The biogenesis, folding, and structure of α-helical membrane proteins (MPs) are important to understand because they underlie virtually all physiological processes in cells including key metabolic ...pathways, such as the respiratory chain and the photosystems, as well as the transport of solutes and signals across membranes. Nearly all MPs require translocons—often referred to as protein-conducting channels—for proper insertion into their target membrane. Remarkable progress toward understanding the structure and functioning of translocons has been made during the past decade. Here, we review and assess this progress critically. All available evidence indicates that MPs are equilibrium structures that achieve their final structural states by folding along thermodynamically controlled pathways. The main challenge for cells is the targeting and membrane insertion of highly hydrophobic amino acid sequences. Targeting and insertion are managed in cells principally by interactions between ribosomes and membrane-embedded translocons. Our review examines the biophysical and biological boundaries of MP insertion and the folding of polytopic MPs in vivo. A theme of the review is the under-appreciated role of basic thermodynamic principles in MP folding and assembly. Thermodynamics not only dictates the final folded structure but also is the driving force for the evolution of the ribosome–translocon system of assembly. We conclude the review with a perspective suggesting a new view of translocon-guided MP insertion.
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•Helical MPs are inserted co-translationally by ribosomes docked to translocons.•Recent ribosome–translocon structures provide dramatic insights into MP assembly.•Folding of inserted MPs is driven by strong thermodynamic forces.•A new view of translocon-guided MP folding is presented.
The first atomic-resolution structure of a membrane protein was solved in 1985. Twenty-four years and more than 180 unique structures later, what have we have learned? An examination of the atomic ...details of several diverse membrane proteins reveals some remarkable biophysical features and suggests that we can expect to achieve much more in the decades to come.
The author first describes his childhood in the South and the ways in which it fostered the values he has espoused throughout his life, his development of a keen fascination with science, and the ...influences that supported his progress toward higher education. His experiences in ROTC as a student, followed by two years in the US Army during the Vietnam War, honed his leadership skills. The bulk of the autobiography is a chronological journey through his scientific career, beginning with arrival at the University of California, Irvine in 1972, with an emphasis on the postdoctoral students and colleagues who have contributed substantially to each phase of his lab's progress. White's fundamental findings played a key role in the development of membrane biophysics, helping establish it as fertile ground for research. A story gradually unfolds that reveals the deeply collaborative and painstakingly executed work necessary for a successful career in science.
Approach to the pruritic horse White, Stephen D
Journal of the American Veterinary Medical Association,
06/2023, Volume:
261, Issue:
S1
Journal Article
Peer reviewed
Pruritus in the horse may be due to several causes, the most common being a hypersensitivity response to salivary proteins in the Culicoides genera, which may coexist with atopic dermatitis, also ...known as an environmental allergy to pollens, molds, dust, storage mites, etc. Less common etiologies are food allergy and contact allergy, the latter often caused by owners applying various products to the skin. Other ectoparasites, such as Chorioptes mites, may also initiate pruritus. Secondary bacterial infections (usually Staphylococcus spp) may be pruritic in and of themselves. This article reviews the questions that need to be asked of owners to obtain a relevant history, always important for any organ system, but perhaps none more so than the skin. The various clinical findings such as alopecia and crusts and their location on the horse, diagnostic methods such as intradermal or serum testing for allergies, and subsequent hyposensitization are also discussed. Therapeutic options currently available for the potential underlying diseases, in particular for the hypersensitivity reactions to Culicoides spp or environmental allergens, are reviewed with the studies of hyposensitization over the last 40 years, as well as medications that may be effective. While the most common causes of pruritus in the horse are known, the current understanding of the pathophysiology still needs to be investigated, and consequently, the most effective treatments for those causes need to be improved. Newer research is discussed that may eventually add to the diagnostic and therapeutic options currently available for the pruritic horse.
In light of many recent critiques of Western modernity and its conceptual foundations, the problem of adequately justifying our most basic moral and political values looms large. Without recourse to ...traditional ontological or metaphysical foundations, how can one affirm--or sustain--a commitment to fundamentals? The answer, according to Stephen White, lies in a turn to "weak" ontology, an approach that allows for ultimate commitments but at the same time acknowledges their historical, contestable character. This turn, White suggests, is already underway. His book traces its emergence in a variety of quarters in political thought today and offers a clear and compelling account of what this might mean for our late modern self-understanding.As he elaborates the idea of weak ontology and the broad criteria behind it, White shows how these are already at work in the thought of contemporary writers of seemingly very different perspectives: George Kateb, Judith Butler, Charles Taylor, and William Connolly. Among these thinkers, often thought to be at odds, he exposes the commonalities that emerge around the idea of weak ontology. In its identification of a critical turn in political theory, and its nuanced explanation of that turn, his book both demonstrates and underscores the strengths of weak ontology.
Atherosclerosis and aneurysms are leading causes of mortality worldwide. MicroRNAs (miRs) are key determinants of gene and protein expression, and atypical miR expression has been associated with ...many cardiovascular diseases; although their contributory role to atherosclerotic plaque and abdominal aortic aneurysm stability are poorly understood.
To investigate whether miR-181b regulates tissue inhibitor of metalloproteinase-3 expression and affects atherosclerosis and aneurysms.
Here, we demonstrate that miR-181b was overexpressed in symptomatic human atherosclerotic plaques and abdominal aortic aneurysms and correlated with decreased expression of predicted miR-181b targets, tissue inhibitor of metalloproteinase-3, and elastin. Using the well-characterized mouse atherosclerosis models of Apoe
and Ldlr
, we observed that in vivo administration of locked nucleic acid anti-miR-181b retarded both the development and the progression of atherosclerotic plaques. Systemic delivery of anti-miR-181b in angiotensin II-infused Apoe
and Ldlr
mice attenuated aneurysm formation and progression within the ascending, thoracic, and abdominal aorta. Moreover, miR-181b inhibition greatly increased elastin and collagen expression, promoting a fibrotic response and subsequent stabilization of existing plaques and aneurysms. We determined that miR-181b negatively regulates macrophage tissue inhibitor of metalloproteinase-3 expression and vascular smooth muscle cell elastin production, both important factors in maintaining atherosclerotic plaque and aneurysm stability. Validation studies in Timp3
mice confirmed that the beneficial effects afforded by miR-181b inhibition are largely tissue inhibitor of metalloproteinase-3 dependent, while also revealing an additional protective effect through elevating elastin synthesis.
Our findings suggest that the management of miR-181b and its target genes provides therapeutic potential for limiting the progression of atherosclerosis and aneurysms and protecting them from rupture.
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•The topology of SecA bound to E. coli large unilamellar vesicles was determined.•25 surface-exposed residues of a Cys-free SecA were mutated to Cys.•The polarity-sensitive ...fluorophore NBD was covalently linked to each Cys.•The disposition of SecA on the membrane in the absence of SecYEG was determined.•Conformation of SecA on the membrane is like that seen in SecA-SecYEG complexes.
The soluble cytoplasmic ATPase motor protein SecA powers protein transport across the Escherichia coli inner membrane via the SecYEG translocon. Although dimeric in solution, SecA associates monomerically with SecYEG during secretion according to several crystallographic and cryo-EM structural studies. The steps SecA follows from its dimeric cytoplasmic state to its active SecYEG monomeric state are largely unknown. We have previously shown that dimeric SecA in solution dissociates into monomers upon electrostatic binding to negatively charged lipid vesicles formed from E. coli lipids. Here we address the question of the disposition of SecA on the membrane prior to binding to membrane embedded SecYEG. We mutated to cysteine, one at a time, 25 surface-exposed residues of a Cys-free SecA. To each of these we covalently linked the polarity-sensitive fluorophore NBD whose intensity and fluorescence wavelength-shift change upon vesicle binding report on the the local membrane polarity. We established from these measurements the disposition of SecA bound to the membrane in the absence of SecYEG. Our results confirmed that SecA is anchored in the membrane interface primarily by the positive charges of the N terminus domain. But we found that a region of the nucleotide binding domain II is also important for binding. Both domains are rich in positively charged residues, consistent with electrostatic interactions playing the major role in membrane binding. Selective replacement of positively charged residues in these domains with alanine resulted in weaker binding to the membrane, which allowed us to quantitate the relative importance of the domains in stabilizing SecA on membranes. Fluorescence quenchers inside the vesicles had little effect on NBD fluorescence, indicating that SecA does not penetrate significantly across the membrane. Overall, the topology of SecA on the membrane is consistent with the conformation of SecA observed in crystallographic and cryo-EM structures of SecA-SecYEG complexes, suggesting that SecA can switch between the membrane-associated and the translocon-associated states without significant changes in conformation.
Research shows that the longer immigrants have been in their settlement country, the more likely they are to vote. This study examines whether when immigrants arrived, rather than how long they have ...resided, is the critical determinant of their electoral participation. Using Canadian data covering a 45‐year time span, this study demonstrates that the apparent relationship between immigrants' length of residence and their propensity to vote in elections is a result of the enduring influence of the historical period in which immigrants arrived in Canada. The results have implications for how researchers interpret immigrant adaptation to new political settings.
Agonism emerged three decades ago as an assault on the overemphasis in political theory on justice and consensus. It has now become the norm. But its character and relation to core values of ...democracy are not as unproblematic today as is often thought, an issue that becomes more pressing as contemporary politics increasingly seem locked into notions of unrelenting conflict between “friends” and “enemies.” This essay traces alternative ontological roots and ethical implications of agonism, distinguishing between “imperializing” and “tempered” modes. The former, exemplified in the popular Schmitt-Mouffe formulation, is shown to be fundamentally flawed in its failure to conceive politics in a fashion that does not allow the dynamic of friend–enemy to imperially trump appeals to democratic norms. In a world of insurgent white nationalism in democratic polities, this is no small fault. “Tempered” agonists, such as William Connolly and Bonnie Honig, offer ontologies where democratic norms can gain traction. Despite the admirable qualities of these alternatives, their formulations are nevertheless not fully persuasive. The difficulty lies in their underarticulated accounts of equality. I suggest an alternative formulation of agonism that embraces a central role for the idea of the moral equality of voice, a value that resides in the seam between notions of difference, resistance, and conflict emphasized by agonists, on the one hand, and the idea of fairness emphasized by notions of democratic justice, on the other.
•The background theory on solar-powered absorption chillers is presented.•A comprehensive review of the recent studies in the field is conducted.•Challenges and future research directions on the ...subject are highlighted.
Solar heating and cooling (SHC) systems are currently under rapid development and deployment due to their potential to reduce fossil fuel use and to alleviate greenhouse gas emissions in the building sector – a sector which is responsible for ∼40% of the world energy use. The available technologies on the market for thermally driven cooling systems are absorption and adsorption chillers, solid and liquid desiccant cooling systems, and ejector refrigeration cycles. Of these, absorption chillers are considered as the most desirable method for harnessing solar thermal energy due to their relative maturity, reliability, and higher efficiency. In addition, absorption chillers can take advantage of economies of scale in large buildings to obtain a relatively good levelized cost of cooling as compared to other thermally-driven air-conditioning systems. In this paper, the background theory on solar-powered absorption chillers is presented followed by a comprehensive literature review of the recent existing theoretical and experimental investigations on this technology is conducted. The review shows that the majority of solar absorption chillers installed and much of the research around the world is based on single-effect chillers and low-temperature solar thermal collectors, while less emphasis has been placed on the combination of high-temperature solar thermal collectors and multi-effect absorption chillers, especially triple-effect chillers. Research studies indicate the use of gas-fired backup systems for single-effect chillers is inefficient due to its very low primary energy savings. It was also found that the storage tank and piping can be major sources of heat losses in solar absorption cooling systems. Thus, special care should be taken to ensure sufficient and appropriate insulation for all heat loss components. In regions with low direct normal incidence solar resources (e.g. most of Europe), solar multi-effect chillers are relatively inefficient, so single-effect chiller-based solar cooling systems are the best techno-economic choice in such regions. Conversely, multi-effect absorption chillers with high-temperature collectors are indeed promising in regions with high solar resources. However, the review shows that using currently available technology, SHC absorption chillers are not able to economically compete with conventional cooling without government subsidies and incentives. Therefore, improving the economic performance of these systems is essential. While there is clearly more that can be done on chiller and solar collector components themselves, we believe some R&D emphasis going forward should also be dedicated to the balance of the system, including optimization of the system configuration, minimizing parasitic losses, improved design and integration of thermal storage and auxiliary system, and numerous controls and operational aspects. To date, many of these topics have been largely overlooked in favor of chiller performance studies.
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