Acne : The Treatment of Acne with Topical Retinoids

( Robert P. Feinstein ) 대한피부과학회 2000 초록집 Vol.38 No.20

Direct force measurements reveal that protein Tau confers short-range attractions and isoform-dependent steric stabilization to microtubules

Chung, Peter J.,Choi, Myung Chul,Miller, Herbert P.,Feinstein, H. Eric,Raviv, Uri,Li, Youli,Wilson, Leslie,Feinstein, Stuart C.,Safinya, Cyrus R. National Academy of Sciences 2015 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.112 No.47

<P><B>Significance</B></P><P>The microtubule-associated protein Tau is known to stabilize microtubules against depolymerization in neuronal axons, ensuring proper trafficking of organelles along microtubules in long axons. Abnormal interactions between Tau and microtubules are implicated in Alzheimer’s disease and other neurodegenerative disorders. We directly measured forces between microtubules coated with Tau isoforms by synchrotron small-angle X-ray scattering of reconstituted Tau–microtubule mixtures under osmotic pressure (mimicking molecular crowding in cells). We found that select Tau isoforms fundamentally alter forces between microtubules by undergoing a conformational change on microtubule surfaces at a coverage indicative of an unusually extended Tau state. This gain of function by longer isoforms in imparting steric stabilization to microtubules is essential in preventing microtubule aggregation and loss of function in organelle trafficking.</P><P>Microtubules (MTs) are hollow cytoskeletal filaments assembled from αβ-tubulin heterodimers. Tau, an unstructured protein found in neuronal axons, binds to MTs and regulates their dynamics. Aberrant Tau behavior is associated with neurodegenerative dementias, including Alzheimer’s. Here, we report on a direct force measurement between paclitaxel-stabilized MTs coated with distinct Tau isoforms by synchrotron small-angle X-ray scattering (SAXS) of MT-Tau mixtures under osmotic pressure (<I>P</I>). In going from bare MTs to MTs with Tau coverage near the physiological submonolayer regime (Tau/tubulin-dimer molar ratio; Φ<SUB>Tau</SUB> = 1/10), isoforms with longer N-terminal tails (NTTs) sterically stabilized MTs, preventing bundling up to <I>P</I><SUB>B</SUB> ∼ 10,000–20,000 Pa, an order of magnitude larger than bare MTs. Tau with short NTTs showed little additional effect in suppressing the bundling pressure (<I>P</I><SUB>B</SUB> ∼ 1,000–2,000 Pa) over the same range. Remarkably, the abrupt increase in <I>P</I><SUB>B</SUB> observed for longer isoforms suggests a mushroom to brush transition occurring at 1/13 < Φ<SUB>Tau</SUB> < 1/10, which corresponds to MT-bound Tau with NTTs that are considerably more extended than SAXS data for Tau in solution indicate. Modeling of Tau-mediated MT–MT interactions supports the hypothesis that longer NTTs transition to a polyelectrolyte brush at higher coverages. Higher pressures resulted in isoform-independent irreversible bundling because the polyampholytic nature of Tau leads to short-range attractions. These findings suggest an isoform-dependent biological role for regulation by Tau, with longer isoforms conferring MT steric stabilization against aggregation either with other biomacromolecules or into tight bundles, preventing loss of function in the crowded axon environment.</P>

ENDOCRINE CHANGES AND CIRCULATING INSULIN-LIKE GROWTH FACTORS IN NEWBORN CALVES FED COLOSTRUM, MILK OR MILK REPLACER

Lee, C.-Y.,Head, H.H.,Feinstein, C.R.,Hayen, J.,Simmen, F.A. Asian Australasian Association of Animal Productio 1995 Animal Bioscience Vol.8 No.1

To examine whether colostral growth factors are transferred to the general circulation, concentrations of plasma cortisol, insulin, prolactin, growth hormone, insulin-like growth factors(IGFs) -I and -II, IGF-binding proteins(IGFBPs) and total protein were measured in newborn calves fed colostrums, milk of milk replacer before and after feeding at 12 h intervals during the first two days after birth. Plasma protein concentrations increased with time after than in milk- or milk replacer-fed calves. The mean protein concentration was greater in colostrum-fed than in milk- or milk replacer-fed calves. Plasma cortisol levels transiently declined after each feeding regardless of the type of diet, while insulin levels tended to increase. Mean concentrations of these hormones did not differ between dietary groups, nor did they change with time after birth. Plasma concentrations of prolactin and growth hormone did not differ between dietary groups and also did not change with time after birth or after feeding. Concentrations of IGF-I and IGF-II transiently increased at the second feeding period, but these, as well as plasma IGFBP profiles, were not different between groups or before and after feeding. Results did not indicate significant transfer of colostral growth factors across the newborn ruminant small intestine.

The Impact of Clinical History on Mammographic Interpretations

Elmore, Joann G.,Wells, Carolyn K.,Howard, Debra H.,Feinstein, Alvan R. MediMedia Korea 1997 JAMA-Korea Vol.12 No.3

Paclitaxel suppresses Tau-mediated microtubule bundling in a concentration-dependent manner

Choi, Myung Chul,Chung, Peter J.,Song, Chaeyeon,Miller, Herbert P.,Kiris, E.,Li, Youli,Wilson, Leslie,Feinstein, Stuart C.,Safinya, Cyrus R. Elsevier 2017 Biochimica et biophysica acta, General subjects Vol.1861 No.1

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>Microtubules (MTs) are protein nanotubes comprised of straight protofilaments (PFs), head to tail assemblies of αβ-tubulin heterodimers. Previously, it was shown that Tau, a microtubule-associated protein (MAP) localized to neuronal axons, regulates the average number of PFs in microtubules with increasing inner radius <<I> R</I> <SUB>in</SUB> <SUP>MT</SUP> > observed for increasing Tau/tubulin-dimer molar ratio Φ<SUB>Tau</SUB> at paclitaxel/tubulin-dimer molar ratio Λ<SUB>Ptxl</SUB> =1/1.</P> <P><B>Methods</B></P> <P>We report a synchrotron SAXS and TEM study of the phase behavior of microtubules as a function of varying concentrations of paclitaxel (1/32≤Λ<SUB>Ptxl</SUB> ≤1/4) and Tau (human isoform 3RS, 0≤Φ<SUB>3RS</SUB> ≤1/2) at room temperature.</P> <P><B>Results</B></P> <P>Tau and paclitaxel have opposing regulatory effects on microtubule bundling architectures and microtubule diameter. Surprisingly and in contrast to previous results at Λ<SUB>Ptxl</SUB> =1/1 where microtubule bundles are absent, in the lower paclitaxel concentration regime (Λ<SUB>Ptxl</SUB> ≤1/4), we observe both microtubule doublets and triplets with increasing Tau. Furthermore, increasing paclitaxel concentration (up to Λ<SUB>Ptxl</SUB> =1/1) slightly decreased the average microtubule diameter (by ~1 PF) while increasing Tau concentration (up to Φ<SUB>3RS</SUB> =1/2) significantly increased the diameter (by ~2–3 PFs).</P> <P><B>Conclusions</B></P> <P>The suppression of Tau-mediated microtubule bundling with increasing paclitaxel is consistent with paclitaxel seeding more, but shorter, microtubules by rapidly exhausting tubulin available for polymerization. Microtubule bundles require the aggregate Tau-Tau attractions along the microtubule length to overcome individual microtubule thermal energies disrupting bundles.</P> <P><B>General significance</B></P> <P>Investigating MAP-mediated interactions between microtubules (as it relates to <I>in vivo</I> behavior) requires the elimination or minimization of paclitaxel.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Increasing paclitaxel suppresses Tau-mediated microtubule bundling. </LI> <LI> A length-dependent mechanism for Tau-mediated microtubule bundling is proposed. </LI> <LI> Understanding MAP/microtubule behavior requires elimination of paclitaxel use. </LI> </UL> </P>

Ion specific effects in bundling and depolymerization of taxol-stabilized microtubules

Needleman, Daniel J.,Ojeda-Lopez, Miguel A.,Raviv, Uri,Miller, Herbert P.,Li, Youli,Song, Chaeyeon,Feinstein, Stuart C.,Wilson, Leslie,Choi, Myung Chul,Safinya, Cyrus R. The Royal Society of Chemistry 2013 Faraday discussions Vol.166 No.-

<P>Microtubules (MTs) are nanometer scale hollow cylindrical biological polyelectrolytes. They are assembled from α/β-tubulin dimers, which stack to form protofilaments (PFs) with lateral interactions between PFs resulting in the curved MT. In cells, MTs and their assemblies are critical components in a range of functions from providing tracks for the transport of cargo to forming the spindle structure during mitosis. Previous studies have shown that while cations with valence equal to or larger than 3+ tend to assemble tight 3D bundles of taxol-stabilized MTs, certain divalent cations induce relatively loose 2D bundles of different symmetry (D. J. Needleman <I>et al.</I>, <I>Proc. Natl. Acad. Sci. U. S. A.</I>, 2004, <B>101</B>, 16099). Similarly, divalent cations form 2D bundles of DNA adsorbed on cationic membranes (I. Koltover <I>et al.</I>, <I>Proc. Natl. Acad. Sci. U. S. A.</I>, 2000, <B>97</B>, 14046). The bundling behavior for these biological polyelectrolyte systems is qualitatively in agreement with current theory. Here, we present results which show that, unlike the case for DNA adsorbed on cationic membranes, bundling of taxol-stabilized MTs occurs only for certain divalent cations above a critical ion concentration (<I>e.g.</I> Ca<SUP>2+</SUP>, Sr<SUP>2+</SUP>, Ba<SUP>2+</SUP>). Instead, many divalent cations pre-empt the bundling transition and depolymerize taxol-stabilized MTs at a lower counterion concentration. Although previous cryogenic TEM has shown that, in the absence of taxol, Ca<SUP>2+</SUP> depolymerizes MTs assembling in buffers containing GTP (guanosine triphosphate), our finding is surprising given the known stabilizing effects of taxol on GDP (guanosine diphosphate)-MTs. The ion concentration required for MT depolymerization decreases with increasing atomic number for the divalents Mg<SUP>2+</SUP>, Mn<SUP>2+</SUP>, Co<SUP>2+</SUP>, and Zn<SUP>2+</SUP>. GdCl<SUB>3</SUB> (3+) is found to be extremely efficient at MT depolymerization requiring ion concentrations of about 1 mM, while oligolysine (2+), is observed not to depolymerize MTs at concentrations as high as 144 mM. The surprising MT depolymerization results are discussed in the context of divalents either disrupting lateral interactions between PFs (which are strengthened for taxol containing β-tubulin), or interfering with taxol's ability to induce flexibility at the interface between two tubulin dimers in the same PF (which has been recently suggested as a mechanism by which taxol stabilizes MTs post-hydrolysis with the induced flexibility counteracting the kink between GDP-tubulin dimers in a PF).</P>

Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease

Nordstrom, U.,Beauvais, G.,Ghosh, A.,Pulikkaparambil Sasidharan, B.C.,Lundblad, M.,Fuchs, J.,Joshi, R.L.,Lipton, J.W.,Roholt, A.,Medicetty, S.,Feinstein, T.N.,Steiner, J.A.,Escobar Galvis, M.L.,Prochi Blackwell Science ; Academic Press 2015 Neurobiology of disease Vol.73 No.-

Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1<SUP>+/-</SUP> mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1<SUP>+/-</SUP> mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1<SUP>+/-</SUP> mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1<SUP>+/-</SUP> mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1<SUP>+/-</SUP> nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1<SUP>+/-</SUP> mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies.

Minireview - Microtubules and Tubulin Oligomers: Shape Transitions and Assembly by Intrinsically Disordered Protein Tau and Cationic Biomolecules

Safinya, Cyrus R.,Chung, Peter J.,Song, Chaeyeon,Li, Youli,Miller, Herbert P.,Choi, Myung Chul,Raviv, Uri,Ewert, Kai K.,Wilson, Leslie,Feinstein, Stuart C. American Chemical Society 2019 Langmuir Vol.35 No.48

<P>In this minireview, which is part of a special issue in honor of Jacob N. Israelachvili’s remarkable research career on intermolecular forces and interfacial science, we present studies of structures, phase behavior, and forces in reaction mixtures of microtubules (MTs) and tubulin oligomers with either intrinsically disordered protein (IDP) Tau, cationic vesicles, or the polyamine spermine (4+). Bare MTs consist of 13 protofilaments (PFs), on average, where each PF is made of a linear stack of αβ-tubulin dimers (i.e., tubulin oligomers). We begin with a series of experiments which demonstrate the flexibility of PFs toward shape changes in response to local environmental cues. First, studies show that MT-associated protein (MAP) Tau controls the diameter of microtubules upon binding to the outer surface, implying a shape change in the cross-sectional area of PFs forming the MT perimeter. The diameter of a MT may also be controlled by the charge density of a lipid bilayer membrane that coats the outer surface. We further describe an experimental study where it is unexpectedly found that the biologically relevant polyamine spermine (+4e) is able to depolymerize <I>taxol-stabilized</I> microtubules with efficiency that increases with decreasing temperature. This MT destabilization drives a dynamical structural transition where inside-out curving of PFs, during the depolymerization peeling process, is followed by reassembly of ring-like curved PF building blocks into an array of helical inverted tubulin tubules. We finally turn to a very recent study on pressure-distance measurements in bundles of MTs employing the small-angle X-ray scattering (SAXS)-osmotic pressure technique, which complements the surface-forces-apparatus technique developed by Jacob N. Israelachvili. These latter studies are among the very few which are beginning to shed light on the precise nature of the interactions between MTs mediated by MAP Tau in 37 °C reaction mixtures containing GTP and lacking taxol.</P> [FIG OMISSION]</BR>

PHOTOMETRICAL INVESTIGATIONS OF LOW-MASS X-RAY BINARIES WITH HIGH TIME RESOLUTION

BESKIN G. M.,MITRONOVA S. N.,NEIZVESTNY S. I.,PLOKHOTNICHENKO V. L.,POPOVA M. Yu.,BARTOLINI C.,GUARNIERI A.,MINARINI R.,PICCIONI A.,BENVENUTO O. G.,FEINSTEIN C.,MENDEZ M. The Korean Astronomical Society 1996 Journal of The Korean Astronomical Society Vol.29 No.suppl1

Human Microtubule-Associated-Protein Tau Regulates the Number of Protofilaments in Microtubules: A Synchrotron X-Ray Scattering Study

Choi, M.C.,Raviv, U.,Miller, H.P.,Gaylord, M.R.,Kiris, E.,Ventimiglia, D.,Needleman, D.J.,Kim, M.W.,Wilson, L.,Feinstein, S.C.,Safinya, C.R. Biophysical Society ; Published for the Biophysica 2009 Biophysical journal Vol.97 No.2

Microtubules (MTs), a major component of the eukaryotic cytoskeleton, are 25 nm protein nanotubes with walls comprised of assembled protofilaments built from αβ heterodimeric tubulin. In neural cells, different isoforms of the microtubule-associated-protein (MAP) tau regulate tubulin assembly and MT stability. Using synchrotron small angle x-ray scattering (SAXS), we have examined the effects of all six naturally occurring central nervous system tau isoforms on the assembly structure of taxol-stabilized MTs. Most notably, we found that tau regulates the distribution of protofilament numbers in MTs as reflected in the observed increase in the average radius <R<SUP>MT</SUP>> of MTs with increasing Φ, the tau/tubulin-dimer molar ratio. Within experimental scatter, the change in <R<SUP>MT</SUP>> seems to be isoform independent. Significantly, <R<SUP>MT</SUP>> was observed to rapidly increase for 0 < Φ < 0.2 and saturate for Φ between 0.2-0.5. Thus, a local shape distortion of the tubulin dimer on tau binding, at coverages much less than a monolayer, is spread collectively over many dimers on the scale of protofilaments. This implies that tau regulates the shape of protofilaments and thus the spontaneous curvature C<SUB>o</SUB><SUP>MT</SUP> of MTs leading to changes in the curvature C<SUP>MT</SUP> (=1/R<SUP>MT</SUP>). An important biological implication of these findings is a possible allosteric role for tau where the tau-induced shape changes of the MT surface may effect the MT binding activity of other MAPs present in neurons. Furthermore, the results, which provide insight into the regulation of the elastic properties of MTs by tau, may also impact biomaterials applications requiring radial size-controlled nanotubes.