The 'Spectraplakins': cytoskeletal giants with characteristics of both spectrin and plakin families

Recent studies have characterised a family of giant cytoskeletal crosslinkers encoded by the short stop gene in Drosophila and the dystonin/BPAG1 and MACF1 genes in mammals. We refer to the products of these genes as spectraplakins to highlight the fact that they share features with both the spectrin and plakin superfamilies. These genes produce a variety of large proteins, up to almost 9000 residues long, which can potentially extend 0.4 µm across a cell. Spectraplakins can interact with all three elements of the cytoskeleton: actin, microtubules and intermediate filaments. The analysis of mutant phenotypes in BPAG1 in mouse and short stop in Drosophila demonstrates that spectraplakins have diverse roles. These include linking the plasma membrane and the cytoskeleton, linking together different elements of the cytoskeleton and organising membrane domains.Katja Röper, Stephen L. Gregory and Nicholas H. Brow

Eliminating Ditransitives

Abstract. We discuss how higher arity verbs such as give or promise can be treated in an algebraic framework that admits only unary and binary relations and does not rely on event variables

Inconsistent boundaries

Research on this paper was supported by a grant from the Marsden Fund, Royal Society of New Zealand.Mereotopology is a theory of connected parts. The existence of boundaries, as parts of everyday objects, is basic to any such theory; but in classical mereotopology, there is a problem: if boundaries exist, then either distinct entities cannot be in contact, or else space is not topologically connected (Varzi in Noûs 31:26–58, 1997). In this paper we urge that this problem can be met with a paraconsistent mereotopology, and sketch the details of one such approach. The resulting theory focuses attention on the role of empty parts, in delivering a balanced and bounded metaphysics of naive space.PostprintPeer reviewe

Interval temporal logic model checking: The border between good and bad HS fragments

The model checking problem has thoroughly been explored in the context of standard point-based temporal logics, such as LTL, CTL, and CTL 17, whereas model checking for interval temporal logics has been brought to the attention only very recently. In this paper, we prove that the model checking problem for the logic of Allen\u2019s relations started-by and finished-by is highly intractable, as it can be proved to be EXPSPACE-hard. Such a lower bound immediately propagates to the full Halpern and Shoham\u2019s modal logic of time intervals (HS). In contrast, we show that other noteworthy HS fragments, namely, Propositional Neighbourhood Logic extended with modalities for the Allen relation starts (resp., finishes) and its inverse started-by (resp., finished-by), turn out to have\u2014maybe unexpectedly\u2014the same complexity as LTL (i.e., they are PSPACE-complete), thus joining the group of other already studied, well-behaved albeit less expressive, HS fragments

The human channel gating–modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome–like phenotype in mice

Germline de novo missense variants of the CACNA1D gene, encoding the pore-forming α1 subunit of Cav1.3 L-type Ca2+ channels (LTCCs), have been found in patients with neurodevelopmental and endocrine dysfunction, but their disease-causing potential is unproven. These variants alter channel gating, enabling enhanced Cav1.3 activity, suggesting Cav1.3 inhibition as a potential therapeutic option. Here we provide proof of the disease-causing nature of such gating-modifying CACNA1D variants using mice (Cav1.3AG) containing the A749G variant reported de novo in a patient with autism spectrum disorder (ASD) and intellectual impairment. In heterozygous mutants, native LTCC currents in adrenal chromaffin cells exhibited gating changes as predicted from heterologous expression. The A749G mutation induced aberrant excitability of dorsomedial striatum–projecting substantia nigra dopamine neurons and medium spiny neurons in the dorsal striatum. The phenotype observed in heterozygous mutants reproduced many of the abnormalities described within the human disease spectrum, including developmental delay, social deficit, and pronounced hyperactivity without major changes in gross neuroanatomy. Despite an approximately 7-fold higher sensitivity of A749G-containing channels to the LTCC inhibitor isradipine, oral pretreatment over 2 days did not rescue the hyperlocomotion. Cav1.3AG mice confirm the pathogenicity of the A749G variant and point toward a pathogenetic role of altered signaling in the dopamine midbrain system

Novel experimental setup for megahertz X-ray diffraction in a diamond anvil cell at the High Energy Density (HED) instrument of the European X-ray Free-Electron Laser (EuXFEL)

The high-precision X-ray diffraction setup for work with diamond anvil cells (DACs) in interaction chamber 2 (IC2) of the High Energy Density instrument of the European X-ray Free-Electron Laser is described. This includes beamline optics, sample positioning and detector systems located in the multipurpose vacuum chamber. Concepts for pump-probe X-ray diffraction experiments in the DAC are described and their implementation demonstrated during the First User Community Assisted Commissioning experiment. X-ray heating and diffraction of Bi under pressure, obtained using 20 fs X-ray pulses at 17.8 keV and 2.2 MHz repetition, is illustrated through splitting of diffraction peaks, and interpreted employing finite element modeling of the sample chamber in the DAC

Fragmentation and Multifragmentation of 10.6A GeV Gold Nuclei

We present the results of a study performed on the interactions of 10.6A GeV gold nuclei in nuclear emulsions. In a minimum bias sample of 1311 interac- tions, 5260 helium nuclei and 2622 heavy fragments were observed as Au projec- tile fragments. The experimental data are analyzed with particular emphasis of target separation interactions in emulsions and study of criticalexponents. Multiplicity distributions of the fast-moving projectile fragments are inves- tigated. Charged fragment moments, conditional moments as well as two and three -body asymmetries of the fast moving projectile particles are determined in terms of the total charge remaining bound in the multiply charged projectile fragments. Some differences in the average yields of helium nuclei and heavier fragments are observed, which may be attributed to a target effect. However, two and three-body asymmetries and conditional moments indicate that the breakup mechanism of the projectile seems to be independent of target mass. We looked for evidence of critical point observable in finite nuclei by study the resulting charged fragments distributions. We have obtained the values for the critical exponents gamma, beta and tau and compare our results with those at lower energy experiment (1.0A GeV data). The values suggest that a phase transition like behavior, is observed.Comment: latex, revtex, 28 pages, 12 figures, 3tables, submitted to Europysics Journal

Nominalization and Alternations in Biomedical Language

Background: This paper presents data on alternations in the argument structure of common domain-specific verbs and their associated verbal nominalizations in the PennBioIE corpus. Alternation is the term in theoretical linguistics for variations in the surface syntactic form of verbs, e.g. the different forms of stimulate in FSH stimulates follicular development and follicular development is stimulated by FSH. The data is used to assess the implications of alternations for biomedical text mining systems and to test the fit of the sublanguage model to biomedical texts. Methodology/Principal Findings: We examined 1,872 tokens of the ten most common domain-specific verbs or their zerorelated nouns in the PennBioIE corpus and labelled them for the presence or absence of three alternations. We then annotated the arguments of 746 tokens of the nominalizations related to these verbs and counted alternations related to the presence or absence of arguments and to the syntactic position of non-absent arguments. We found that alternations are quite common both for verbs and for nominalizations. We also found a previously undescribed alternation involving an adjectival present participle. Conclusions/Significance: We found that even in this semantically restricted domain, alternations are quite common, and alternations involving nominalizations are exceptionally diverse. Nonetheless, the sublanguage model applies to biomedica

Sex-specific disruption of murine midbrain astrocytic and dopaminergic developmental trajectories following antenatal GC treatment

The mammalian midbrain dopaminergic systems arising in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) are critical for coping behaviours and are implicated in neuropsychiatric disorders where early life challenges comprise significant risk factors. Here, we aimed to advance our hypothesis that glucocorticoids (GCs), recognised key players in neurobiological programming, target development within these systems, with a novel focus on the astrocytic population. Mice received antenatal GC treatment (AGT) by including the synthetic GC, dexamethasone, in the mothers' drinking water on gestational days 16-19; controls received normal drinking water. Analyses of regional shapes and volumes of the adult SNc and VTA demonstrated that AGT induced long-term, dose-dependent, structural changes that were accompanied by profound effects on astrocytes (doubling/tripling of numbers and/or density). Additionally, AGT induced long-term changes in the population size and distribution of SNc/VTA dopaminergic neurons, confirming and extending our previous observations made in rats. Furthermore, glial/neuronal structural remodelling was sexually dimorphic and depended on the AGT dose and sub-region of the SNc/VTA. Investigations within the neonatal brain revealed that these long-term organisational effects of AGT depend, at least in part, on targeting perinatal processes that determine astrocyte density and programmed cell death in dopaminergic neurons. Collectively, our characterisation of enduring, AGT-induced, sex-specific cytoarchitectural disturbances suggests novel mechanistic links for the strong association between early environmental challenge (inappropriate exposure to excess GCs) and vulnerability to developing aberrant behaviours in later life, with translational implications for dopamine-associated disorders (such as schizophrenia, ADHD, autism, depression), which typically show a sex bia