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"Rutter, Benjamin"
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Hegel on the modern arts
\"Debates over the 'end of art' have tended to obscure Hegel's work on the arts themselves. Benjamin Rutter opens this study with a defence of art's indispensability to Hegel's conception of modernity; he then seeks to reorient discussion toward the distinctive values of painting, poetry, and the novel. Working carefully through Hegel's four lecture series on aesthetics, he identifies the expressive possibilities particular to each medium. Thus, Dutch genre scenes animate the everyday with an appearance of vitality; metaphor frees language from prose; and Goethe's lyrics revive the banal routines of love with imagination and wit. Rutter's important study reconstructs Hegel's view not only of modern art but of modern life and will appeal to philosophers, literary theorists, and art historians alike\"-- Provided by publisher.
Book
Acoustic properties of repair sequences in dysarthric conversational speech: An interactional phonetic study
The acoustic properties of intelligibility enhanced modes of speech in disordered populations are of interest to both speech-language pathologists and speech scientists. They inform theories of intelligibility, and point to potential targets for conversationally focused speech therapy. Previous studies looking at the phonetic events associated with the normal to clear speech transformation in disordered speakers have been exclusively experimental in nature. This dissertation used self-repair in naturally occurring spontaneous conversational speech as a window into intelligibility modification. The corpus of data was drawn from conversations between three primary participants, all suffering from a dysarthria secondary to multiple sclerosis, and several members of their social network. Self-repair sequences were identified and extracted and acoustic analyses were conducted in order to compare the trouble source with the repair region. The sequential organization of the surrounding talk was also considered in order to evaluate the communicative impact of the repair attempts. The findings suggest that dysarthric speakers address both the errors of the trouble source while also manipulating some global properties of the speech signal. It was noted that repairs seemed to exploit phonetic parameters that crossed the segmental/prosodic boundary and interaction between short and long domain features was regularly observed. The extent to which the modifications brought about idealized, canonical realizations in the repaired speech was variable and some degree of phonetic disturbance still resided in the repair. Nonetheless, repair attempts were overwhelmingly successful, with only one failed repair attempt found in the corpus. The findings add to the existing literature on interactional phonetics, clear speech, intelligibility, and speech therapy that focuses on understandability in conversation.
Dissertation
The effect of phase morphology and volume fraction of retained austenite on the formability of transformation induced plasticity steels
Transformation induced plasticity (TRIP) steels are a class of steels with exceptional formability properties, due mainly to the presence of meta-stable retained austenite which transforms to martensite under loading, locally hardening the steel. The volume fraction and mechanical stability of the retained austenite play an important role in producing the high formabilities of TRIP steels. In this thesis, two separate morphologies of retained austenite, equiaxed versus lamellar, have been produced through thermo-mechanical processing of a single common TRIP steel chemistry. The sheet formability characteristics of these two microstructures were examined, with varying volume fractions of retained austenite, through uniaxial tensile and in-plane plane-strain (IPPS) testing. It was found that higher levels of retained austenite produced better formability properties for both microstructures and strain paths. In uniaxial tension it was seen that the lamellar microstructure attained higher strains at maximum load, and exhibited more sustained instantaneous n values than the equiaxed structure, despite having a lower volume fraction of retained austenite. IPPS testing was performed using an optical measurement of local strain and a comparative forming limit based on differences in strain rate between a developing neck and the surrounding material. It was found that the lamellar microstructure performed better than the equiaxed microstructure for this strain path, achieving higher strains before reaching the comparative forming limit.
Dissertation
Hegel on the modern arts
Hegel's lectures on aesthetics bear witness not to the cessation of artistic activity as such, but to a progressive decline in its significance for human self-understanding. Still, the nature and extent of this decline remain contested. Is the creation of new art a vestigial activity in a world governed by philosophical forms of understanding? Or does Hegel grant the arts an indispensable role in modern life? This dissertation defends the latter view. I begin by responding to Dieter Henrich's claim that, in light of art's subordination to philosophy, the deliverances of modern painting and literature are necessarily redundant. First, the logic of sublation itself suggests an ongoing role for art; second, Hegel sketches a mutually collaborative, rather than competitive, relationship among art, religion, and philosophy. If art can afford us distinctive forms of self-knowledge which, though unavailable to philosophical thought, are nonetheless asymmetrically dependent upon the framework it erects, then art can escape redundancy without violating its subordination. What are the distinctive forms of human self-understanding modern art might afford us? This is the second, constructive question that occupies the remaining chapters of the project. Roughly, I claim, artworks can help reconcile us to those dimensions of our experience too trivial or too unreflective to admit of anything but cursory, and thus unsatisfying, philosophic treatment. Thus, Hegel appreciates in Dutch genre painting not only a feat of national self-assertion, but an attempt, visible in the painter's choice of a \"repugnantly\" common subject matter, to confront worries about the possibilities of self-determination implicit in the wage labor and domestic ennui that characterize the modern West. The poetry of Goethe and his Persian forebear Hafiz, meanwhile addresses themselves to the erotic and the personal---a realm, again, in which we may feel ourselves prisoner to contingency. Central to both painting and literature, finally, is a notion of artistic virtuosity, for it is virtuosity that takes the place of beauty in the table of modern artistic values.
Dissertation
Induced protein degradation for therapeutics: past, present, and future
The concept of induced protein degradation by small molecules has emerged as a promising therapeutic strategy that is particularly effective in targeting proteins previously considered \"undruggable.\" Thalidomide analogs, employed in the treatment of multiple myeloma, stand as prime examples. These compounds serve as molecular glues, redirecting the CRBN E3 ubiquitin ligase to degrade myeloma-dependency factors, IKZF1 and IKZF3. The clinical success of thalidomide analogs demonstrates the therapeutic potential of induced protein degradation. Beyond molecular glue degraders, several additional modalities to trigger protein degradation have been developed and are currently under clinical evaluation. These include heterobifunctional degraders, polymerization-induced degradation, ligand-dependent degradation of nuclear hormone receptors, disruption of protein interactions, and various other strategies. In this Review, we will provide a concise overview of various degradation modalities, their clinical applications, and potential future directions in the field of protein degradation.
Journal Article
Mortality from pandemic A/H1N1 2009 influenza in England: public health surveillance study
Objective To establish mortality from pandemic A/H1N1 2009 influenza up to 8 November 2009.Design Investigation of all reported deaths related to pandemic A/H1N1 in England.Setting Mandatory reporting systems established in acute hospitals and primary care. Participants Physicians responsible for the patient.Main outcome measures Numbers of deaths from influenza combined with mid-range estimates of numbers of cases of influenza to calculate age specific case fatality rates. Underlying conditions, time course of illness, and antiviral treatment.Results With the official mid-range estimate for incidence of pandemic A/H1N1, the overall estimated case fatality rate was 26 (range 11-66) per 100 000. It was lowest for children aged 5-14 (11 (range 3-36) per 100 000) and highest for those aged ≥65 (980 (range 300-3200) per 100 000). In the 138 people in whom the confirmed cause of death was pandemic A/H1N1, the median age was 39 (interquartile range 17-57). Two thirds of patients who died (92, 67%) would now be eligible for the first phase of vaccination in England. Fifty (36%) had no, or only mild, pre-existing illness. Most patients (108, 78%) had been prescribed antiviral drugs, but of these, 82 (76%) did not receive them within the first 48 hours of illness.Conclusions Viewed statistically, mortality in this pandemic compares favourably with 20th century influenza pandemics. A lower population impact than previous pandemics, however, is not a justification for public health inaction. Our data support the priority vaccination of high risk groups. We observed delayed antiviral use in most fatal cases, which suggests an opportunity to reduce deaths by making timely antiviral treatment available, although the lack of a control group limits the ability to extrapolate from this observation. Given that a substantial minority of deaths occur in previously healthy people, there is a case for extending the vaccination programme and for continuing to make early antiviral treatment widely available.
Journal Article
The International Network on Oesophageal Atresia (INoEA) consensus guidelines on the transition of patients with oesophageal atresia–tracheoesophageal fistula
Oesophageal atresia–tracheoesophageal fistula (EA-TEF) is a common congenital digestive disease. Patients with EA-TEF face gastrointestinal, surgical, respiratory, otolaryngological, nutritional, psychological and quality of life issues in childhood, adolescence and adulthood. Although consensus guidelines exist for the management of gastrointestinal, nutritional, surgical and respiratory problems in childhood, a systematic approach to the care of these patients in adolescence, during transition to adulthood and in adulthood is currently lacking. The Transition Working Group of the International Network on Oesophageal Atresia (INoEA) was charged with the task of developing uniform evidence-based guidelines for the management of complications through the transition from adolescence into adulthood. Forty-two questions addressing the diagnosis, treatment and prognosis of gastrointestinal, surgical, respiratory, otolaryngological, nutritional, psychological and quality of life complications that patients with EA-TEF face during adolescence and after the transition to adulthood were formulated. A systematic literature search was performed based on which recommendations were made. All recommendations were discussed and finalized during consensus meetings, and the group members voted on each recommendation. Expert opinion was used when no randomized controlled trials were available to support the recommendation. The list of the 42 statements, all based on expert opinion, was voted on and agreed upon.Currently, systematic care for adults and adolescents with oesophageal atresia–tracheoesophageal fistula (EA-TEF) as they transition into adulthood is lacking. A multidisciplinary group of experts structured this Consensus Statement offering guidelines for the care of adolescents and adults with EA-TEF during transition.
Journal Article
The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia
Zinc transporter ZIP12 expression is increased in many cell types in remodelled mammalian pulmonary arterioles in hypoxia-induced pulmonary hypertension.
Zinc transport in pulmonary vascular homeostasis
Pulmonary hypertension is a serious disease triggered by chronic hypoxia. Lan Zhao and colleagues now link a zinc transporter to this disease in rats. The Fischer 344 rat strain is naturally resistant to hypoxia-induced pulmonary hypertension and the authors use a congenic breeding program and comparative genomics to establish that a mutation in the zinc transporter ZIP12 underlies the resistance to this disease. ZIP12 expression in vascular smooth muscle cells is hypoxia dependent, and genetic disruption of ZIP12 can prevent the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. The results suggest that ZIP12 might be a viable drug target for the treatment of pulmonary hypertension.
The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension
1
,
2
,
3
. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene
Slc39a12
as a major regulator of hypoxia-induced pulmonary vascular remodelling.
Slc39a12
encodes the zinc transporter ZIP12. Here we report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This new and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.
Journal Article
Template-assisted covalent modification underlies activity of covalent molecular glues
Molecular glues are proximity-inducing small molecules that have emerged as an attractive therapeutic approach. However, developing molecular glues remains challenging, requiring innovative mechanistic strategies to stabilize neoprotein interfaces and expedite discovery. Here we unveil a
trans
-labeling covalent molecular glue mechanism, termed ‘template-assisted covalent modification’. We identified a new series of BRD4 molecular glue degraders that recruit CUL4
DCAF16
ligase to the second bromodomain of BRD4 (BRD4
BD2
). Through comprehensive biochemical, structural and mutagenesis analyses, we elucidated how pre-existing structural complementarity between DCAF16 and BRD4
BD2
serves as a template to optimally orient the degrader for covalent modification of DCAF16
Cys58
. This process stabilizes the formation of BRD4–degrader–DCAF16 ternary complex and facilitates BRD4 degradation. Supporting generalizability, we found that a subset of degraders also induces GAK–BRD4
BD2
interaction through
trans
-labeling of GAK. Together, our work establishes ‘template-assisted covalent modification’ as a mechanism for covalent molecular glues, which opens a new path to proximity-driven pharmacology.
Characterization of DCAF16-based BRD4 molecular glue degraders revealed a
trans
-labeling mechanism termed ‘template-assisted covalent modification’, which opens a new path for proximity-driven pharmacology.
Journal Article