The SLC3 and SLC7 families of amino acid transporters

Amino acids are necessary for all living cells and organisms. Specialized transporters mediate the transfer of amino acids across plasma membranes. Malfunction of these proteins can affect whole-body homoeostasis giving raise to diverse human diseases. Here, we review the main features of the SLC3 and SLC7 families of amino acid transporters. The SLC7 family is divided into two subfamilies, the cationic amino acid transporters (CATs), and the L-type amino acid transporters (LATs). The latter are the light or catalytic subunits of the heteromeric amino acid transporters (HATs), which are associated by a disulfide bridge with the heavy subunits 4F2hc or rBAT. These two subunits are glycoproteins and form the SLC3 family. Most CAT subfamily members were functionally characterized and shown to function as facilitated diffusers mediating the entry and efflux of cationic amino acids. In certain cells, CATs play an important role in the delivery of L-arginine for the synthesis of nitric oxide. HATs are mostly exchangers with a broad spectrum of substrates and are crucial in renal and intestinal re-absorption and cell redox balance. Furthermore, the role of the HAT 4F2hc/LAT1 in tumor growth and the application of LAT1 inhibitors and PET tracers for reduction of tumor progression and imaging of tumors are discussed. Finally, we describe the link between specific mutations in HATs and the primary inherited aminoacidurias, cystinuria and lysinuric protein intolerance.

Transient Neonatal Zinc Deficiency Caused by a Heterozygous G87R Mutation in the Zinc Transporter ZnT-2 (SLC30A2) Gene in the Mother Highlighting the Importance of Zn (2+) for Normal Growth and Development

Suboptimal dietary zinc (Zn(2+)) intake is increasingly appreciated as an important public health issue. Zn(2+) is an essential mineral, and infants are particularly vulnerable to Zn(2+) deficiency, as they require large amounts of Zn(2+) for their normal growth and development. Although term infants are born with an important hepatic Zn(2+) storage, adequate Zn(2+) nutrition of infants mostly depends on breast milk or formula feeding, which contains an adequate amount of Zn(2+) to meet the infants' requirements. An exclusively breast-fed 6 months old infant suffering from Zn(2+) deficiency caused by an autosomal dominant negative G87R mutation in the Slc30a2 gene (encoding for the zinc transporter 2 (ZnT-2)) in the mother is reported. More than 20 zinc transporters characterized up to date, classified into two families (Slc30a/ZnT and Slc39a/Zip), reflect the complexity and importance of maintaining cellular Zn(2+) homeostasis and dynamics. The role of ZnTs is to reduce intracellular Zn(2+) by transporting it from the cytoplasm into various intracellular organelles and by moving Zn(2+) into extracellular space. Zips increase intracellular Zn(2+) by transporting it in the opposite direction. Thus the coordinated action of both is essential for the maintenance of Zn(2+) homeostasis in the cytoplasm, and accumulating evidence suggests that this is also true for the secretory pathway of growth hormone.

Congenital factor XIII deficiency in Pakistan: characterization of seven families and identification of four novel mutations

Deficiency of coagulation factor XIII (FXIII) belongs to the rare bleeding disorders and its incidence is higher in populations with consanguineous marriages. The aims of this study were to characterize patients and relatives from seven families with suspected FXIII deficiency from Pakistan and to identify the underlying mutations. As a first indicator of FXIII deficiency, a 5M urea clot solubility test was used. Plasma FXIII A- and B-subunit antigen levels were determined by ELISA. FXIII activity was measured with an incorporation assay. Sequencing of all exons and intron/exon boundaries of F13A was performed, and a novel splice site defect was confirmed by RT-PCR analysis. Genetic analysis revealed six different mutations in the F13A gene. Two splice site mutations were detected, a novel c.1460+1G>A mutation in the first nucleotide of intron 11 and a previously reported c.2045G>A mutation in the last nucleotide of exon 14. Neither of them was expressed at protein level. A novel nonsense mutation in exon 4, c.567T>A, p.Cys188X, was identified, leading in homozygous form to severe FXIII deficiency. Two novel missense mutations were found in exons 8 and 9, c.1040C>A, p.Ala346Asp and c.1126T>C, p.Trp375Arg, and a previously reported missense mutation in exon 10, c.1241C>T, p.Ser413Leu. All patients homozygous for these missense mutations presented with severe FXIII deficiency. We have analysed a cohort of 27 individuals and reported four novel mutations leading to congenital FXIII deficiency.

What constitutes vulnerable self-esteem? Comparing the prospective effects of low, unstable, and contingent self-esteem on depressive symptoms

A growing body of longitudinal studies suggests that low self-esteem is a risk factor for depression. However, it is unclear whether other characteristics of self-esteem, besides its level, explain incremental or even greater variance in subsequent depression. We examined the prospective effects of self-esteem level, instability (i.e., the degree of variability in self-esteem across short periods), and contingency (i.e., the degree to which self-esteem fluctuates in response to self-relevant events) on depressive symptoms in 1 overarching model, using data from 2 longitudinal studies. In Study 1, 372 adults were assessed at 2 waves over 6 months, including 40 daily diary assessments at Wave 1. In Study 2, 235 young adults were assessed at 2 waves over 6 weeks, including about 6 daily diary assessments at each wave. Self-esteem contingency was measured by self-report and by a statistical index based on the diary data (capturing event-related fluctuations in self-esteem). In both studies self-esteem level, but not self-esteem contingency, predicted subsequent depressive symptoms. Self-esteem instability predicted subsequent depressive symptoms in Study 2 only, with a smaller effect size than self-esteem level. Also, level, instability, and contingency of self-esteem did not interact in the prediction of depressive symptoms. Moreover, the effect of self-esteem level held when controlling for neuroticism and for all other Big Five personality traits. Thus, the findings provide converging evidence for a vulnerability effect of self-esteem level, tentative evidence for a smaller vulnerability effect of self-esteem instability, and no evidence for a vulnerability effect of self-esteem contingency.

On restricted families of projections in ℝ3

We study projections onto non-degenerate one-dimensional families of lines and planes in R 3 . Using the classical potential theoretic approach of R. Kaufman, one can show that the Hausdorff dimension of at most 12 -dimensional sets [Math Processing Error] is typically preserved under one-dimensional families of projections onto lines. We improve the result by an ε , proving that if [Math Processing Error], then the packing dimension of the projections is almost surely at least [Math Processing Error]. For projections onto planes, we obtain a similar bound, with the threshold 12 replaced by 1 . In the special case of self-similar sets [Math Processing Error] without rotations, we obtain a full Marstrand-type projection theorem for 1-parameter families of projections onto lines. The [Math Processing Error] case of the result follows from recent work of M. Hochman, but the [Math Processing Error] part is new: with this assumption, we prove that the projections have positive length almost surely.

Evaluation of three different families of bombesin receptor radioantagonists for targeted imaging and therapy of gastrin releasing peptide receptor (GRP-R) positive tumors.

Two new classes of radiolabeled GRP receptor antagonists are studied and compared with the well-established statine-based receptor antagonist DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (RM2, 1; DOTA:1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; Sta:(3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid). The bombesin-based pseudopeptide DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leuψ(CHOH-CH2)-(CH2)2-CH3 (RM7, 2), and the methyl ester DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-OCH3 (ARBA05, 3) analogues are labeled with (111)In and evaluated in vitro in PC-3 cell line and in vivo in PC-3 tumor-bearing nude mice. Antagonist potency was assessed by immunofluorescence-based receptor internalization and Ca(2+) mobilization assays. The conjugates showed good binding affinity, the IC50 value of 2 (3.2 ± 1.8 nM) being 2 and 10 times lower than 1 and 3. Compared to (111)In-1, (111)In-2 showed higher uptake in target tissues such as pancreas (1.5 ± 0.5%IA/g and 39.8 ± 9.3%IA/g at 4 h, respectively), whereas the compounds had similar tumor uptake (11.5 ± 2.4%IA/g and 11.8 ± 3.9%IA/g at 4h, respectively). The displacement of the radioligand in vivo was different in different receptor positive organs and depended on the displacing peptide.

Variation in life-history traits and their plasticities to elevational transplantation among seed families suggests potential for adaptative evolution of 15 tropical plant species to climate change

• Premise of the study: Because not all plant species will be able to move in response to global warming, adaptive evolution matters largely for plant persistence. As prerequisites for adaptive evolution, genetic variation in and selection on phenotypic traits are needed, but these aspects have not been studied in tropical species. We studied how plants respond to transplantation to different elevations on Mt. Kilimanjaro, Tanzania, and whether there is quantitative genetic (among-seed family) variation in and selection on life-history traits and their phenotypic plasticity to the different environments. • Methods: We reciprocally transplanted seed families of 15 common tropical, herbaceous species of the montane and savanna vegetation zone at Mt. Kilimanjaro to a watered experimental garden in the montane (1450 m) and in the savanna (880 m) zone at the mountain’s slope and measured performance, reproductive, and phenological traits. • Results: Plants generally performed worse in the savanna garden, indicating that the savanna climate was more stressful and thus that plants may suffer from future climate warming. We found significant quantitative genetic variation in all measured performance and reproductive traits in both gardens and for several measures of phenotypic plasticity in response to elevational transplantation. Moreover, we found positive selection on traits at low and intermediate trait values levelling to neutral or negative selection at high values. • Conclusions: We conclude that common plants at Mt. Kilimanjaro express quantitative genetic variation in fitness-relevant traits and in their plasticities, suggesting potential to adapt evolutionarily to future climate warming and increased temperature variability.

The Vulnerable Text. Verwundbarkeit als textuelles Phänomen in Wolframs ›Parzival‹

Intertextuality imposes vulnerability – unter diesem Motto entwickelt der Renaissance-Forscher Thomas M. Greene die These, dass Texte im Zuge von Prozessen der Übertragung und Aneignung ‚verwundbar’ werden (Thomas M. Greene, The vulnerable text, New York 1986). Die so verstandene ‚Verwundbarkeit’ sei insbesondere ein Symptom vormoderner Textualität, die Texte zumeist ‚aus zweiter Hand’ produziere und den Begriff der ‚Originalität’ noch nicht kenne: „Part of the text’s vulnerability lies in its dependence on second hand signifiers, a vulnerability aggravated in a culture which does not yet fetishize originality.“ Während Greenes Ansatz in der Altgermanistik bereits im Hinblick auf die zwischen der Eigengesetzlichkeit vormoderner Texte und deren philologischer Erschließung bestehende Spannung zur Anwendung gebracht und problematisiert wurde (so von Christian Kiening für den ›Ackermann‹: Schwierige Modernität, Tübingen 1998), harrt er in Bezug auf das Verständnis von Intertextualität noch der altgermanistischen Auseinandersetzung. Diese versucht der eingereichte Vorschlag mit einem Fallbeispiel in Gang zu bringen. Als Textgrundlage werden Chrétiens ›Perceval ou le Conte du Graal‹ und dessen Aneignung durch Wolfram von Eschenbach gewählt, dies im Blick auf die Anfortas- und Sigune-Handlung (was es ermöglicht, den ›Titurel‹ mit einzubeziehen). Der Beitrag geht (im Anschluss an Jean Fourquet, Wolfram d’Eschenbach et le Conte del Graal, Paris 1938, 21966) davon aus, dass Wolfram die Bücher III bis VI des ›Parzival‹ (Jugendgeschichte bis zu Kundries Verfluchung wegen der unterlassenen Mitleidsfrage) nach einer handschriftlichen Vorlage des französischen Textes gestaltete, die ihm nach Abschluss dieses Teils abhanden kam. Für die Anfertigung der übrigen Bücher dürfte Wolfram eine anders geartete handschriftliche Vorlage zur Verfügung gehabt haben, was zur Überarbeitung eines bereits in Umlauf befindlichen deutschsprachigen Textes führte, die sich noch in Fassungsvarianten der Überlieferung wiederspiegelt. Aufgrund veränderter intertextueller Relationen wird also Wolframs eigener Text im Zuge der Redaktion ‚verwundbar’. Dieser Sachverhalt soll an Varianzen der Anfortas-Handlung aufgezeigt werden, wie sie insbesondere zwischen Buch V (Parzivals erster Besuch auf der Gralburg) und Buch IX (Parzivals Aufklärung durch den Einsiedler Trevrizent) fassbar werden. Der wunde Anfortas kann dabei auf Handlungsebene als Prototyp der Verletzbarkeit schlechthin gelten – einer Verletzbarkeit, die mit jener des Textes interagiert. Mit in diese Perspektive einbezogen werden sollen Elemente der Sigune-Handlung. Der Vorlagenwechsel veranlasst Wolfram auch im Hinblick auf den Kampfestod von Sigunes Geliebtem Schionatulander (bei Chrétien sind beide Figuren namenlos) zu den erwähnten Adaptationen und hat wohl seinerseits die Entstehung des ›Titurel‹ motiviert, wo die Verletzbarkeit im Umgang mit textlichen ‚Vorlagen’ sogar thematisiert wird: Sigune zerschürft ihre Hände beim Versuch, das beschriftete Brackenseil zu behalten. Das Paradox der ›Titurel‹-Dichtung besteht dabei darin, dass die erwähnte Szene und die darin beschriebene Verwundbarkeit der Figur eine Vorlage thematisiert, die der Text selbst gerade nicht hat. Denn der ›Titurel‹ dürfte unabhängig von einer konkreten Quelle, wie sie Chrétiens ›Perceval‹ darstellt, entstanden sein und besitzt damit gerade jene ‚Originalität’, die Greene im Rahmen seines Konzepts von ‚vulnerabilty’ vormodernen Texten abspricht.

Collisional Formation and Modeling of Asteroid Families

In the last decade, thanks to the development of sophisticated numerical codes, major breakthroughs have been achieved in our understanding of the formation of asteroid families by catastrophic disruption of large parent bodies. In this review, we describe numerical simulations of asteroid collisions that reproduced the main properties of families, accounting for both the fragmentation of an asteroid at the time of impact and the subsequent gravitational interactions of the generated fragments. The simulations demonstrate that the catastrophic disruption of bodies larger than a few hundred meters in diameter leads to the formation of large aggregates due to gravitational reaccumulation of smaller fragments, which helps explain the presence of large members within asteroid families. Thus, for the first time, numerical simulations successfully reproduced the sizes and ejection velocities of members of representative families. Moreover, the simulations provide constraints on the family dynamical histories and on the possible internal structure of family members and their parent bodies.