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A recent global meta‐analysis reported a decrease in terrestrial but increase in freshwater insect abundance and biomass (van Klink et al., Science 368, p. 417). The authors suggested that water quality has been improving, thereby challenging recent reports documenting drastic global declines in freshwater biodiversity. We raise two major concerns with the meta‐analysis and suggest that these account for the discrepancy with the declines reported elsewhere. First, total abundance and biomass alone are poor indicators of the status of freshwater insect assemblages, and the observed differences may well have been driven by the replacement of sensitive species with tolerant ones. Second, many of the datasets poorly represent global trends and reflect responses to local conditions or nonrandom site selection. We conclude that the results of the meta‐analysis should not be considered indicative of an overall improvement in the condition of freshwater ecosystems.
The causative/anticausative alternation has been the topic of much typological and theoretical discussion in the linguistic literature. This alternation is characterized by verbs with transitive and intransitive uses, such that the transitive use of a verb V means roughly "cause to Vintransitive" (see Levin 1993). The discussion revolves around two issues: the first one concerns the similarities and differences between the anticausative and the passive, and the second one concerns the derivational relationship, if any, between the transitive and intransitive variant. With respect to the second issue, a number of approaches have been developed. Judging the approach conceptually unsatisfactory, according to which each variant is assigned an independent lexical entry, it was concluded that the two variants have to be derivationally related. The question then is which one of the two is basic and where this derivation takes place in the grammar. Our contribution to this discussion is to argue against derivational approaches to the causative / anticausative alternation. We focus on the distribution of PPs related to external arguments (agent, causer, instrument, causing event) in passives and anticausatives of English, German and Greek and the set of verbs undergoing the causative/anticausative alternation in these languages. We argue that the crosslinguistic differences in these two domains provide evidence against both causativization and detransitivization analyses of the causative / anticausative alternation. We offer an approach to this alternation which builds on a syntactic decomposition of change of state verbs into a Voice and a CAUS component. Crosslinguistic variation in passives and anticausatives depends on properties of Voice and its combinations with CAUS and various types of roots.
It has often been noticed that one syntactic argument position can be realized by elements which seem to realize different thematic roles. This is notably the case with the external argument position of verbs of change of state which licenses volitional agents, instruments or natural forces/causers, showing the generality and abstractness of the external argument relation. (1) a. John broke the window (Agent) b. The hammer broke the window (Instrument) c. The storm broke the window (Causer) In order to capture this generality, Van Valin & Wilkins (1996) and Ramchand (2003) among others have proposed that the thematic role of the external argument position is in fact underspecified. The relevant notion is that of an effector (in Van Valin & Wilkins) or of an abstract causer/initiator (in Ramchand). In this paper we argue against a total underspecification of the external argument relation. While we agree that (1b) does not instantiate an instrument theta role in subject position, we argue that a complete underspecification of the external theta-position is not feasible, but that two types of external theta roles have to be distinguished, Agents and Causers. Our arguments are based on languages where Agents and Causers show morpho-syntactic independence (section 2.1) and the behavior of instrument subjects in English, Dutch, German and Greek (section 2.2 and 3). We show that instrument subjects are either Agent or Causer like. In section (4) we give an analysis how arguments realizing these thematic notions are introduced into syntax.
In this paper we compare the distribution of PPs introducing external arguments in nominalizations with PPs introducing external arguments in the verbal domain. We show that several mismatches exist between the behavior of PPs in nominalizations and PPs in the verbal domain. This leads us to suggest that while PPs in the verbal domain are licensed by functional structure alone, within the nominal domain, PPs can also be licensed via an interplay of the encyclopaedic meaning of the root involved and the properties of the preposition itself. This second mechanism kicks in in the absence of functional structure.
The transcription factor p63 is expressed as at least six different isoforms, of which two have been assigned critical biological roles within ectodermal development and skin stem cell biology on the one hand and supervision of the genetic stability of oocytes on the other hand. These two isoforms contain a C-terminal inhibitory domain that negatively regulates their transcriptional activity. This inhibitory domain contains two individual components: one that uses an internal binding mechanism to interact with and mask the transactivation domain and one that is based on sumoylation. We have carried out an extensive alanine scanning study to identify critical regions within the inhibitory domain. These experiments show that a stretch of ~13 amino acids is crucial for the binding function. Further, investigation of transcriptional activity and the intracellular level of mutants that cannot be sumoylated suggests that sumoylation reduces the concentration of p63. We therefore propose that the inhibitory function of the C-terminal domain is in part due to direct inhibition of the transcriptional activity of the protein and in part due to indirect inhibition by controlling the concentration of p63. Keywords: p63, transcriptional regulation, auto-inhibition, sumoylation
Nephronectin regulates atrioventricular canal differentiation via Bmp4-Has2 signaling in zebrafish
(2011)
The extracellular matrix is crucial for organogenesis. It is a complex and dynamic component that regulates cell behavior by modulating the activity, bioavailability and presentation of growth factors to cell surface receptors. Here, we determined the role of the extracellular matrix protein Nephronectin (Npnt) in heart development using the zebrafish model system. The vertebrate heart is formed as a linear tube in which myocardium and endocardium are separated by a layer of extracellular matrix termed the cardiac jelly. During heart development, the cardiac jelly swells at the atrioventricular (AV) canal, which precedes valve formation. Here, we show that Npnt expression correlates with this process. Morpholino-mediated knockdown of Npnt prevents proper valve leaflet formation and trabeculation and results in greater than 85% lethality at 7 days post-fertilization. The earliest observed phenotype is an extended tube-like structure at the AV boundary. In addition, the expression of myocardial genes involved in cardiac valve formation (cspg2, fibulin 1, tbx2b, bmp4) is expanded and endocardial cells along the extended tube-like structure exhibit characteristics of AV cells (has2, notch1b and Alcam expression, cuboidal cell shape). Inhibition of has2 in npnt morphants rescues the endocardial, but not the myocardial, expansion. By contrast, reduction of BMP signaling in npnt morphants reduces the ectopic expression of myocardial and endocardial AV markers. Taken together, our results identify Npnt as a novel upstream regulator of Bmp4-Has2 signaling that plays a crucial role in AV canal differentiation.
Die Idee photolabile Schutzgruppen zur temporären Inaktivierung von Biomolekülen zu verwenden, um deren Funktion dann in einem biologischen System präzise orts- und zeitaufgelöst wieder zu aktivieren und so biologische Prozesse genau steuern zu können, wurde erstmals Ende der 1970er Jahre von J. W. Engels und von J. F. Hoffman verfolgt. Seit diesen ersten Arbeiten im Bereich des „Cagings“ wurde in den vergangenen Jahrzehnten eine Vielzahl von Arbeiten auf diesem Gebiet veröffentlicht und mit nahezu alle wichtigen Klassen von Biomolekülen wurden Caging-Experimente durchgeführt. Das Caging von Nukleinsäuren ist noch ein recht neues Feld. Es gab aber aufgrund der Beteiligung von Nukleinsäuren an vielen zentralen zellulären Prozessen im letzten Jahrzehnt ein enorm gesteigertes Interesse an lichtinduzierbaren Nukleinsäuren, vornehmlich zur lichtgesteuertem Genregulation. Der Arbeitskreis von Prof. Heckel befasst sich unter anderem mit dem Caging von Nukleinsäuren, wobei die zentrale Strategie im Anbringen der photolabilen Schutzgruppen an den Nukleobasen besteht. Dies hat den Hintergrund, dass auf diese Art und Weise die Wechselwirkung mit anderen Strängen durch Störung der Watson-Crick-Basenpaarung verhindert werden kann. Die Watson-Crick-Basenpaarung ist das zentrale Element für die Funktionalität nahezu aller Nukleinsäure-vermittelter Prozesse. In den vergangenen Jahren konnte mit dieser Strategie unter anderem erfolgreich die Aktivität von siRNAs und Aptameren mit Licht kontrolliert werden. Alle vier Projekte, welche in dieser Arbeit verfolgt wurden, befassten sich mit dem Caging von Nukleinsäuren. ...
Aptamers that can be regulated with light allow precise control of protein activity in space and time and hence of biological function in general. In a previous study, we showed that the activity of the thrombin-binding aptamer HD1 can be turned off by irradiation using a light activatable "caged" intramolecular antisense-domain. However, the activity of the presented aptamer in its ON state was only mediocre. Here we studied the nature of this loss in activity in detail and found that switching from 5'- to 3'-extensions affords aptamers that are even more potent than the unmodified HD1. In particular we arrived at derivatives that are now more active than the aptamer NU172 that is currently in phase 2 clinical trials as an anticoagulant. As a result, we present light-regulatable aptamers with a superior activity in their ON state and an almost digital ON/OFF behavior upon irradiation.
Intrinsically disordered regions (IDRs) are essential for membrane receptor regulation but often remain unresolved in structural studies. TRPV4, a member of the TRP vanilloid channel family involved in thermo- and osmosensation, has a large N-terminal IDR of approximately 150 amino acids. With an integrated structural biology approach, we analyze the structural ensemble of the TRPV4 IDR and identify a network of regulatory elements that modulate channel activity in a hierarchical lipid-dependent manner through transient long-range interactions. A highly conserved autoinhibitory patch acts as a master regulator by competing with PIP2 binding to attenuate channel activity. Molecular dynamics simulations show that loss of the interaction between the PIP2-binding site and the membrane reduces the force exerted by the IDR on the structured core of TRPV4. This work demonstrates that IDR structural dynamics are coupled to TRPV4 activity and highlights the importance of IDRs for TRP channel function and regulation.