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Zielinski, R.

Publications and source records attributed to Zielinski, R..

4 recordsLinked to original sources

Task context is broadly encoded in the human brain

Cognitive control depends on the task context as a top-down modulatory influence on ongoing processing. Cognitive neuroscience theories of cognitive control have associated the maintenance of context, and its deployment as a control signal, with neural populations in the dorsolateral prefrontal cortex (DLPFC). Importantly, however, the way information about the task context is propagated and used throughout the brain remains largely unspecified. A longstanding hypothesis is that neural representations of context in DLPFC directly influence neural processing only where this information is needed to resolve competition, integrating top-down context inputs from DLPFC conjunctively with local processing. However, an alternative hypothesis is that context is broadcast and maintained more widely throughout the brain than necessary. In this way, context is available for integration with local populations when needed. Here, we tested these hypotheses by analyzing a large multisession fMRI data set collected while participants performed a context-dependent task using a hierarchical rule that features one superordinate context versus a control task that used a non-hierarchical, flat rule. Across a range of analyses, we found that the superordinate task context is robustly and widely coded throughout the cortex, evident in every largescale cortical network. Across a range of controls, the superordinate context was the only task feature to show this property. Indeed, context accounted for the most variance in cortex-wide activity patterns across analyses. In contrast, the integration of this context with coding of other task features was evident in only a subset of context-coding regions, principally those in higher-order control and attentional networks and visual perceptual stream areas. These latter areas showed interactions with context that were consistent with object-based attentional modulation, as needed by the task. These results provide initial empirical support for a context broadcast model of top-down control in the brain.

neuroscience↗

Temperature and food chain length, but not latitude, explain region-specific kelp forest responses to an unprecedented heatwave

Kelp forests are among the most abundant coastal marine habitats but are vulnerable to the impacts of climate change. Between 2014 and 2016, an unprecedented heatwave and associated changes in trophic dynamics threatened kelp forests across the Northeast Pacific, with impacts documented from Mexico to Alaska. However, responses have varied substantially and remain poorly characterized across large stretches of coast, especially British Columbia (B.C.), which represents a significant percentage of the range of floating kelp species in the Northeast Pacific. Here, we explore variation in floating kelp (Macrocystis, Nereocystis) persistence pre- and post-heatwave across a >675 km latitudinal gradient, asking whether B.C. kelp forests are of conservation concern. We assembled and analyzed available quantitative kelp data, comparing snapshots of kelp extent before (1994 - 2007) and after (2018 - 2021) the heatwave in 11 regions spanning a range of temperature and sea otter-occupancy statuses, and contextualizing these with time series analyses, where available (n = 7 regions). We provide strong evidence that kelp forests have declined in many regions but with evidence of refugia at both local and regional scales. Kelp forest persistence was negatively correlated with summer sea temperatures in southern B.C., where temperatures varied by ~6{degrees}C across sites, at times exceeding species thermal tolerances. Kelp dynamics in northern regions appeared instead to be modulated by top-down control by urchins and sea otters. Our results demonstrate that B.C.s kelp forest have been substantially reduced in recent years but that regional and local-scale factors influence the resilience of forests to large-scale perturbations.

ecology↗

Lactose-based surfactants complexable with oligonucleic acids as gene delivery agents

Advances in molecular medicine related to the treatment of genetic disorders and cancer require finding new pathways for gene transfer. Nonviral delivery methods rely on the application of polymers, liposomes and cationic lipid systems used as vehicle. Among these systems, there is increasing interest in surfactants, which, due to their ability to complex with nucleic acids can deliver into cell DNA or RNA molecules of almost any size, which is unattainable with viral gene delivery systems.The main aim of this study was to determine the effect of the concentration of lactose-based surfactants (zwitterionic derivatives of sulfobetaine with carbohydrate moieties) on the structure of DNA/RNA as well as to explore their abilities of nucleic acid complexation. Structural studies of DNA or RNA in complexes with surfactants of two types at various concentrations were conducted using circular dichroism (CD) spectroscopy, gel electrophoresis (GE) and synchrotron radiation small angle X-ray scattering (SR-SAXS). Our studies showed that the examined surfactants have excellent properties of forming complexes with DNA and RNA. Additionally, to determine the cytotoxicity and transfection abilities of the studied lipoplexes, preliminary tests were performed in HeLa and fibroblast cells. The obtained results suggest that these systems have relatively low toxicity; however, further research is needed in this area.

biophysics↗

Eradication of ENO1-deleted Glioblastoma through Collateral Lethality

Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We recently demonstrated that SF2312, a natural product phosphonate antibiotic, is a potent inhibitor of the glycolytic enzyme Enolase with potential utility for the collateral lethality-based treatment of Enolase-deficient glioblastoma (GBM). However, phosphonates are anionic at physiological pH, limiting cell and tissue permeability. Here, we show that addition of pivaloyloxymethyl (POM) groups to SF2312 (POMSF) dramatically increases potency, leading to inhibition of glycolysis and killing of ENO1-deleted glioma cells in the low nM range. But the utility of POMSF in vivo is dose-limited by severe hemolytic anemia. A derivative, POMHEX, shows equipotency to POMSF without inducing hemolytic anemia. POMHEX can eradicate intracranial orthotopic ENO1-deleted tumors, despite sub-optimal pharmacokinetic properties. Taken together, our data provide in vivo proof-of-principal for collateral lethality in precision oncology and showcase POMHEX as a useful molecule for the study of glycolysis in cancer metabolism.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC=\"FIGDIR/small/331538_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (20K):\norg.highwire.dtl.DTLVardef@1b78ebcorg.highwire.dtl.DTLVardef@1fc0ccforg.highwire.dtl.DTLVardef@ad268corg.highwire.dtl.DTLVardef@1bdee32_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗