Homeostatic active zone remodeling consolidates memories in the Drosophila mushroom body

Establishing a detailed understanding of how the distinct forms of synaptic plasticity spatio-temporally engage into the initial storage and subsequent consolidation of memories remains a fundamental challenge of neuroscience. In addition to the better understood postsynaptic plasticity, different forms of presynaptic plasticity are widely expressed in mammalian brains and apparently operate along Hebbian or homeostatic rules. Their behavioral relevance remains enigmatic, however. Lately, acute upregulation of active zone (AZ) scaffold protein BRP and release factor Unc13A via specific axonal transport factors were shown to mediate stable expression of presynaptic homeostatic plasticity (PHP) at Drosophila neuromuscular junctions (NMJs). We here demonstrate that AZ scaling processes are specifically needed for stable expression of both, NMJ PHP as well as aversive olfactory mid-term memory within intrinsic neurons of the Drosophila mushroom body (MB). We first demonstrate that AZ upscaling via BRP is specifically needed for expression but not induction of NMJ homeostatic plasticity, thus establishing a direct temporal plasticity sequence of molecularly distinct AZ remodeling steps. Notably, when we reduced BRP and associated transport factors in MB intrinsic neurons, short-term memory persisted but robust deficits in stable memory expression for a few hours after conditioning were observed. In contrast, AZ release site protein RIM-BP affecting PHP induction was additionally needed for successful formation of short-term memory. Taken together, our data establish a specific role of homeostatic presynaptic long-term plasticity for memory consolidation. Such homeostatic refinement processes might well be needed to successfully integrate and display synaptic engrams constituting intermediary term memories.

Unraveling the stepwise maturation of the yeast telomerase including a Cse1 and Mtr10 mediated quality control checkpoint

Telomerases elongate the ends of chromosomes required for cell immortality through their reverse transcriptase activity. By using the model organism Saccharomyces cerevisiae we defined the order in which the holoenzyme matures. First, a longer precursor of the telomerase RNA, TLC1 is transcribed and exported into the cytoplasm, where it associates with the protecting Sm-ring, the Est and the Pop proteins. This partly matured telomerase is re-imported into the nucleus via Mtr10 and a novel TLC1-import factor, the karyopherin Cse1. Remarkably, while mutations in all known transport factors result in short telomere ends, mutation in CSE1 leads to the amplification of Y′ elements in the terminal chromosome regions and thus elongated telomere ends. Cse1 does not only support TLC1 import, but also the Sm-ring stabilization on the RNA enableling Mtr10 contact and nuclear import. Thus, Sm-ring formation and import factor contact resembles a quality control step in the maturation process of the telomerase. The re-imported immature TLC1 is finally trimmed into the 1158 nucleotides long mature form via the nuclear exosome. TMG-capping of TLC1 finalizes maturation, leading to mature telomerase.

Concept and algorithm of justification of transport and logistics schemes for delivery of export-import dry cargo with participation of river transport of Russia

The article discusses the development of the transport of dry goods, including in containers, along the inland waterways of Russia. The authors presented the concept and algorithm of substantiating transport and logistics schemes for the delivery of export-import dry cargo with the participation of river transport, since it is here that justified and comprehensive state measures are needed to increase the role of this transport in cooperation with railway, road and sea modes of transport. Factors that negatively affect the functioning of river transport are described, topical transport and logistics schemes for the transport of dry cargo are proposed: through the Northern Sea Route or railway transport (Alternative - through Gibraltar and the Suez Canal); through the international transport corridor (ITC) «North-South»; the scheme of transportation of export-import dry cargo to the regions of Russia and vice versa "Western Europe - Russia." The conclusion contains a list of measures to develop further research.

Maturation and shuttling of the yeast telomerase RNP: assembling something new using recycled parts

As the limiting component of the budding yeast telomerase, the Tlc1 RNA must undergo multiple consecutive modifications and rigorous quality checks throughout its lifecycle. These steps will ensure that only correctly processed and matured molecules are assembled into telomerase complexes that subsequently act at telomeres. The complex pathway of Tlc1 RNA maturation, involving 5'- and 3'-end processing, stabilisation and assembly with the protein subunits, requires at least one nucleo-cytoplasmic passage. Furthermore, it appears that the pathway is tightly coordinated with the association of various and changing proteins, including the export factor Xpo1, the Mex67/Mtr2 complex, the Kap122 importin, the Sm7 ring and possibly the CBC and TREX-1 complexes. Although many of these maturation processes also affect other RNA species, the Tlc1 RNA exploits them in a new combination and, therefore, ultimately follows its own and unique pathway. In this review, we highlight recent new insights in maturation and subcellular shuttling of the budding yeast telomerase RNA and discuss how these events may be fine-tuned by the biochemical characteristics of the varying processing and transport factors as well as the final telomerase components. Finally, we indicate outstanding questions that we feel are important to be addressed for a complete understanding of the telomerase RNA lifecycle and that could have implications for the human telomerase as well.

Potential Impacts of Autonomous Vehicles on Urban Sprawl: A Comparison of Chinese and US Car-Oriented Adults

Autonomous vehicles (AVs) may significantly impact people’s choice of residential locations and spatial structures. The impact may vary across different countries, but few studies have focused on it. This study drew on China and the United States (US) as two cases to study car drivers’ knowledge of AVs and willingness to move farther if AVs were available by estimating ordered logistic regression models. The results showed that 42.3% of Chinese and 29.8% of US respondents were likely to consider moving farther away from the nearest city or the destination for the most frequent trip if they had an AV. The Chinese sample had less knowledge of AVs than the US sample, but they were more likely to consider a move. AVs may lead to a new round of urban sprawl, but the challenge may be greater for China. We captured the socio-economic and transport factors that affected this result.

Unraveling the stepwise maturation of the yeast telomerase

Telomerases elongate the ends of chromosomes required for cell immortality through their reverse transcriptase activity. By using the model organism Saccharomyces cerevisiae we defined the order in which the holoenzyme matures. First, a longer precursor of the telomerase RNA, TLC1 is transcribed and exported into the cytoplasm, where it associates with the protecting Sm-ring, the Est- and the Pop-proteins. This partly matured telomerase is re-import into the nucleus via Mtr10 and a novel TLC1-import factor, the karyopherin Cse1. Remarkably, while mutations in all known transport factors result in short telomere ends, mutation in CSE1 bypasses this defect and become Type I like survivors. Interestingly, both import receptors contact the Sm-ring for nuclear import, which therefore resembles a quality control step in the maturation process of the telomerase. The re-imported immature TLC1 is finally trimmed into the ~1150 nucleotide long mature form. TMG-capping of TLC1 finalizes maturation, leading to mature telomerase.

C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy

TAR DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), including cases caused by G4C2 repeat expansions in the C9orf72 gene (c9FTD/ALS). Providing mechanistic insight into the link between C9orf72 mutations and TDP-43 pathology, we demonstrated that a glycine-arginine repeat protein [poly(GR)] translated from expanded G4C2 repeats was sufficient to promote aggregation of endogenous TDP-43. In particular, toxic poly(GR) proteins mediated sequestration of full-length TDP-43 in an RNA-independent manner to induce cytoplasmic TDP-43 inclusion formation. Moreover, in GFP-(GR)200 mice, poly(GR) caused the mislocalization of nucleocytoplasmic transport factors and nuclear pore complex proteins. These mislocalization events resulted in the aberrant accumulation of endogenous TDP-43 in the cytoplasm where it co-aggregated with poly(GR). Last, we demonstrated that treating G4C2 repeat–expressing mice with repeat-targeting antisense oligonucleotides lowered poly(GR) burden, which was accompanied by reduced TDP-43 pathology and neurodegeneration, including lowering of plasma neurofilament light (NFL) concentration. These results contribute to clarification of the mechanism by which poly(GR) drives TDP-43 proteinopathy, confirm that G4C2-targeted therapeutics reduce TDP-43 pathology in vivo, and demonstrate that alterations in plasma NFL provide insight into the therapeutic efficacy of disease-modifying treatments.

Methodology for Gender Analysis in Transport: Factors with Influence in Women’s Inclusion as Professionals and Users of Transport Infrastructures

This work analyzes gendered processes by a methodology based on clustering factors with influence in the decision-making process of women as users or employees of the transport system. Considering gender as a social construction which changes over time and space, this study is based on the concept of a woman as a person who adopts this role in society. This paper performs a deep analysis of those factors women consider as needs and barriers to use or work in the transport system in four scenarios: railway public transport infrastructures, automated vehicles, bicycle sharing, and jobholders. A literature review and focus group discussions were performed under the consideration that the definition of woman includes the addition of several personal characteristics (age, sexual orientation, family responsibilities, and culture). The data analysis allowed the identification of fairness characteristics (FCs) that affect the interaction of women with the transport system for each scenario. A methodology for clustering the fairness characteristics identified the main areas of action to improve the inclusion of women within each use case. Further studies will be focused on the quantification and prioritization of the FCs through mathematical methods and the suggestion of inclusive measures by an interdisciplinary panel.