4-Hydroxynonenal-modified amyloid-beta peptide inhibits the proteasome: possible importance in Alzheimer's disease

The amyloid β-peptide (Aβ) is a 4-kDa species derived from the amyloid precursor protein, which accumulates in the brains of patients with Alzheimer’s disease. Although we lack full understanding of the etiology and pathogenesis of selective neuron death, considerable data do imply roles for both the toxic Aβ and increased oxidative stress. Another significant observation is the accumulation of abnormal, ubiquitin-conjugated proteins in affected neurons, suggesting dysfunction of the proteasome proteolytic system in these cells. Recent reports have indicated that Aβ can bind and inhibit the proteasome, the major cytoslic protease for degrading damaged and ubiquitin-conjugated proteins. Earlier results from our laboratory showed that moderately oxidized proteins are preferentially recognized and degraded by the proteasome; however, severely oxidized proteins cannot be easily degraded and, instead, inhibit the proteasome. We hypothesized that oxidatively modified Aβ might have a stronger (or weaker) inhibitory effect on the proteasome than does native Aβ. We therefore also investigated the proteasome inhibitory action of Aβ _1–40 (a peptide comprising the first 40 residues of Aβ) modified by the intracellular oxidant hydrogen peroxide, and by the lipid peroxidation product 4-hydroxynonenal (HNE). H₂O₂ modification of Aβ _1–40 generates a progressively poorer inhibitor of the purified human 20S proteasome. In contrast, HNE modification of Aβ _1–40 generates a progressively more selective and efficient inhibitor of the degradation of fluorogenic peptides and oxidized protein substrates by human 20S proteasome. This interaction may contribute to certain pathological manifestations of Alzheimer’s disease Received 26 September 2000; accepted 26 September 2000     

Simple integrated rate equations for reversible bimolecular reactions

Summary If the complete rate equations for reversible, one-step, bimolecular reactions are written withP _e–P as the concentration variable (whereP _e is the equilibrium, andP is the instantaneous, product concentration), the 3 possible stoichiometries can be reduced to a single straightforward differential equation. This can be solved very economically. For each stoichiometry, weret is time,k ₁ is the forward rate constant,K _e is the equilibrium constant, and P isP–P _o. The termsP _c–P _o andD+P _c–P _o are the physically possible and physically impossible roots of the quadratic equation forP _e–P _o in terms of the initial concentrations andK _c.D is the discriminant in this equation. All 3 quantities can be calculated if the equilibrium constant is known. A plot oft against ln{[1–P/(D+P _c–P _o)]/[1–P/(P _c–P _o)]} should be a straight line for any second order reaction. For each stoichiometry,P _c–P _o approachesA _o, the initial concentration of the first reactant, as the equilibrium constant increases. When a second reactant is present,D+P _e–P _o approachesB _o. The limiting equation is then that of an irreversible bimolecular reaction. For AP+Q,D approaches –K _e as the equilibrium constant becomes large, and the value of the second logarithmic term in the integrated equation approaches zero. The limiting equation is that of an irreversible, unimolecular reaction.Acknowledgments. I thank Dr. Athel Cornish-Bowden for many helpful discussions. This work was partially supported by a grant from Utah State University.     

Atomism, Poincaré and Planck

Planck's change in attitude to the question of whether atomic hypotheses were scientifically accessible, is discussed. It is argued contra Holton, that Planck's change in attitude to this question did not signal a methodological shift towards realism. The point of doing this is not just to investigate a significant episode in the history of quantum theory, but also to use the episode as a case study in support of a broader historical thesis. This thesis is that there was a widespread late-nineteenth century methodological tradition which motivated the change in status of certain ontological claims — e.g., that atoms exist — from ‘inaccessible to science’ to ‘scientifically acceptable’ even though those claims were not strictly ‘observable’. This methodological tradition is a hybrid of positivist and realist views. Thus, contrary to one popular view, the fin de siécle triumph of atomism is not to be seen as a triumph for a realist view of science Poincare's views are also used as an illustration.     

Integrins and cardiovascular disease

Cardiovascular diseases involve abnormal cell-cell interactions leading to the development of atherosclerotic plaque, which when ruptured causes massive platelet activation and thrombus formation. Parts of a loose thrombus may detach to form an embolus, blocking circulation at a more distant point. The integrins are a family of adhesive cell receptors interacting with adhesive proteins or with counterreceptors on other cells. There is now solid evidence that the major integrin on platelets, the fibrinogen receptor α _IIb  β ₃ , has an important role in several aspects of cardiovascular diseases and that its regulated inhibition leads to a reduction in incidence and mortality due to these disorders. The development of α _IIb  β ₃ inhibitors is an important strategy of many pharmaceutical companies which foresee a large market for the treatment of acute conditions in surgery, the symptoms of chronic conditions and, it is hoped, maybe even the successful prophylaxis of these conditions. Although all the associated problems have not been solved, the undoubted improvements in patient care resulting from the first of these treatments in the clinic have stimulated further research on the role of integrins on other vascular cells in these processes and in the search for new inhibitors. Both the development of specific inhibitors and of mice with specific integrin subunit genes ablated have contributed to a better understanding of the function of integrins in development of the cardiovascular system.     

The distribution of α2β1, α3β1 and α6β4 integrins identifies distinct subpopulations of basal keratinocytes in the outer root sheath of the human anagen hair follicle

The human hair follicle is composed of different concentric compartments, which reflect different programmes of differentiation. Using monoclonal antibodies against α2β1 and α3β1 integrins we demonstrated a shift in their expression, from a basolateral distribution in the basal cells of the lower outer root sheath, to an apicolateral expression in the upper outer root sheath, as in epidermis. This shift takes place in a transition zone, localized to the midpart of the follicle. The distinct basolateral distribution of α2β1 and α3β1 integrins in the lower portion of the outer root sheath coincides with the presence of basal cell protrusions and is probably linked to the presence of the vitreous membrane which surrounds the bottom part of the anagen human hair follicle. Moreover, we showed that the expression of α6β4 integrin is discontinuous along the hair follicle and coincides with that of laminin 5. Together these results establish that within a given compartment – namely the outer root sheath – several domains can be clearly identified, which probably reflect the onset of successive differentiation pathways along the hair follicle. Received 17 January 1997; received after revision 18 February 1997; accepted 24 February 1997     

Growth ofNostoc muscorum mutants in the presence of diuron (DCMU) and L-methionine-DL-sulfoximine

Summary Diuron (DCMU) is inhibitory to the photoautotrophic and photoheterotrophic growth of the N₂-fixing blue-green algaNostoc muscorum at concentrations of 1.0×10^–5 M and 2.0×10^–5 M, respectively. A mutant of this organism resistant to 5.0×10^–5 M DCMU under its photoheterotrophic growth conditions, with the ability to utilize DCMU as a carbon and nitrogen source for growth, and complete inability to grow photoautotrophically has been isolated. With the apparent defect in its photosynthetic ability, it is suggested that theDCMU ^r mutant lacks the step inhibited by 1.0×10^–5 M DCMU, and metabolizes DCMU by an existing enzyme system in the absence of such inhibition. That this enzyme may be glutamine synthetase (GS) is explained with the help of a L-methionine-DL-sulfoximine (MSO)-resistant mutant ofN. muscorum which is able to grow faster with 2.0×10^–5 DCMU and is known to contain an altered GS.Thanks are due to the Council of Scientific and Industrial Research, CSIR Complex, Govt. of India, New Delhi-110012, for appointing the author to the Scientists' Pool for undertaking researches on the physiological and genetic controls of nitrogen metabolism in blue-green algae, a part of which is presented in this literature.     

Newton's Easy Quadratures ``Omitted for the Sake of Brevity'

In the 1687 Principia, Newton gave a solution to the direct problem (given the orbit and center of force, find the central force) for a conic-section with a focal center of force (answer: a reciprocal square force) and for a spiral orbit with a polar center of force (answer: a reciprocal cube force). He did not, however, give solutions for the two corresponding inverse problems (given the force and center of force, find the orbit). He gave a cryptic solution to the inverse problem of a reciprocal cube force, but offered no solution for the reciprocal square force. Some take this omission as an indication that Newton could not solve the reciprocal square, for, they ask, why else would he not select this important problem? Others claim that ``it is child's play' for him, as evidenced by his 1671 catalogue of quadratures (tables of integrals). The answer to that question is obscured for all who attempt to work through Newton's published solution of the reciprocal cube force because it is done in the synthetic geometric style of the 1687 Principia rather than in the analytic algebraic style that Newton employed until 1671. In response to a request from David Gregory in 1694, however, Newton produced an analytic version of the body of the proof, but one which still had a geometric conclusion. Newton's charge is to find both ``the orbit' and ``the time in orbit.' In the determination of the dependence of the time on orbital position, t(r), Newton evaluated an integral of the form ∫dx/x <sup>n</sup> to calculate a finite algebraic equation for the area swept out as a function of the radius, but he did not write out the analytic expression for time t = t(r), even though he knew that the time t is proportional to that area. In the determination of the orbit, θ (r), Newton obtained an integral of the form ∫dx/√(1−x<sup>2</sup>) for the area that is proportional to the angle θ, an integral he had shown in his 1669 On Analysis by Infinite Equations to be equal to the arcsin(x). Since the solution must therefore contain a transcendental function, he knew that a finite algebraic solution for θ=θ(r) did not exist for ``the orbit' as it had for ``the time in orbit.' In contrast to these two solutions for the inverse cube force, however, it is not possible in the inverse square solution to generate a finite algebraic expression for either ``the orbit' or ``the time in orbit.' In fact, in Lemma 28, Newton offers a demonstration that the area of an ellipse cannot be given by a finite equation. I claim that the limitation of Lemma 28 forces Newton to reject the inverse square force as an example and to choose instead the reciprocal cube force as his example in Proposition 41. (Received August 14, 2002) Published online March 26, 2003 Communicated by G. Smith     

Structure and assembly of the 20S proteasome

The barrel-shaped 20S proteasome is one of the two components of a larger 26S particle, the multicatalytic 2000-kDa protease complex. The proteolytic sites are located in the inner chamber of the 20S particle and are only accessible via narrow entrances. This paper reviews the current knowledge concerning proteasome formation, proteolytic activities, structural aspects and assembly. Eukaryotic proteasomes are made up by four rings each of which contains seven different subunits occurring at fixed positions. While the outer rings contain α-type subunits, the inner ones comprise β-type subunits. The current assembly model for eukaryotic 20S proteasomes is based upon the detection of 13S and 16S intermediates, respectively, in addition to previous findings with archaebacterial and eubacterial proteasome assembly. The available data suggest a cooperative assembly of the α-type and β-type subunits into half proteasome-like complexes followed by dimerization into proteasomes. During or after dimerization of half proteasomes, the β-type subunits are processed. The prosequence of the β-type subunits is essential for the assembly process and prevents protease activity of immature proteasomes.     

The significance of temperature and barometric pressure changes for the snow surface activity ofIsotoma hiemalis (Collembola)

Summary Temperature is limiting for the snow surface activity ofIsotoma hiemalis: values below a threshold of –2.5° to –3°C are avoided. Changing barometric pressure leads to increased surface activity, thus being responsible for mass appearances. These experiments provide the first evidence for sensitivity to and reaction to barometric pressure changes in insects.The financial support by the Swiss National Science Foundation is highly acknowledged. I thank W. Matthey for the unpublished data onGerris remigis.     

Das Parallelenproblem im Corpus Aristotelicum

Summary In the Corpus Aristotelicum are numerous items suggesting that the assertion of the fifth postulate in Euclid's Elements had been preceded by attempts to demonstrate this postulate itself, or some equivalent fundamental proposition, within the rigorous frame of Absolute Geometry in Bolyai's sense. Thus geometers contemporary with Aristotle tried to solve the problem which became known commonly in later centuries as the Problem of Parallels.Probably these geometers first attempted a direct solution. Only one text at our disposal supports this hypothesis: (1) Anal. Prior. 65 a 4–7. My analysis below in Chapter I shows that a mathematical meaning can be read from this somewhat obscure text only if it is interpreted as an allusion by Aristotle to those geometers who believe they are demonstrating, obviously in an absolute way, the proposition Elem. I 29, equivalent to the fifth postulate, but do not realize that in the process they are using lemmas which result themselves from the proposition to be demonstrated. Such a lemma would assert the uniqueness of the parallels, existence of which was shown in an absolute way in Elem. I 27. My conjecture and reconstruction afford a natural explanation for an inconsequence singular for Book I of the Elements, namely, the presence of the proposition Elem. I 31 in the purely Euclidean part of the book, in spite of the fact that the assertion merely repeats the absolute proposition Elem. I 27 without explicitly containing any Euclidean element.It is probable that the failure of these direct attempts led to an indirect approach to the problem through reductio ad absurdum of some hypothesis contrary to what was to become Postulate V or to some equivalent proposition. Numerous texts survive from which it is clear that geometers contemporary with Aristotle followed fairly far the consequences of an hypothesis contrary to the fifth postulate, obtaining important results which are partly identical with some theorems of Saccheri. Some of these texts attest first of all that what Saccheri called the Hypothesis of the Obtuse Angle had been stated in an independent and explicit way and that the fundamental result, identical with Prop. 14 of Saccheri's Euclides ab omni naevo vindicatus (1733), had been obtained, namely, that within Bolyai's Absolute Geometry this hypothesis leads to the remarkable formal contradiction that parallels intersect. This conclusion followed from two different formulations of the Obtuse Angle Hypothesis: (2) Anal. Prior. 66a 11–14, if the exterior angle (formed by a secant which intersects two parallel straight lines) is smaller than the interior angle (opposite and situated on the same side of the secant), and (3) 66a 14–15, if the sum of the angles in a triangle is greater than 2R. Finally, an item in (4) Ethica ad Eudemum 1222b 35–36 shows us that by investigating the Obtuse Angle Hypothesis, the Greek geometers also discovered the quadrilateral in which the sum of the angles is equal to 8R; this quadrilateral, which does not appear even in Saccheri's book, is the maximal quadrilateral of the Riemann geometry, a quadrilateral degenerated into a straight line closed upon itself (Chapter IV 20).Nowhere in the Corpus does the Hypothesis of the Acute Angle appear in an independent formulation. Nevertheless in (5) Anal. Poster. 90a 33–34 this Hypothesis is mentioned along with the other two: namely, Aristotle states that the essence of the triangle consists in the sum of its angles' being equal to, greater than or less than 2R (Chapter V 27). The formulation of the fifth postulate in the Elements allows greater probability to the conjecture of independent existence of the Acute Angle Hypothesis as well. Indeed, in its original formulation the fifth postulate is redundant, since it unnecessarily specifies in which of the half-planes (bounded by the secant) the intersection of the two straight lines occurs; this specification is itself a theorem. The Acute Angle Hypothesis must have been formulated not only symmetrically to (3) Anal. Prior. 66 a 14–15, that is, the sum of the angles of the triangle is less than 2R, as results from (5) Anal. Poster. 90 a 33–34, but also symmetrically to (2) Anal. Prior. 66 a 11–14. In the latter case the following final conclusion should have been reached in order to reduce to absurdity the Acute Angle Hypothesis: Two straight lines cut by a secant are incident if the sum of the interior angles (on the same side of the secant) is smaller than 2R, and the incidence occurs on that side of the secant where the sum of the angles is less than 2R. In the frame of the Acute Angle Hypothesis, this end conclusion is relevant only if this final specification (concerning the half-plane where the incidence occurs) is explicitly emphasised. According to my conjecture, it was precisely the practical impossibility of reaching this conclusion as a theorem of Absolute Geometry that later determined Euclid to transpose this decisive end conclusion from the Acute Angle Hypothesis, without changing its wording, and to include it among the postulates (Chapter II 13).A queer passage of Proklos (In primum Euclidis Elementorum, ed. Friedlein p. 368, 26–369, 1) in which the Acute Angle Hypothesis is presented in the form of a Zenonian paradox reinforces the conjecture that this hypothesis was studied independently by the ancient geometers (Chapter VI 33). Thus failure to solve the Problem of Parallels preceded not only the later Non-Euclidean geometry but also Euclidean geometry itself.The general undifferentiated Contra-Euclidean Hypothesis appears in the following form in all the other texts examined: The sum of the angles in the triangle is not equal to 2R. This hypothesis is nowhere qualified by Aristotle as being absurd or impossible: On the contrary, he takes it always as being just as much justified a priori as is the Euclidean theorem Elem. I 32 which contradicts it. For instance in (6) Anal. Poster. 93 a 33–35 Aristotle puts the problematical alternative: Which of the two propositions is right (or, which of the two constitutes the Logos, the raison d'être of the triangle), the one that states that the sum of the angles in the triangle is equal to 2R, or on the contrary, the one that states that the sum of the angles in the triangle is not equal to 2R (Chapter V 28)?In a number of texts the theorem Elem. I 32 itself and the general Contra-Euclidean Hypothesis are treated as being a sort of principle, and stress is laid on the idea that the logical consequences of each of these items invariantly preserve its specific (Euclidean or non-Euclidean) geometrical content [(7) 1187 a 35–38 (Chapter IV 18); (8) 1222 b 23–26 (Chapter IV 19); (9) 1187 b 1–2 (Chapter IV 18); (10) 1222 b 41–42 Chapter IV 21); (11) 1187 b 2–4 (Chapter IV 18)]; (12) Physica 200 a 29–30: If the sum of the angles in the triangle is not equal to 2R, then the principles of geometry cannot remain the same (Chapter V 25); (13) Metaph. 1052 a 6–7: It is impossible that the sum of the angles in the triangle be sometimes equal to 2R and sometimes not equal to 2R (Chapter V 24). Finally, the most important item of this sort is to be found in (14) De Caelo 281 b 5–7: If we accept as a starting hypothesis that it is impossible for the sum of the angles in the triangle to be equal to 2R, then the diagonal of the square is commensurable with its side (Chapter III).Another group of texts reveal Aristotle's attitude as regard these Contra-Euclidean theorems: (15) 1222 b 38–39 (Chapter IV 20); (16) 200 a 16–19 (Chapter VI 30); (17) 402 b 18–21 (Chapter VI 31); (18) 171 a 12–16 (Chapter VI 32); (19) 77 b 22–26 (Chapter V 26); (20) 101 a 15–17 (Chapter VI 31); (21) 76 b 39–77 a 3 (Chapter VI 31). These passages reveal Aristotle's conviction that these paradoxical Contra-Euclidean propositions (which cannot be annihilated by reductio ad absurdum) are nevertheless inacceptable as bad, probably because their graphical construction requires curved lines for representing the concept of straight lines.Finally, another group of texts show that Aristotle sensed in a way the necessity of adding to the foundations of Geometry a new postulate, from which the proposition Elem. I 32 should follow rigorously.

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Aram Frenkian zum Gedächtnis

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Vorgelegt von J. E. Hofmann     

Substrate binding and catalytic mechanism of class B β-lactamases: a molecular modelling study

Increased resistance to β-lactam antibiotics is mainly due to β-lactamases whose production by pathogenic bacteria makes their broad activity spectrum especially frightening. X-ray structures of several zinc β-lactamases have revealed the coordination of the two metal ions, but their mode of action remains unclear. Geometry optimisation of stable complexes along the reaction pathway of benzylpenicillin hydrolysis highlighted a proton shuttle occurring from D120 of the Bacillus cereus β-lactamase to the β-lactam nitrogen via Zn2 which is central to the network. First, the Zn1 ion has a structural role maintaining Zn-bound waters, WAT1 and WAT2, either directly or through the Zn1 tetrahedrally coordinated histidine ligands. The Zn2 ion has a more catalytic role, stabilising the tetrahedral intermediate, accepting the β-lactam nitrogen atom as a ligand. The role of Zn2 and the flexibility in the coordination geometry of both Zn ions is of crucial importance for catalysis. Received 14 August 2001; received after revision 19 October 2001; accepted 30 October 2001     

Ligand recognition by the I domain-containing integrins

Seven of the integrin α subunits described to date, α ₁ , α ₂ , α _L , α _X , α _d , α _M and α _E , contain a highly conserved I (or A) domain of approximately 200 amino acid residues inserted near the amino-terminus of the subunit. As the result of a variety of independent experimental approaches, a large body of data has recently accumulated that indicates that the I domains are independent, autonomously folding domains capable of directly binding ligands that play a necessary and important role in ligand binding by the intact integrins. Recent crystallographic studies have elucidated the structures of recombinant α _M and α _L I domains and also delineated a novel divalent cation-binding motif within the I domains (metal ion-dependent adhesion site, MIDAS) that appears to mediate the divalent cation binding of the I domains and the I domain-containing integrins to their ligands.     

Mid-anaphase arrest in S. cerevisiae cells eliminated for the function of Cin8 and dynein

S. cerevisiae anaphase spindle elongation is accomplished by the overlapping function of dynein and the kinesin-5 motor proteins, Cin8 and Kip1. Cin8 and dynein are synthetically lethal, yet the arrest phenotypes of cells eliminated for their function had not been identified. We found that at a non-permissive temperature, dyn1Δ cells that carry a temperature-sensitive cin8 – 3 mutation arrest at mid-anaphase with a unique phenotype, which we named TAN (two microtubule asters in one nucleus). These cells enter anaphase, but fail to proceed through the slow phase of anaphase B. At a permissive temperature, dyn1Δ, cin8 – 3 or dyn1Δcin8 – 3 cells exhibit perturbed spindle midzone morphologies, with dyn1Δcin8 – 3 anaphase spindles also being profoundly bent and nonrigid. Sorbitol, which has been suggested to stabilize microtubules, corrects these defects and suppresses the TAN phenotype. We conclude that dynein and Cin8 cooperate in anaphase midzone organization and influence microtubule dynamics, thus enabling progression through the slow phase of anaphase B. Received 10 August 2008; received after revision 22 October 2008; accepted 27 October 2008     

Über das Problem der Welkekrankheiten bei Pflanzen

Summary Lycomarasmin is a plasma poison produced byFusarium lycopersici Sacc., the pathogen of tomato wilt. In a dilution of 10^–2 and 10^–3 mol it causes a pathological wilting of tomato plants and usually disturbs their water balance; in a dilution of 10^–4 mol it only disturbs the latter.In the present paper, we develop the theory that in sufficient concentration lycomariasmin damages or destroys thesemipermeability of the plasma boundary layer.In a dilution of 10^–2 and 10^–3 mol of lycomarasmin the semipermeability of the plasma membranes iscompletely destroyed. Thus on the one hand the conditions for osmotic pressure disappear and irreversible pathological wilting appears, and on the other hand cellular fluid passes into the transpiration current of the cell-membrane and leads to a momentary excess humidity, particularly in the leaf-tissues, and thus also to a momentaryexcess transpiration.The water-deficit regularly observed in wilt-literature is therefore not the cause of pathological wilting but, just as the wilting itself, a consequence of the distruction of the semipermeability of the plasma boundary layer.In a dilution of 10^–4 mol lycomarasmin apparently only affects the permeability of the exterior plasma boundary layer forwater, but not for sugars etc. Therefore it only produces an excess of fluid in the leaf tissues and thus an excess transpiration, but no definite inactivation of the plasma membrane and therefore also no pathological wilt.     

Die symmetrische Kugelzone als extremaler Rotationskörper

Summary For a convex body in three dimensions letV be the volume,F the surface area, andM the total mean curvature.TheBrunn-Minkowski theory gives the following well-known result: Among all the convex bodies withV andF fixed the spherical cap-body gives the maximum ofM.—The question regarding the minimum ofM has not yet been solved for the general case.—The authors prove that the minimum ofM is given by the symmetrical spherical zone, if we restrict our investigation to bodies of revolution.     

Signal regulation by family conspiracy

The signal regulating proteins (SIRPs) are a family of ubiquitously expressed transmembrane glycoproteins composed of two subgroups: SIRPα and SIRPβ, containing more than ten members. SIRPα has been shown to inhibit signalling through a variety of receptors including receptor tyrosine kinases and cytokine receptors. This function involves protein tyrosine kinases and is dependent on immunoreceptor tyrosine-based inhibition motifs which recruit key protein tyrosine phosphatases to the membrane. Negative regulation by SIRPα may also involve its ligand, CD47, in a bi-directional signalling mechanism. The SIRPβ subtype has no cytoplasmic domain but instead associates with at least one other transmembrane protein (DAP-12, or KARAP). DAP-12 possesses immunoreceptor tyrosine-based activation motifs within its cytoplasmic domain that are thought to link SIRPβ to activating machinery. SIRPα and SIRPβ thus have complementary roles in signal regulation and may conspire to tune the response to a stimulus. Received 6 July 2000; revised 2 August 2000; accepted 5 August 2000     

Beeinflussung der ATPase aminspeichernder Granula von Nebennierenmark und Milznerven durch Thallium

Summary ATPases of the amine storing granules from bovine adrenal medulla and splenic nerves are inhibited by Tl⁺⁺⁺ 3×10^–5 and 5×10^–6 M, respectively. Tl⁺ up to 10^–3 M is ineffective. By T1⁺⁺⁺ in concentrations of 10^–4 M or more, proteins are precipitated, so that the enzyme inhibiton by these concentrations is unspecific. If T1⁺ is oxidized to Tl⁺⁺⁺ in the organism, the inhibition of granular ATPase may be responsible for the alterations of the catecholamine metabolism observed in thallium intoxication.     

The cephalopod heart: The evolution of a high-performance invertebrate pump

Cephalopods typically have high metabolic rates. They have blood in which the oxygen carrier is haemocyanin, a pigment that is found only in solution and which never seems to be present in concentrations that will transport more than 4–5 vols % of oxygen. Their hearts must in consequence have very high cardiac outputs. In this account the performance of the heart ofNautilus, the only surviving ectocochleate, is contrasted with the performance of the hearts of coleoids,Octopus which has a relatively low metabolic rate (for a coleoid) and squids which have very high oxygen uptakes by any standards. In all these animals, heartbeat frequency is temperature-dependent and the additional oxygen demand in exercise is met very largely by a 2–3-fold increase in stroke volume. With the exception ofNautilus, cephalopods tend to utilise nearly all of the oxygen transported in the blood even at rest; they show very limited factorial scopes. Specific power output has, however, increased dramatically from 2.7 mWg^–1 in an activeNautilus to 5.5 mWg^–1 inOctopus and up to 20 or 30 mWg^–1 in species ofLoligo. The increase is almost entirely due to a 10-fold increase in heartbeat frequency. It is argued that frequency cannot be used as a means of responding to extra demand in an animal that must also carry automatic compensation for changes in metabolic rate dependent upon the ambient temperature, and that the use of frequency in some squid may be associated with a reduced temperature tolerance. Cephalopod systemic hearts do not scale directly with body mass, like the hearts of fish and the higher vertebrates. Smaller cephalopods have relatively larger hearts (as Mass^0.9). A typical 100-g coleoid would have a heart mass of 0.15 g. Oegopsid squids appear to be exceptional with hearts twice as large.     

A newTrichoplusia ni antennal receptor neuron that responds to attomolar concentrations of a minor pheromone component

Summary A newly discovered third class of sensillum trichodea on the antenna ofTrichoplusia ni contains an olfactory receptor neuron that responds to (Z)-9-tetradecen-1-ol acetate at 1×10^–18 M. The threshold of this neuron is 100–1000 times lower than the thresholds of two previously described pheromone-sensitive neurons that detect (Z)-7-dodecen-1-ol acetate and (Z)-7-tetradecen-1-ol acetate. The sensitivity and selectivity of this receptor neuron is evidence that (Z)-9-tetradecen-1-ol acetate may be important for sexual behavior.