13 research outputs found
Anina from Mining for Coal to Mining for Ideas. A Possible Path for Regeneration / Anina, de la Mina de carbuni la Mina de idei. O posibilă renastere
No full textEntire Minimizers of Allen–Cahn Systems with Sub-Quadratic Potentials
No full textWe study entire minimizers of the Allen–Cahn systems. The specific feature of our systems are potentials having a finite number of global minima, with sub-quadratic behaviour locally near their minima. The corresponding formal Euler–Lagrange equations are supplemented with free boundaries. We do not study regularity issues but focus on qualitative aspects. We show the existence of entire solutions in an equivariant setting connecting the minima of W at infinity, thus modeling many coexisting phases, possessing free boundaries and minimizing energy in the symmetry class. We also present a very modest result of existence of free boundaries under no symmetry hypotheses. The existence of a free boundary can be related to the existence of a specific sub-quadratic feature, a dead core, whose size is also quantified. © 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature
The radial-hedgehog solution in Landau–de Gennes' theory for nematic liquid crystals
No full textWe study the radial-hedgehog solution in a three-dimensional spherical droplet, with homeotropic boundary conditions, within the Landau-de Gennes theory for nematic liquid crystals. The radial-hedgehog solution is a candidate for a global Landau-de Gennes minimiser in this model framework and is also a prototype configuration for studying isolated point defects in condensed matter physics. The static properties of the radial-hedgehog solution are governed by a non-linear singular ordinary differential equation. We study the analogies between Ginzburg-Landau vortices and the radial-hedgehog solution and demonstrate a Ginzburg-Landau limit for the Landau-de Gennes theory. We prove that the radial-hedgehog solution is not the global Landau-de Gennes minimiser for droplets of finite radius and sufficiently low temperatures and prove the stability of the radial-hedgehog solution in other parameter regimes. These results contain quantitative information about the effect of geometry and temperature on the properties of the radial-hedgehog solution and the associated biaxial instabilities. © Copyright Cambridge University Press 2011.This publication is based on work supported by Award No. KUK-C1-013-04, made by King Abdullah University of Science and Technology (KAUST) to the Oxford Centre for Collaborative Applied Mathematics. The author gratefully acknowledges stimulating discussions with Chong Luo, Valeriy Slastikov and Epifanio Virga. We thank Luc Nguyen and Arghir Zarnescu for helpful comments and suggestions on an earlier version
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DCAF12 Is Required For Synaptic Function and Plasticity at the Drosophila Neuromuscular Junction
No full textWe employed imaging, electrophysiological, and molecular techniques with the genetically tractable model organism Drosophila melanogaster to unravel fundamental biological and genetic underpinnings regulating synaptic function and plasticity. Using a forward genetic screen, we identified mutations in the Drosophila ortholog of a human WD40 repeat-containing protein termed DDB1 and CUL4 associated factor 12 (DCAF12). We show that DCAF12 likely serves as an adaptor protein for the DDB1-Cul4 E3 ubiquitin ligase complex by recruiting specific target proteins for ubiquitination. DCAF12 is expressed in neurons, muscles, and glia. In mitotically active cells such as muscles, DCAF12 is localized to nuclei and co-localizes in distinct foci with CUL4, suggesting that DCAF12 mediates a nuclear role for the CUL4 E3 ubiquitin ligase complex. In neurons, DCAF12 is localized to both cytoplasmic and nuclear compartments of motor neuron cell bodies, where it colocalizes with Cul4 in nuclei. DCAF12 is also expressed at the periactive zone of presynaptic terminals, but does not distinctly associate with DDB1 or Cul4 at this region. Evoked neurotransmitter release at larval NMJs is significantly reduced in DCAF12 mutants. These defects are rescued by presynaptic expression of wild-type DCAF12, demonstrating that DCAF12 is required presynaptically and serves as an important component of the machinery that facilitates evoked release. In addition, our studies show that DCAF12 is required for the differential expression of glutamate receptor subunits at the larval NMJ through transcriptional and post-translational mechanisms. GluRIID subunit mRNA levels and GluRIIA/C/D subunit protein levels are increased at DCAF12 mutant NMJs. Normal GluRIIA subunit levels can be restored by postsynaptic expression of wild-type DCAF12, but not with a truncated DCAF12 protein lacking a nuclear localization signal (∆NLS-DCAF12). Furthermore, DCAF12 overexpression in muscle nuclei reduces synaptic GluRIIA levels, an effect that can be suppressed by removing a copy of Cul4. These data strongly indicate that DCAF12 in muscle nuclei is required for GluRIIA expression and/or function in a Cul4-dependent manner. Moreover, homozygous DCAF12-GluRIIA double mutants show a strong synthetic lethality phenotype, providing further support for the hypothesis that GluRIIA directly or indirectly requires DCAF12. Mutations in glutamate receptors at larval NMJs trigger a retrograde trans-synaptic signal that leads to a compensatory increase in presynaptic release, which precisely restores the normal efficacy of synaptic transmission and muscle excitation. Reducing the gene dosage of DCAF12 by one gene copy suppresses the initiation and maintenance of GluRIIA-mediated synaptic homeostatic potentiation. This block of synaptic homeostatic potentiation can be rescued by presynaptic expression of DCAF12. In our studies, we determined that DCAF12 is critical for 3 distinct synaptic mechanisms: evoked neurotransmitter release, neurotransmitter reception by regulation of GluR subunit composition, and retrograde synaptic homeostatic signaling. Future research will strive to identify presynaptic and postsynaptic protein targets of DCAF12 and the Cul4 E3 ubiquitin ligase complex and the role of ubiquitination in regulating these synaptic processes.Release after 12-Apr-2019Originally embargoed until 12-Apr-2018; contacted by author / Grad College to extend through 12-Apr-2019; 26-Mar-2018, kimberl
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TDP-43 proteinopathy alters the ribosome association of multiple mRNAs including the glypican Dally-like protein (Dlp)/GPC6
No full textAmyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease in which 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP-43. Using tagged ribosome affinity purifications in Drosophila models of TDP-43 proteinopathy, we identified TDP-43 dependent translational alterations in motor neurons impacting the spliceosome, pentose phosphate and oxidative phosphorylation pathways. A subset of the mRNAs with altered ribosome association are also enriched in TDP-43 complexes suggesting that they may be direct targets. Among these, dlp mRNA, which encodes the glypican Dally like protein (Dlp)/GPC6, a wingless (Wg/Wnt) signaling regulator is insolubilized both in flies and patient tissues with TDP-43 pathology. While Dlp/GPC6 forms puncta in the Drosophila neuropil and ALS spinal cords, it is reduced at the neuromuscular synapse in flies suggesting compartment specific effects of TDP-43 proteinopathy. These findings together with genetic interaction data show that Dlp/GPC6 is a novel, physiologically relevant target of TDP-43 proteinopathy. © 2021, The Author(s).Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]
Peisajul industrial Anina: reprezentări şi interpretări patrimoniale
No full textThe present publication is focused on the case study of Anina (Romania), best known for its long tradition in mining activity, which influenced directly the settlement, the local community and its urban life, currently highly challenged by the mine closing in 2007. Colonized since 1773, the town was populated by Germans, Austrians, Czechs, Slovaks, and Romanians initially brought here for timber exploitation and, in a later phase, for coal mining. Although now it may seem to many a mere relic with no future, Anina includes 49 buildings and sites present on the List of Historical Monuments - a record number for the official recognition of the patrimonial value of the industrial legacy in Romanian context. Moreover, Anina is characterized by the juxtaposition of multiple identity elements from various eras, and is appreciated by locals for the quality of its natural elements - air, water and landscape. Therefore, already acknowledged for its patrimonial values, but lacking an intervention strategy, the publication tries to read and interpret for the larger audience - local community, local administration, local and national stakeholders - the (post)industrial landscape of Anina found in continuous transformation. Through the contribution of several Romanian and Italian specialists in the field of cultural heritage, industrial archaeology and industrial photography, the (post)industrial landscape of Anina is illustrated from the larger territorial scale to the more specific details of its technological legacy. In this manner, approaching all aspects of its tangible manifestation, the publication intends to create a common vocabulary for all actors involved in the local, but also national, initiatives that look into the destiny of the former industrial town. Moreover, for the first time in Romanian context, the publication brings forward the issue of industrial landscape as a live organism in need of being understood and approached in itself, emphasizing the importance of every single material testimony as component elements of the wider perspective. This aspect is further illustrated through a variety of photographic methods used for Anina’s industrial landscape recording during the interval 2014 – 2016, fixing in space and time a certain aspect of the town’s post-industrial transformation
Author Correction: Mutations disrupting neuritogenesis genes confer risk for cerebral palsy
No full textThe M1311V variant of ATP7A is associated with impaired trafficking and copper homeostasis in models of motor neuron disease
No full text© 2020 The Author(s) Disruption in copper homeostasis causes a number of cognitive and motor deficits. Wilson\u27s disease and Menkes disease are neurodevelopmental disorders resulting from mutations in the copper transporters ATP7A and ATP7B, with ATP7A mutations also causing occipital horn syndrome, and distal motor neuropathy. A 65 year old male presenting with brachial amyotrophic diplegia and diagnosed with amyotrophic lateral sclerosis (ALS) was found to harbor a p.Met1311Val (M1311V) substitution variant in ATP7A. ALS is a fatal neurodegenerative disease associated with progressive muscle weakness, synaptic deficits and degeneration of upper and lower motor neurons. To investigate the potential contribution of the ATP7AM1311V variant to neurodegeneration, we obtained and characterized both patient-derived fibroblasts and patient-derived induced pluripotent stem cells differentiated into motor neurons (iPSC-MNs), and compared them to control cell lines. We found reduced localization of ATP7AM1311V to the trans-Golgi network (TGN) at basal copper levels in patient-derived fibroblasts and iPSC-MNs. In addition, redistribution of ATP7AM1311V out of the TGN in response to increased extracellular copper was defective in patient fibroblasts. This manifested in enhanced intracellular copper accumulation and reduced survival of ATP7AM1311V fibroblasts. iPSC-MNs harboring the ATP7AM1311V variant showed decreased dendritic complexity, aberrant spontaneous firing, and decreased survival. Finally, expression of the ATP7AM1311V variant in Drosophila motor neurons resulted in motor deficits. Apilimod, a drug that targets vesicular transport and recently shown to enhance survival of C9orf72-ALS/FTD iPSC-MNs, also increased survival of ATP7AM1311V iPSC-MNs and reduced motor deficits in Drosophila expressing ATP7AM1311V. Taken together, these observations suggest that ATP7AM1311V negatively impacts its role as a copper transporter and impairs several aspects of motor neuron function and morphology
Global disparities in surgeons' workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study
No full text: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI
