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Seth L. Alper

Bio: Seth L. Alper is an academic researcher from Beth Israel Deaconess Medical Center. The author has contributed to research in topics: Intracellular pH & Cotransporter. The author has an hindex of 74, co-authored 397 publications receiving 21932 citations. Previous affiliations of Seth L. Alper include Broad Institute & Yale University.


Papers
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Journal ArticleDOI
01 Dec 1999-JAMA
TL;DR: The functional regulation of the endothelium by local hemodynamic shear stress provides a model for understanding the focal propensity of atherosclerosis in the setting of systemic factors and may help guide future therapeutic strategies.
Abstract: Atherosclerosis, the leading cause of death in the developed world and nearly the leading cause in the developing world, is associated with systemic risk factors including hypertension, smoking, hyperlipidemia, and diabetes mellitus, among others. Nonetheless, atherosclerosis remains a geometrically focal disease, preferentially affecting the outer edges of vessel bifurcations. In these predisposed areas, hemodynamic shear stress, the frictional force acting on the endothelial cell surface as a result of blood flow, is weaker than in protected regions. Studies have identified hemodynamic shear stress as an important determinant of endothelial function and phenotype. Arterial-level shear stress (>15 dyne/cm2) induces endothelial quiescence and an atheroprotective gene expression profile, while low shear stress (<4 dyne/cm2), which is prevalent at atherosclerosis-prone sites, stimulates an atherogenic phenotype. The functional regulation of the endothelium by local hemodynamic shear stress provides a model for understanding the focal propensity of atherosclerosis in the setting of systemic factors and may help guide future therapeutic strategies.

3,246 citations

Journal ArticleDOI
TL;DR: The phenotypes of the AVP1 transgenic plants suggest that increasing the vacuolar proton gradient results in increased solute accumulation and water retention, and sequestration of cations in the vacUole reduces their toxic effects.
Abstract: Transgenic plants overexpressing the vacuolar H+-pyrophosphatase are much more resistant to high concentrations of NaCl and to water deprivation than the isogenic wild-type strains. These transgenic plants accumulate more Na+ and K+ in their leaf tissue than the wild type. Moreover, direct measurements on isolated vacuolar membrane vesicles derived from the AVP1 transgenic plants and from wild type demonstrate that the vesicles from the transgenic plants have enhanced cation uptake. The phenotypes of the AVP1 transgenic plants suggest that increasing the vacuolar proton gradient results in increased solute accumulation and water retention. Presumably, sequestration of cations in the vacuole reduces their toxic effects. Genetically engineered drought- and salt-tolerant plants could provide an avenue to the reclamation of farmlands lost to agriculture because of salinity and a lack of rainfall.

730 citations

Journal ArticleDOI
TL;DR: The regulation of AtNHX1 by NaCl and the ability of the plant gene to suppress the yeast nhx1 mutant suggest that the mechanism by which cations are detoxified in yeast and plants may be similar.
Abstract: Overexpression of the Arabidopsis thaliana vacuolar H+-pyrophosphatase (AVP1) confers salt tolerance to the salt-sensitive ena1 mutant of Saccharomyces cerevisiae. Suppression of salt sensitivity requires two ion transporters, the Gef1 Cl- channel and the Nhx1 Na+/H+ exchanger. These two proteins colocalize to the prevacuolar compartment of yeast and are thought to be required for optimal acidification of this compartment. Overexpression of AtNHX1, the plant homologue of the yeast Na+/H+ exchanger, suppresses some of the mutant phenotypes of the yeast nhx1 mutant. Moreover, the level of AtNHX1 mRNA in Arabidopsis is increased in the presence of NaCl. The regulation of AtNHX1 by NaCl and the ability of the plant gene to suppress the yeast nhx1 mutant suggest that the mechanism by which cations are detoxified in yeast and plants may be similar.

612 citations

Journal ArticleDOI
TL;DR: This GT-like cDNA clone isolated from a rat soleus lambda gt10 cDNA library encodes a 509-amino acid protein whose sequence and predicted membrane structure is very similar to those of the rat brain and liver GTs.
Abstract: Using low-stringency hybridization to the rat brain glucose transporter (GT), a 2489-base-pair cDNA clone was isolated from a rat soleus lambda gt10 cDNA library. It encodes a 509-amino acid protein whose sequence and predicted membrane structure is very similar to those of the rat brain and liver GTs. The muscle GT-like protein is 65% identical in amino acid sequence to the rat brain GT and 52% identical to the rat liver GT; the major differences are in the NH2- and COOH-terminal hydrophilic segments. This GT-like mRNA is expressed predominately in tissues where glucose transport is sensitive to insulin, including striated muscle, cardiac muscle, and adipose tissue; low-level expression is also detected in smooth muscle and kidney mRNA. This GT-like cDNA is the fourth member of the mammalian GT-related gene family identified to date. We propose that it encodes an insulin-sensitive GT.

397 citations

Journal ArticleDOI
TL;DR: Results demonstrate the coexpression of H+-ATPase and band 3 in opposite plasma membrane domains of a subpopulation of intercalated cells that are probably the acid-excreting (type A) cells and probably include the bicarbonate-exCreting ( type B) cells.
Abstract: The cellular distributions of the kidney form of the erythrocyte band 3 chloride/bicarbonate exchanger and the kidney vacuolar H+-transporting ATPase were examined in rat kidney collecting duct by immunocytochemical staining of adjacent semithin sections. Polyclonal anti-peptide antibodies directed against two regions of murine erythroid band 3 gave a pattern of basolateral labeling similar to that seen with antibodies directed against the entire protein. In the medullary collecting duct almost all intercalated cells expressed basolateral membrane band 3 and displayed apical membrane H+-ATPase. In the cortical collecting duct and the connecting segment, band 3 labeling was restricted to a subpopulation of intercalcated cells. In the cortical collecting duct 46% of intercalated cells had apical H+-ATPase and basolateral band 3. Cells that had either basolateral or diffuse cytoplasmic staining for H+-ATPase were all band 3-negative and accounted for 53% of the intercalated cells. In addition, occasional intercalated cells with apical H+-ATPase appeared to lack basolateral band 3. These results demonstrate the coexpression of H+-ATPase and band 3 in opposite plasma membrane domains of a subpopulation of intercalated cells that are probably the acid-excreting (type A) cells. All other intercalated cells lacked immunoreactive band 3 and probably include the bicarbonate-excreting (type B) cells.

374 citations


Cited by
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Journal ArticleDOI
TL;DR: The physiological and molecular mechanisms of tolerance to osmotic and ionic components of salinity stress are reviewed at the cellular, organ, and whole-plant level and the role of the HKT gene family in Na(+) exclusion from leaves is increasing.
Abstract: The physiological and molecular mechanisms of tolerance to osmotic and ionic components of salinity stress are reviewed at the cellular, organ, and whole-plant level. Plant growth responds to salinity in two phases: a rapid, osmotic phase that inhibits growth of young leaves, and a slower, ionic phase that accelerates senescence of mature leaves. Plant adaptations to salinity are of three distinct types: osmotic stress tolerance, Na + or Cl − exclusion, and the tolerance of tissue to accumulated Na + or Cl − . Our understanding of the role of the HKT gene family in Na + exclusion from leaves is increasing, as is the understanding of the molecular bases for many other transport processes at the cellular level. However, we have a limited molecular understanding of the overall control of Na + accumulation and of osmotic stress tolerance at the whole-plant level. Molecular genetics and functional genomics provide a new opportunity to synthesize molecular and physiological knowledge to improve the salinity tolerance of plants relevant to food production and environmental sustainability.

9,966 citations

Journal ArticleDOI
TL;DR: The evidence for this hypothesis, and the origins of the different kinetic phases of synaptic enhancement, as well as the interpretation of statistical changes in transmitter release and roles played by other factors such as alterations in presynaptic Ca(2+) influx or postsynaptic levels of [Ca(2+)]i are discussed.
Abstract: ▪ Abstract Synaptic transmission is a dynamic process. Postsynaptic responses wax and wane as presynaptic activity evolves. This prominent characteristic of chemical synaptic transmission is a crucial determinant of the response properties of synapses and, in turn, of the stimulus properties selected by neural networks and of the patterns of activity generated by those networks. This review focuses on synaptic changes that result from prior activity in the synapse under study, and is restricted to short-term effects that last for at most a few minutes. Forms of synaptic enhancement, such as facilitation, augmentation, and post-tetanic potentiation, are usually attributed to effects of a residual elevation in presynaptic [Ca2+]i, acting on one or more molecular targets that appear to be distinct from the secretory trigger responsible for fast exocytosis and phasic release of transmitter to single action potentials. We discuss the evidence for this hypothesis, and the origins of the different kinetic phases...

4,687 citations

Journal Article
TL;DR: Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional, and suggestions are made where such possibilities may be worth pursuing.
Abstract: Flavonoids are nearly ubiquitous in plants and are recognized as the pigments responsible for the colors of leaves, especially in autumn. They are rich in seeds, citrus fruits, olive oil, tea, and red wine. They are low molecular weight compounds composed of a three-ring structure with various substitutions. This basic structure is shared by tocopherols (vitamin E). Flavonoids can be subdivided according to the presence of an oxy group at position 4, a double bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring. These characteristics appear to also be required for best activity, especially antioxidant and antiproliferative, in the systems studied. The particular hydroxylation pattern of the B ring of the flavonoles increases their activities, especially in inhibition of mast cell secretion. Certain plants and spices containing flavonoids have been used for thousands of years in traditional Eastern medicine. In spite of the voluminous literature available, however, Western medicine has not yet used flavonoids therapeutically, even though their safety record is exceptional. Suggestions are made where such possibilities may be worth pursuing.

4,663 citations

Journal ArticleDOI
01 Jun 2000
TL;DR: Evidence for plant stress signaling systems is summarized, some of which have components analogous to those that regulate osmotic stress responses of yeast, some that presumably function in intercellular coordination or regulation of effector genes in a cell-/tissue-specific context required for tolerance of plants.
Abstract: ▪ Abstract Plant responses to salinity stress are reviewed with emphasis on molecular mechanisms of signal transduction and on the physiological consequences of altered gene expression that affect biochemical reactions downstream of stress sensing. We make extensive use of comparisons with model organisms, halophytic plants, and yeast, which provide a paradigm for many responses to salinity exhibited by stress-sensitive plants. Among biochemical responses, we emphasize osmolyte biosynthesis and function, water flux control, and membrane transport of ions for maintenance and re-establishment of homeostasis. The advances in understanding the effectiveness of stress responses, and distinctions between pathology and adaptive advantage, are increasingly based on transgenic plant and mutant analyses, in particular the analysis of Arabidopsis mutants defective in elements of stress signal transduction pathways. We summarize evidence for plant stress signaling systems, some of which have components analogous to t...

4,596 citations