many criticisms of such views exist, none have succeeded in substituting a different, widely accepted view. Viewing the genome with its protein packaging as a brain gets rid of Gods and ghosts while plausibly integrating machine and information-based views. While the ‘wetware’ of brains and genomes are very different, many fundamental principles of how they function are similar. Eukaryotic cells are compound entities in which case the nuclear (...) genome might best be thought of more as a government than simply as a brain. (shrink)

Cytoplasmic messenger ribonucleoprotein particles (mRNPs) represent the cellular transcriptome, and recent data have challenged our current understanding of their architecture, transport, and complexity before translation. Pre‐translational mRNPs are composed of a single transcript, whereas P‐bodies and stress granules are condensates. Both pre‐translational mRNPs and actively translating mRNPs seem to adopt a linear rather than a closed‐loop configuration. Moreover, assembly of pre‐translational mRNPs in physical RNA regulons is an unlikely event, and co‐regulated translation may occur locally following extracellular cues. We envisage (...) a stochastic mRNP transport mechanism where translational repression of single mRNPs—in combination with microtubule‐mediated cytoplasmic streaming and docking events—are prerequisites for local translation, rather than direct transport. (shrink)

Some properties – like charge – are natural, some – like grue are unnatural. The distinction between natural and unnatural properties is normally taken as primitive. However, Barry Loewer’s Package Deal Account (PDA) aims to provide an reductive account of natural properties, integrated with a reductive account of laws of nature. In addition, the account seems to be able to apply to natural properties at the level of fundamental physics, and higher-level, special science, properties. -/- If the account is successful, (...) then, it looks to be incredibly powerful and attractive. The PDA, however, is somewhat underexplored in the literature. So the first aim of the paper is to understand the PDA better -- to map the connections between naturalness and laws on the traditional BSA and to consider how those connections have to adapted in order to develop different versions of the PDA. -/- The second aim is to start to evaluate different versions of the PDA. In particular, perhaps the most promising version of the PDA construes it as an instance of a larger approach to Humeanism — one that has been very visible in the recent literature — that focuses on the role of 'ideal observers' or 'ideal scientists'. While such an approach might be feasible, I claim, it gets its proponents much less than they were originally hoping for. (shrink)

Whether or not quantum physics can account for molecular structure is a matter of considerable controversy. Three of the problems raised in this regard are the problems of molecular structure. We argue that these problems are just special cases of the measurement problem of quantum mechanics: insofar as the measurement problem is solved, the problems of molecular structure are resolved as well. In addition, we explore one consequence of our argument: that claims about the reduction or emergence (...) of molecular structure cannot be settled independently of the choice of a particular resolution to the measurement problem. Specifically, we consider how three standard putative solutions to the measurement problem inform our under- standing of a molecule in isolation, as well as of chemistry’s relation to quantum physics. (shrink)

This paper develops an account of the metaphysics of fundamental laws I call “the Package Deal Account ” that is a descendent of Lewis’ BSA but differs from it in a number of significant ways. It also rejects some elements of the metaphysics in which Lewis develops his BSA. First, Lewis proposed a metaphysical thesis about fundamental properties he calls “Humean Supervenience” according to which all fundamental properties are instantiated by points or point sized individuals and the only fundamental relations (...) are geometrical spatial and temporal relations between these. While the BSA does not require HS Lewis seems to hope that it is true. In contrast, the PDA is not committed to HS or even to the fundamental arena in which fundamental properties are instantiated possessing geometrical structure and thus is able to accommodate relations and structures found in contemporary physics that apparently conflict with HS. Second, although Lewis’ BSA doesn’t require HS his Humeanism does require that fundamental properties are categorical. In contrast, the PDA allows for the possibility that fundamental properties are individuated in terms of laws and so are not categorical. Third, the PDA expands and develops the criteria for what counts in favor of a candidate system with more attention to the criteria employed by physicists in evaluating proposed theories. Fourth and most importantly, unlike Lewis’ BSA, the PDA does not presuppose metaphysically primitive elite properties/quantities that Lewis calls “perfectly natural” properties/quantities or presuppose a metaphysically preferred language whose terms denote such properties/quantities. It replaces Lewis’ account with an account on which natural properties are not metaphysically prior to the laws but are elements of a package that includes a fundamental arena that plays the role of space-time as well as fundamental laws and properties. By doing so it responds to some epistemological and metaphysical issues that have been raised regarding natural properties and their role in the BSA. In sum, the PDA goes further in explicating the notion of laws in terms of the aims and practices of science especially fundamental physics rather than in terms of prior metaphysics. I begin by reviewing Lewis’ account of perfectly natural properties and his Humean BSA of laws. (shrink)

There is consensus within the chemosciences that olfactory perception is of the molecular structure of chemical compounds, yet within philosophical theories of smell there is little agreement about the nature of smell. The paper critically assesses the current state of debate regarding smells within philosophy in the hopes of setting it upon firm scientific footing. The theories to be covered are: Naïve Realism, Hedonic Theories, Process Theory, Odor Theories, and non-Objectivist Theories. The aforementioned theories will be evaluated based on (...) their explanations of the (a) the olfactory quality of a smell, (b) smells as distal entities, and (c) our experience of smells as intentional objects. The paper concludes with a defense of Molecular Structure Theory that demonstrating its superiority in accounting for each of these three aspects of smell. (shrink)

Despite the transformation in biological practice and theory brought about by discoveries in molecular biology, until recently philosophy of biology continued to focus on evolutionary biology. When the Human Genome Project got underway in the late 1980s and early 1990s, philosophers of biology -- unlike historians and social scientists -- had little to add to the debate. In this landmark collection of essays, Sahotra Sarkar broadens the scope of current discussions of the philosophy of biology, viewing molecular biology (...) as a unifying perspective on life that complements that of evolutionary biology. His focus is on molecular biology, but the overriding question behind these papers is what molecular biology contributes to all traditional areas of biological research.Molecular biology -- described with some foresight in a 1938 Rockefeller Foundation report as a branch of science in which "delicate modern techniques are being used to investigate ever more minute details" -- and its modeling strategies apparently argue in favor of physical reductionism. Sarkar's first three chapters explore reductionism -- defending it, but cautioning that reduction to molecular interactions is not necessarily a reduction to genetics. The next sections of the book discuss function, exploring how functional explanations pose a problem for reductionism; the informational interpretation of biology and how it interacts with reductionism; and the tension between the unifying framework of molecular biology and the received framework of evolutionary theory. The concluding chapter is an essay in the emerging field of developmental evolution, exploring what molecular biology may contribute to the transformation of evolutionary theory as evolutionary theory takes into account morphogenetic development. (shrink)

Phage DNA packaging occurs by DNA translocation into a prohead. Terminases are enzymes which initiate DNA packaging by cutting the DNA concatemer, and they are closely fitted structurally to the portal vertex of the prohead to form a ‘packasome’. Analysis among a number of phages supports an active role of the terminases in coupling ATP hydrolysis to DNA translocation through the portal. In phage T4 the small terminase subunit promotes a sequence‐specific terminase gene amplification within the chromosome. This (...) link between recombination and packaging suggests a DNA synapsis mechanism by the terminase to control packaging initiation, formally homologous to eukaryotic chromosome segregation. (shrink)

In this collection, Stations on the Journey of Inquiry, David Burrell launches a revolutionary reinterpretation of how any inquiry proceeds, boldly critiquing presumptuous theories of knowledge, language, and ethics. While his later publications, Analogy and Philosophical Language (1973) and Aquinas: God and Action (1979), elucidate Aquinas's linguistic theology, these early writings show what often escapes articulation: how one comes to understanding and "takes" a judgment. Although Aquinas serves as an axial figure for Burrell's expansive corpus of scholarship spanning more than (...) fifty years, this selection of essays presents other positions and counterpositions to whom his own philosophical theology is beholden: Plato, Aristotle, Cajetan, Kant, Peirce, Moore, Wittgenstein, Sellars, Weiss, Ross, McInerny, and Lonergan. With renewed interest in philosophy of language by postmodern thinkers as well as in the wake of Mulhall's Stanton Lectures on Wittgenstein and "Grammatical Thomism," the publication of these formative writings proves timely for the academy at large. Burrell invites us to reconsider not only the way in which we conduct an inquiry, but what it is we take language to be and how we take responsibility for what we say. (shrink)

Recent work on gene concepts has been influenced by recognition of the extent to which RNA transcripts from a given DNA sequence yield different products in different cellular environments. These transcripts are altered in many ways and yield many products based, somehow, on the sequence of nucleotides in the DNA. I focus on alternative splicing of RNA transcripts (which often yields distinct proteins from the same raw transcript) and on 'gene sharing', in which a single gene produces distinct proteins with (...) the exact same amino acid sequence. These are instances of molecular pleiotropy, in which distinct molecules are derived from a single putative gene. In such cases the cellular and external environments play major roles in determining which protein is produced. Where there is molecular pleiotropy, alternative gene concepts are naturally deployed; molecular epigenesis (revision of sequence-based information by altering molecular conformations or by action of non-informational molecules) plays a major role in orderly development. These results show that gene concepts in molecular biology do, and should, have both structural and functional components. They also show the need for a plurality of gene concepts and reveal fundamental difficulties in stabilizing gene concepts solely by reference to nucleotide sequence. (shrink)

Biologists and historians often present natural history and molecular biology as distinct, perhaps conflicting, fields in biological research. Such accounts, although supported by abundant evidence, overlook important areas of overlap between these areas. Focusing upon examples drawn particularly from systematics and molecular evolution, I argue that naturalists and molecular biologists often share questions, methods, and forms of explanation. Acknowledging these interdisciplinary efforts provides a more balanced account of the development of biology during the post-World War II era.

Much of the recent philosophical debate on causation and causal explanation in the biological and biomedical sciences has focused on the notion of mechanism. Mechanisms, their nature and epistemic roles have been tackled by a range of so-called neo-mechanistic theories, and widely discussed. Without denying the merits of this approach, our paper aims to show how lately it has failed to give proper credit to processes, which are central to the field, especially of contemporary molecular biology. Processes can be (...) summed up in the notion of ‘pathway’, which is far from being just equivalent to that of ‘mechanism’ and has a profound epistemological and explanatory relevance. It is argued that an adequate consideration of pathways impels some rethinking of scientific explanation in molecular biology, namely its functional and contextual features. A number of examples are given to suggest that the focus of philosophical attention in this disciplinary field should shift from the notion of mechanism to the notion of pathway. (shrink)

The intellectual origins of molecular biology are usually traced back to the 1930s. By contrast, molecular biology acquired a social reality only around 1960. To understand how it came to designate a community of researchers and a professional identity, I examine the creation of the first institutes of molecular biology, which took place around 1960, in four European countries: Germany, the United Kingdom, France, and Switzerland. This paper shows how the creation of these institutes was linked to (...) the results of post-war economic reconstruction. Then, it compares how the promoters of these different institutional projects delimited the goals of their discipline, reflected on its history, and suggested how research should be organised. I show how they carefully positioned their new discipline within the emerging national science policy discourse of the 1950s, and aligned it with the current vision of scientific modernity. In particular, I discuss how they articulated the meaning of molecular biology with respect to five common themes: the role of physics in the atomic age, the relations between fundamental research and medical applications, the ‘Americanisation’ of scientific research, the value of science in the reconstruction of national identities, and the drive towards interdisciplinary research. This paper thus demonstrates that beyond the local and national accounts there is a European history of molecular biology. (shrink)

Philosophical discussion of molecular and developmental biology began in the late 1960s with the use of genetics as a test case for models of theory reduction. With this exception, the theory of natural selection remained the main focus of philosophy of biology until the late 1970s. It was controversies in evolutionary theory over punctuated equilibrium and adaptationism that first led philosophers to examine the concept of developmental constraint. Developmental biology also gained in prominence in the 1980s as part of (...) a broader interest in the new sciences of self-organization and complexity. The current literature in the philosophy of molecular and developmental biology has grown out of these earlier discussions under the influence of twenty years of rapid and exciting growth of empirical knowledge. Philosophers have examined the concepts of genetic information and genetic program, competing definitions of the gene itself and competing accounts of the role of the gene as a developmental cause. The debate over the relationship between development and evolution has been enriched by theories and results from the new field of 'evolutionary developmental biology'. Future developments seem likely to include an exchange of ideas with the philosophy of psychology, where debates over the concept of innateness have created an interest in genetics and development. (shrink)

Senior molecular geneticists were interviewed about their perceptions of the ethical and social implications of genetic knowledge. Inductive analysis of these interviews identified a number of strategies through which the scientists negotiated their moral responsibilities as they participated in generating knowledge that presents difficult ethical questions. These strategies included: further analysis and application of scientific method; clarification of multiple roles; negotiation with the public through public debate, institutional processes of funding, ethics committees and legislation; and personal responsibility.

Background There are intense discussions about the ethical and societal implications of biomedical engineering, but little data to suggest how scientists think about the ethics of their work. The aim of this study is to describe how scientists frame the ethics of their research, with a focus on the field of molecular systems engineering.Methods Semi-structured qualitative interviews were conducted during 2021–2022, as part of a larger study. This analysis includes a broad question about how participants view ethics as related (...) to their work, with follow up probes about the topics they consider most important. Interviews were transcribed, inductively coded by two researchers to consensus, and analyzed thematically.Results Twenty-four scientists participated in the study. Interviewees hold positions as professors, principal investigators, and senior staff researchers in universities or research institutes in the United States and Europe. Among those scientists who reported reflecting on ethical considerations in their work, many equated ethics with research ethics topics (e.g., safety, replicability), or with regulation and guidelines. Participants expressed the view that ethical issues are primarily relevant for clinical trials of bioengineered products, or for those working with animal or human subjects. Scientists described their research as “too early” or “not examining anything living” with regard to ethical reflection. Finally, many felt that ethics is seen as territory for experts and therefore beyond scientists’ competencies.Conclusions Molecular systems engineering scientists currently focus on regulatory aspects as the framework for their ethical analyses. They describe using a framework to define when life arises, as a means to determine when further ethical engagement is warranted. Further research is needed to investigate how scientists relate to the ethics of their scientific work, and build consensus around concepts of life, autonomous behavior, and physiological relevance of bioengineered systems. (shrink)

Biologists employ a suggestive metaphor to describe the complexities of molecular interactions within cells and embryos: cytological components are said to be part of “ecosystems” that integrate them in a complex network of relations with many other entities. The aim of this essay is to scrutinize the molecular ecosystem, a metaphor that, despite its longstanding history, has seldom be articulated in detail. I begin by analyzing some relevant analogies between the cellular environment and the biosphere. Next, I discuss (...) the applicability of the molecular ecosystem concept in actual scientific practice. (shrink)

In this article, two issues regarding mechanisms are discussed. The first concerns the relationships between “mechanism description” and “mechanism explanation.” It is proposed that it is rather plausible to think of them as two distinct epistemic acts. The second deals with the different molecular biology explanatory contexts, and it is shown that some of them require physics and its laws.

The molecular genetic age can be said to have begun with the letter in Nature in 1953 by Watson and Crick, describing the helical structure of DNA. Some outstanding scientific work preceded that discovery, including especially the recognition by Chargaff of base-pair complementarity, but no discovery quite captured the imagination of the biomedical world as a few understated words by Watson and Crick in their famous one-page paper: "It has not escaped our notice that the specific pairing we have (...) postulated immediately suggests a possible copying mechanism for the genetic material". The manner in which genetic material was passed on from generation to generation had been decoded.That discovery was... (shrink)

Summary This article discusses the intersection of science and culture in the marketplace and explores the ways in which radium quack and medicinal products were packaged and labelled in the early twentieth century US. Although there is an interesting growing body of literature by art historians on package design, historians of science and medicine have paid little to no attention to the ways scientific and medical objects that were turned into commodities were packaged and commercialized. Thinking about packages not as (...) mere containers but as multifunctional tools adds to historical accounts of science as a sociocultural enterprise and reminds us that science has always been part of consumer culture. This paper suggests that far from being receptacles that preserve their content and facilitate their transportation, bottles and boxes that contained radium products functioned as commercial and epistemic devices. It was the 1906 Pure Food and Drug Act that enforced such functions. Packages worked as commercial devices in the sense that they were used to boost sales. In addition, ‘epistemic’ points to the fact that the package is an artefact that ascribes meaning to and shapes its content while at the same time working as a device for distinguishing between patent and orthodox medicines. (shrink)

Molecular imprints of organisms serving as both the agents and the products of the underlying sign activities are quantum mechanical in their origins. In particular, molecules in any reaction networks constituting a biological organism are semiotic or context-dependent in the sense that their activities reside within the proper coordination of the entire networks. The origin of life could have been related to a specific aspect of molecular semiotics, especially in the transition from molecules as the physical symbols of (...) material units to molecules as the semiotic signs having the capacity of pointing to something else other than the molecules themselves. Quantum mechanical underpinning of the molecular imprints leading to the emergence of life is in the appraisal of the material capacities of both coherent assimilation and decoherent dissociation already latent in the imprints. One empirical evidence suggesting the likelihood of both coherent assimilation and decoherent dissociation in prebiotic settings could have been found in synthetic chemical reactions running in hydrothermal circulation of seawater through hot vents in the Haedean ocean on the primitive Earth. (shrink)

In 1949, Linus Pauling and collaborators published in Science a paper provocatively titled: 'Sickle cell anemia, a molecular disease'. What was actually meant by 'molecular disease'? We interpret the concept of molecular disease in the frame of the traditional positions about the nature of diseases: the ontological and the physiological positions. We conclude that the physiological does not give an adequate account of what molecular diseases are. The ontological position, when correctly reinterpreted, leads to an understanding (...) of molecular diseases where the macromolecule is seen as a symptom or as a part of a mechanism leading to the symptoms of the disease. We then show that the concept of molecular disease leads to a particular view of therapy, emphasizing eugenics as a way of eliminating disease. On the individual level, this concept leads to an increased power of diagnosis, and especially predictive diagnosis, but has little therapeutic consequence. Lastly, we examine how this concept of disease unifies two contemporary classifications of diseases, one based on the location of the diseases, the other on the cause of the diseases. (shrink)

Analysis of the mechanisms underlying sex determination and sex differentiation in Drosophila has provided evidence for a complex but comprehensible regulatory hierarchy governing these developmental decisions. It is suggested here that the pattern of sexual differentiation and dosage compensation characteristic of the male is a default regulatory state. Recent results have provided, in addition, some surprising and intriguing conclusions: (1) that several of the critical controlling genes produce more transcripts than was predicted from the genetic analyses; (2) that setting of (...) the alternative sex‐specific states of the doublesex (dsx) locus involves differential transcript processing; and (3) that some aspects of sexual differentation require the prolonged action of certain elements of the regulatory hierarchy. These findings are discussed in connection with the current model of sex determination in Drosophila. (shrink)

This paper compares the central theses of Edmund M. Pincoffs’s Quandaries and Virtues with those of F. H. Bradley’s Ethical Studies. Both Pincoffs and Bradley understand virtues and duties as functional in respect of the common good of the social order. Both reject the individualism of Kantian and utilitarian theories. Both believe that ordinary moral agents do not appeal to and do not need to appeal to the kinds of justification for action defended by such theories. It is argued that (...) the importance of these resemblances is partly disguised by the differences between Pincoffs’s and Bradley’s view. Pincoffs and Bradley are among those who, in the debates of modern moral philosophy, have recurrently defended an antitheoretical account against a variety of theorists. It is claimed that this debate is and must be inconclusive. (shrink)

This paper compares the central theses of Edmund M. Pincoffs’s Quandaries and Virtues with those of F. H. Bradley’s Ethical Studies. Both Pincoffs and Bradley understand virtues and duties as functional in respect of the common good of the social order. Both reject the individualism of Kantian and utilitarian theories. Both believe that ordinary moral agents do not appeal to and do not need to appeal to the kinds of justification for action defended by such theories. It is argued that (...) the importance of these resemblances is partly disguised by the differences between Pincoffs’s and Bradley’s view. Pincoffs and Bradley are among those who, in the debates of modern moral philosophy, have recurrently defended an antitheoretical account against a variety of theorists. It is claimed that this debate is and must be inconclusive. (shrink)

In team-based tasks, successful communication and mutual understanding are essential to facilitate team coordination and performance. It is well-established that an important component of human conversation is the maintenance of common ground. Maintaining common ground has a number of associated processes in which conversational participants engage. Many of these processes are lacking in current synthetic teammates, and it is unknown to what extent this lack of capabilities affects their ability to contribute during team-based tasks. We focused our research on how (...) teams package information within a conversation, by which we mean specifically whether information is explicitly mentioned or implied, and how multiple pieces of information are ordered both within single communications and across multiple communications. We re-analyzed data collected from a simulated remotely-piloted aerial system task in which team members had to specify speed, altitude, and radius restrictions. The data came from three experiments: the “speech” experiment, the “text” experiment, and the “evaluation” experiment. We asked first whether teams settled on a specific routine for communicating the speed, altitude, and radius restrictions, and whether this process was different if the teams communicated in speech compared to text. We then asked how receiving special communication instructions in the evaluation experiment impacted the way the human teammates package information. We found that teams communicating in either speech or text tended to use a particular order for mentioning the speed, altitude, and radius. Different teams also chose different orders from one another. The teams in the evaluation experiment, however, showed unnaturally little variability in their information ordering and were also more likely to explicitly mention all restrictions even when they did not apply. Teams in the speech and text experiments were more likely to leave unnecessary restrictions unmentioned, and were also more likely to convey the restrictions across multiple communications. The option to converge on different packaging routines may have contributed to improved performance in the text experiment compared some of the conditions in the evaluation experiment. (shrink)

Molecular biology is a relatively new and very successful branch of science but currently it faces challenges posed by very complex issues that cannot be addressed by a traditional reductionist approach. However, despite its origins in the providential shift of some theoretical physicists to biology, currently molecular biology is immersed in a blind trend in which high-throughput technology, able to generate trillions of data, is becoming the leading edge of a discipline that has traded rational and critical thinking (...) for computer power, data crunching and statistics in hope of finding, once more, its way. However, the complex questions facing MB may only be solved by a paradigm shift in the causal way of thinking, so that complex, emergent, non-linear phenomena may be effectively understood in top-down and not in bottom-up terms. (shrink)