Monogenic determinants of familial Alzheimer's disease: presenilin-2 mutations

Presenilin-2 (PS2) is one of three genes [amyloid precursor protein (APP), presenilin-1 (PS1) and PS2] shown to cause familial Alzheimer's disease (FAD), and is highly homologous to PS1. Currently demonstrated functions of PS2 include interactions with APP and Aβ, and participation in apoptotic pathways. PS2 FAD mutations influence APP processing in a manner predicted to promote amyloid formation and also enhance the proapoptotic effect of wild-type PS2. Other possible functions of PS2 are related to its homology to Notch pathway genes in Caenorhabditis elegans, suggesting it may have a developmental role. PS2-associated AD is the most reminiscent of the sporadic form of the disease in terms of older age of onset and longer disease duration. Since PS2 mutations are incompletely penetrant and age of onset in carriers is highly variable (40 – 88 years), elucidation of PS2 mechanisms may reveal factors which modify AD and are therapeutically relevant to sporadic AD.     

On the usefulness of macroeconomic forecasts as inputs to forecasting models

A forecasting model for y_t based on its relationship to exogenous variables (e.g. x?_t) must use x?_t, the forecast of x?_t. An example is given where commercially available x?_t's are sufficiently inaccurate that a univariate model for y_t appears preferable. For a variety of types of models inclusion of an exogenous variable x?_t is shown to worsen the y_t forecasts whenever x?_t must itself be forecast by x?_t and MSE (x?_t) > Var (x?_t). Tests with forecasts from a variety of sources indicate that, with a few notable exceptions, MSE (x?_t) > Var (x?_t) is common for macroeconomic forecasts more than a quarter or two ahead. Thus, either:

• (a) available medium range forecasts for many macroeconomic variables (e.g. the GNP growth rate) are not an improvement over the sample mean (so that such variables are not useful explanatory variables in forecasting models), and/or
• (b) the suboptimization involved in directly replacing x?_t by x?_t is a luxury that we cannot afford.

     

Beta-carotene affects gene expression in lungs of male and female <Emphasis Type="Italic">Bcmo1</Emphasis><Superscript>−/−</Superscript> mice in opposite directions

Molecular mechanisms triggered by high dietary beta-carotene (BC) intake in lung are largely unknown. We performed microarray gene expression analysis on lung tissue of BC supplemented beta-carotene 15,15′-monooxygenase 1 knockout (Bcmo1 ^−/−) mice, which are—like humans—able to accumulate BC. Our main observation was that the genes were regulated in an opposite direction in male and female Bcmo1 ^−/− mice by BC. The steroid biosynthetic pathway was overrepresented in BC-supplemented male Bcmo1 ^−/− mice. Testosterone levels were higher after BC supplementation only in Bcmo1 ^−/− mice, which had, unlike wild-type (Bcmo1 ^+/+) mice, large variations. We hypothesize that BC possibly affects hormone synthesis or metabolism. Since sex hormones influence lung cancer risk, these data might contribute to an explanation for the previously found increased lung cancer risk after BC supplementation (ATBC and CARET studies). Moreover, effects of BC may depend on the presence of frequent human BCMO1 polymorphisms, since these effects were not found in wild-type mice.     

RTA2 is involved in calcineurin-mediated azole resistance and sphingoid long-chain base release in Candida albicans

The calcineurin pathway has been reported to be essential for the development of azole resistance in Candida albicans. The depletion or ectopic over-expression of RTA2 increased or decreased susceptibility of C. albicans to azoles, respectively. CaCl₂- induced activation of the calcineurin pathway in wildtype C. albicans promoted resistance to azoles, while the Ca ²⁺ chelator (EGTA), calcineurin inhibitors (FK506 and cyclosporin A) and the deletion of RTA2 blocked the resistance-promoting effects of CaCl₂. Furthermore, we found that RTA2 was up-regulated in a calcineurin-dependent manner. The depletion of RTA2 also made the cell membrane of C. albicans liable to be destroyed by azoles and RTA2 over-expression attenuated the destroying effects. Finally, the disruption of RTA2 caused an increased accumulation of dihydrosphingosine (DHS), one of the two sphingolipid long-chain bases, by decreasing release of DHS. In conclusion, our findings suggest that RTA2 is involved in calcineurin-mediated azole resistance and sphingoid long-chain base release in C. albicans. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Received 14 July 2008; received after revision 29 August 2008; accepted 16 September 2008     

Kinetik der hepatischen Farbstoffaufnahme von Indocyaningrün. Einfluss von Bilirubin und Natriumglykocholat

Summary Kinetics of hepatic uptake of indocyanine green, a dye which is used for evaluation of liver function, were studied in the rat. The results indicate that the relationship between ICG-dose and initial hepatic dye uptake obeys Michaelis-Menten kinetics suggesting an interaction of the dye with a carrier or fixed site in the liver cell. Thus it was possible to calculate maximum ICG-uptake (v _max ) and the Michaelis constant (K _m ) of this transport system from several submaximal values.v _max was 7.65 (6-06-9.65)²² mg per 100 g liver/min and K _m 0.56 (0.31–0.81)²². Under the influence of substances which inhibit the elimination of dyes by the liver the parametersv _max and K _m showed changes which allowed characterization of the type of inhibition. While sodium glycocholate had no influence on maximum hepatic ICG-uptake and the Michaelis constant bilirubin caused a significant increase of K _m to 1.29 (0.68–1.90)²² without significantly changingv _max . These data suggest that bilirubin interferes with hepatic uptake of indocyanine green by competitive inhibition and that uptake of bile acids is dependent on a different mechanism.     

Explaining Leibniz equivalence as difference of non-inertial appearances: Dis-solution of the Hole Argument and physical individuation of point-events

“The last remnant of physical objectivity of space–time” is disclosed in the case of a continuous family of spatially non-compact models of general relativity (GR). The physical individuation of point-events is furnished by the autonomous degrees of freedom of the gravitational field (viz., the Dirac observables) which represent—as it were—the ontic part of the metric field. The physical role of the epistemic part (viz. the gauge variables) is likewise clarified as embodying the unavoidable non-inertial aspects of GR. At the end the philosophical import of the Hole Argument is substantially weakened and in fact the Argument itself dissolved, while a specific four-dimensional holistic and structuralist view of space–time (called point-structuralism) emerges, including elements common to the tradition of both substantivalism and relationism. The observables of our models undergo real temporal change: this gives new evidence to the fact that statements like the frozen-time character of evolution, as other ontological claims about GR, are model dependent.     

Biomedicine and diseases: the Klippel-Trenaunay syndrome, vascular anomalies and vascular morphogenesis

Vascular morphogenesis is a vital process for embryonic development, normal physiologic conditions (e.g. wound healing) and pathological processes (e.g. atherosclerosis, cancer). Genetic studies of vascular anomalies have led to identification of critical genes involved in vascular morphogenesis. A susceptibility gene, VG5Q (formally named AGGF1), was cloned for Klippel-Trenaunay syndrome (KTS). AGGF1 encodes a potent angiogenic factor, and KTS-associated mutations enhance angiogenic activity of AGGF1, defining ‘increased angiogenesis’ as one molecular mechanism for the pathogenesis of KTS. Similar studies have identified other genes involved in vascular anomalies as important genes for vascular morphogenesis, including TIE2, VEGFR-3, RASA1, KRIT1, MGC4607, PDCD10, glomulin, FOXC2, NEMO, SOX18, ENG, ACVRLK1, MADH4, NDP, TIMP3, Notch3, COL3A1 and PTEN. Future studies of vascular anomaly genes will provide insights into the molecular mechanisms for vascular morphogenesis, and may lead to the development of therapeutic strategies for treating these and other angiogenesis-related diseases, including coronary artery disease and cancer.Received 24 November 2004; received after revision 21 January 2005; accepted 2 March 2005     

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     

Furan fatty acid steryl esters from the marine spongeDictyonella incisa which show inflammatory activity

Summary Three new furan fatty acids, (9Z, 19Z)-3, 6-epoxyhexacosa-3,5,19-tetraenoic acid (1a), (8Z, 11Z, 14Z, 17Z)-3, 6-epoxyeicosa-3,5,8,11,14,17-hexaenoic acid (2a), and (8Z, 11Z, 14Z, 17E)-3, 6-epoxyeicosa-3,5,8,11,14,17-hexaenoic acid (3a), and a new polyunsaturated fatty acid (5Z, 8Z, 11Z, 14Z, 17E)-eicosa-5,8,11,14,17-pentaenoic acid (6a), present in the spongeDictyonella incisa as the respective steryl esters, have been isolated as methyl esters and their structures have been determined by spectral and chemical analysis. The furan fatty acid esters have shown a high inflammatory activity, which suggests their potential role as feeding deterrents.     

Die Synthese des Novobiocins

Summary The synthesis of the antibiotic novobiocin is described. First the essential carbohydrate, the 3-O-carbamoylnoviose was synthesized fromd-glucose. A number of steps (1–6) led to the 3,5,6-tri-O-benzyl-2-O-methyl-d-galactono--lactone (6) which is characterized by the correct array of carbon atoms inherent to the noviose. Further transformations (7–15) finally yielded the carbohydrate. The problem of glycosidation is discussed in some detail. Glycosidation of a suitable aglycon precursor (18) with 2,3-O-carbonyl--noviosyl-chloride (22) proved possible and led to the isolation of an-glycoside (23) which was further transformed (24–28) into novobiocin.

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Chemische Forschungsabteilung der F. Hoffmann-La Roche & Co. AG, Basel.

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Vortrag Dr.B. P. Vaterlaus, gehalten an der Gordon Research Conference on Steroids and other Natural Products, 16.–20. Juli 1962, New Hampton, N.H., USA, und vor der Basler Chemischen Gesellschaft, 8. November 1962. Im Auszug:H. Spiegelberg,Synthèse du 3-O-carbamoylnoviose, sucre de la novobiocine, Symposium international de chimie organique, Bruxelles, 15. Juni 1962;J. Kiss,The Synthesis of Noviose and Allied Compounds, Birkbeck College (Univ. London), 23. Oktober 1962. Der vorliegende Aufsatz ist Gegenstand von Detailpublikationen in den Helv. chim. Acta, in Vorbereitung (1963).     

The somatic chromosomes of 3 lizard species:Gekko gecko,Iguana iguana,andCrotaphytus collaris

Zusammenfassung Die somatischen Chromosomen der 3 EidechsenartenGekko gecko (2N=38),Iguana iguana (2N=34) undCrotophytus collaris (2N=36), werden dargestellt.G. gecko besitzt metazentrische, subteleozentrische und teleozentrische Elemente, aber keine Mikrochromosomen.I. iguana undC. collaris besitzen Makrochromosomen (6 Paare) und Mikrochromosomen. Bei den ArtenG. gecko undI. iguana waren in keinen von beiden Geschlechtern heteromorphische Chromosomenpaare nach zuweisen.

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Supported by Project No. 417 from the U.S. Children's Bureau and Grant No. 08737 from the National Cancer Institute.     

<Emphasis Type="Italic">LAPTM4A</Emphasis> interacts with <Emphasis Type="Italic">hOCT2</Emphasis> and regulates its endocytotic recruitment

Human organic cation transporter 2 (hOCT2) is involved in the transport of endogenous and exogenous organic cations mainly in cells of the kidney and the brain. Here, we focus on the regulation of hOCT2 by direct protein–protein interaction. Screening within a mating-based split-ubiquitin-yeast-two-hybrid system (mBSUS) revealed the lysosomal-associated protein transmembrane 4 alpha (LAPTM4A) as a potential interacting protein. Interaction of LAPTM4A and hOCT2 was confirmed by pulldown assays, FRET microscopy analysis and immunofluorescence microscopy. Functionally, overexpression of LAPTM4A significantly decreased ASP⁺ uptake in HEK293 cells stably transfected with hOCT2, suggesting a negative regulation of hOCT2-mediated transport. Furthermore, overexpression of LAPTM4A leads to a significantly decreased hOCT2 plasma membrane expression in surface biotinylation experiments. In addition, significant expression of LAPTM4A in human kidney was demonstrated by immunoblotting and immunofluorescence.     

Zur Stereochemie der Propandioldehydrase-Reaktion

Summary Propanedioldehydrase is shown to convert both (+)-(S)-2-²H-propanediol,3, and (–)-(R)-1-²H₂-propanediol,5, to specimens of deuterated propion-aldehyde, for which the (S)-configuration has been established. Thus, in the propanedioldehydrase reaction migration of hydrogen atoms from C–1 to C–2 always occurs with inversion of configuration.     

Redundant and unique roles of coronin proteins in <Emphasis Type="Italic">Dictyostelium</Emphasis>

Dictyostelium discoideum harbors a short (CRN12) and a long coronin (CRN7) composed of one and two beta-propellers, respectively. They are primarily present in the cell cortex and cells lacking CRN12 (corA ⁻) or CRN7 (corB ⁻) have defects in actin driven processes. We compared the characteristics of a mutant cell line (corA ⁻ /corB ⁻) lacking CRN12 and CRN7 with the single mutants focusing on cytokinesis, phagocytosis, chemotaxis and development. Cytokinesis, uptake of small particles, and developmental defects were not enhanced in the corA ⁻ /corB ⁻ strain as compared to the single mutants, whereas motility and phagocytosis of yeast particles were more severely impaired. It appears that although both proteins affect the same processes they do not act in a redundant manner. Rather, they often act antagonistically, which is in accordance with their proposed roles in the actin cytoskeleton where CRN12 acts in actin disassembly whereas CRN7 stabilizes actin filaments and protects them from disassembly.     

Semiparametric forecast intervals

Consider forecasting the economic variable Y_t+h with predictors X _t, where h is the forecast horizon. This paper introduces a semiparametric method that generates forecast intervals of Y_t+h| X _t from point forecast models. First, the point forecast model is estimated, thereby taking advantage of its predictive power. Then, nonparametric estimation of the conditional distribution function (CDF) of the forecast error conditional on X _t builds the rest of the forecast distribution around the point forecast, from which symmetric and minimum‐length forecast intervals for Y_t+h| X _t can be constructed. Under mild regularity conditions, asymptotic analysis shows that (1) regardless of the quality of the point forecast model (i.e., it may be misspecified), forecast quantiles are consistent and asymptotically normal; (2) minimum length forecast intervals are consistent. Proposals for bandwidth selection and dimension reduction are made. Three sets of simulations show that for reasonable point forecast models the method has significant advantages over two existing approaches to interval forecasting: one that requires the point forecast model to be correctly specified, and one that is based on fully nonparametric CDF estimate of Y_t+h| X _t. An application to exchange rate forecasting is presented. Copyright © 2010 John Wiley & Sons, Ltd.     

Caryotypes de quelques hybrides interspécifiques dePitymys (Mammalia,Rodentia)

Summary The Robertsonian polymorphism ofPitymys subterraneus involves only 1 pair of metacentric autosomes. The crosses of forms with 52, 53 and 54 chromosomes do not show any differences in their reproductive rate. So a single autosome trivalent does not affect the fecondity. Many hybrids have been obtained betweenP. subterraneus (2N=52 or 54) andP. multiplex (2N=48) with 50 or 51 chromosomes, respectively. Even with a heterogenous karyotype they are not entirely sterile. 2 progeny were produced from back-crosses. The 2 parental species seem to result from recent speciation. Only fecondation or embryogenesis occurs in crossingP. duodecimcostatus withP. subterraneus orP. multiplex. The chromosome complement of 1 hybrid embryo ofP. duodecimcostatus (2N=62)×P. multiplex (2N=48) has been studied showing 55 chromosomes.P. duodecimcostatus appears to belong to a more distant evolutionary group.     

Recombinant synthesis of mouse Zn3-β and Zn4-α metallothionein 1 domains and characterization of their cadmium(II) binding capacity

Genetic engineering, coupled with spectro scopic analyses, has enabled the metal binding proper ties of the α and β subunits of mouse metallothionein 1 (MT) to be characterized. A heterologous expression system in E.coli has led to high yields of their pure zinc-complexed forms. The cadmium(II) binding properties of recombinant Zn₄-αMT and Zn₃-βMT have been studied by electronic absorption and circular dichroism. The former binds Cd(II) identically to α fragments obtained from mammalian organs, showing that the recombinant polypeptide behaves like the na tive protein. Titration of Zn₃-βMT with CdCl₂ results in the formation of Cd₃-βMT. The addition of excess Cd(II) leads to Cd₄-βMT which, with the extra loading of Cd(II), unravels to give rise isodichroically to Cd₉-βMT. The effect of cadmium-displaced Zn(II) ions and excess Cd(II) above the full metal occupancy of three has been studied using Chelex-100. The Cd₃-βMT species is stable in the presence of this strong metal-chelating agent. Received 20 May 1997; received after revision 7 July 1997; accepted 9 July 1997     

Unstable genetic system inDrosophila melanogaster: I. Instability at theCinnabar locus

Summary A mutant strain containing acinnabar allele (cn ^rbr ,rojo brillante) is reported, that produces wild-type revertants at thecinnabar (cn) locus. Incn ^rbr /cn heterozygotes the rate of mutation is highly increased. The presence of a mutator agent acting premeiotically is indicated.D.L. Lindsley and E.H. Grell, Genetic variations ofDrosophila melanogaster. Carnegie Institution of Washington, Washington, 1968; Publication No. 627.