Biology subjects

Li, V.

Publications and source records attributed to Li, V..

26 records · Page 2Linked to original sources

bioRxiv2022

Antagonistic roles of canonical and alternative RPA in tandem CAG repeat diseases

Tandem CAG repeat expansion mutations cause >15 neurodegenerative diseases, where ongoing expansions in patients brains are thought to drive disease onset and progression. Repeat length mutations will involve single-stranded DNAs prone to form mutagenic DNA structures. However, the involvement of single-stranded DNA binding proteins (SSBs) in the prevention or formation of repeat instability is poorly understood. Here, we assessed the role of two SSBs, canonical RPA (RPA1-RPA2-RPA3) and the related Alternative-RPA (Alt-RPA, RPA1-RPA4-RPA3), where the primate-specific RPA4 replaces RPA2. RPA is essential for all forms of DNA metabolism, while Alt-RPA has undefined functions. RPA and Alt-RPA are upregulated 2- and 10-fold, respectively, in brains of Huntington disease (HD) and spinocerebellar ataxia type 1 (SCA1) patients. Correct repair of slipped-CAG DNA structures, intermediates of expansion mutations, is enhanced by RPA, but blocked by Alt-RPA. Slipped-DNAs are bound and melted more efficiently by RPA than by Alt-RPA. Removal of excess slipped-DNAs by FAN1 nuclease is enhanced by RPA, but blocked by Alt-RPA. Protein-protein interactomes (BioID) reveal unique and shared partners of RPA and Alt-RPA, including proteins involved in CAG instability and known modifiers of HD and SCA1 disease. RPA overexpression inhibits rampant CAG expansions in SCA1 mouse brains, coinciding with improved neuron morphology and rescued motor phenotypes. Thus, SSBs are involved in repeat length mutations, where Alt-RPA antagonistically blocks RPA from suppressing CAG expansions and hence pathogenesis. The processing of repeat length mutations is one example by which an Alt-RPA{leftrightarrow}RPA antagonistic interaction can affect outcomes, illuminating questions as to which of the many processes mediated by canonical RPA may also be modulated by Alt-RPA.

genetics↗

bioRxiv2022

Mitochondrial-encoded complex I impairment induces a targetable dependency on aerobic fermentation in H&uumlrthle cell carcinoma of the thyroid

A metabolic hallmark of cancer identified by Warburg is the increased consumption of glucose and secretion of lactate, even in the presence of oxygen. Although many tumors exhibit increased glycolytic activity, most forms of cancer rely on mitochondrial respiration for tumor growth. We report here that Hurthle cell carcinoma of the thyroid (HTC) models harboring mitochondrial DNA-encoded defects in complex I of the mitochondrial electron transport chain exhibit impaired respiration and alterations in glucose metabolism. CRISPR/Cas9 pooled screening identified glycolytic enzymes as selectively essential in complex I-mutant HTC cells. We demonstrate in cultured cells and a PDX model that small molecule inhibitors of lactate dehydrogenase selectively induce an ATP crisis and cell death in HTC. This work demonstrates that complex I loss exposes fermentation as a therapeutic target in HTC and has implications for other tumors bearing mutations that irreversibly damage mitochondrial respiration.

cancer biology↗

bioRxiv2022

Visual Perception of 3D Space and Shape in Time - Part III: 2D Shape Recognition by Log-Scaling

Human vision has a remarkable ability to recognize complex 3D objects such as faces that appear with any size and 3D orientations at any 3D location. If we initially memorize a face only with a normalized size and viewed from directly head on, the direct comparison between the one-sized memory and a new incoming image would demand tremendous mental frame translations in 7D. How can we perform such a demanding task so promptly and reliably as we experience the objects in the world around us? Intriguingly, our primary visual cortex exhibits a 2D retinotopy with a log-polar coordinate system, where scaling up/down of shape is converted to linear frame translation. As a result, mental scaling can be performed by linearly translating the memory or the perceptual image until they overlap with each other. According to our new model of NHT (Neural Holography Tomography), alpha brainwaves traveling at a constant speed can conduct this linear translation. With this scheme, every scaling up/down by a factor of two should take the same amount of extra mental time to recognize a smaller/larger face. To test this hypothesis, we designed a reaction time (RT) experiment, where participants were first asked to memorize sets of unfamiliar faces with a given specific size (4{degrees} or 8{degrees}). Following the memorization phase, similar stimuli with a wide range of sizes (from 1{degrees} to 32{degrees}) were presented, and RTs were recorded. As predicted, the increase in RT was proportional to the scaling factor in the log scale. Furthermore, we observed that RTs were fastest for 8{degrees} faces even if the memorized face was 4{degrees}. This supports our hypothesis that we always memorize faces at the exact size of ~8 {degrees}. To our surprise, the increases in RT were also consistent with the mentally-estimated depth sensation, which indicates that the apparent size of the recognized face can create a proper depth sensation.

neuroscience↗

bioRxiv2021

TK216 targets microtubules in Ewing sarcoma cells

Ewing sarcoma (EWS) is a pediatric malignancy driven by the EWSR1-FLI1 fusion protein formed by the chromosomal translocation t(11;22). The small molecule TK216 was developed as a first-in-class direct EWSR1-FLI1 inhibitor and is in phase II clinical trials in combination with vincristine for EWS patients. However, TK216 exhibits anti-cancer activity against cancer cell lines and xenografts that do not express EWSR1-FLI1, and the mechanism underlying cytotoxicity remains unresolved. We apply a forward genetics screening platform utilizing engineered hypermutation in EWS cell lines and identify recurrent mutations in TUBA1B, encoding -tubulin, that prove sufficient to drive resistance to TK216. Using reconstituted microtubule (MT) polymerization in vitro and cell-based chemical probe competition assays, we demonstrate that TK216 acts as an MT destabilizing agent. This work defines the mechanism of cytotoxicity of TK216, explains the synergy observed with vincristine, and calls for a reexamination of ongoing clinical trials with TK216.

cancer biology↗

bioRxiv2021

Structural Basis for pH-Gating of the K+ Channel TWIK1 at the Selectivity Filter

TWIK1 is a widely expressed pH-gated two-pore domain K+ channel (K2P) that contributes to cardiac rhythm generation and insulin release from pancreatic beta cells. TWIK1 displays unique properties among K2Ps including low basal activity and inhibition by extracellular protons through incompletely understood mechanisms. Here, we present cryo-EM structures of TWIK1 in lipid nanodiscs at high and low pH that reveal a novel gating mechanism at the K+ selectivity filter. At high pH, TWIK1 adopts an open conformation. At low pH, protonation of an extracellular histidine results in a cascade of conformational changes that close the channel by sealing the top of the selectivity filter, displacing the helical cap to block extracellular ion access pathways, and opening gaps for lipid block of the intracellular cavity. These data provide a mechanistic understanding for extracellular pH-gating of TWIK1 and show how diverse mechanisms have evolved to gate the selectivity filter of K+ channels.

neuroscience↗

bioRxiv2020

Diverse viruses have restricted biogeography in deep-sea hydrothermal vent fluids

In the ocean, viruses impact microbial mortality, regulate biogeochemical cycling, and alter the metabolic potential of microbial lineages. At deep-sea hydrothermal vents, abundant viruses infect a wide range of hosts among the archaea and bacteria that inhabit these dynamic habitats. However, little is known about viral diversity, host range, and biogeography across different vent ecosystems, which has important implications for how viruses manipulate microbial function and evolution. Here, we examined viral diversity, viral and host distribution, and viral-host interactions in microbial metagenomes generated from venting fluids from several vent sites within three different geochemically and geographically distinct hydrothermal systems: Piccard and Von Damm vent fields at the Mid-Cayman Rise in the Caribbean Sea, and at several vent sites within Axial Seamount in the Pacific Ocean. Analysis of viral sequences and Clustered Regularly InterSpaced Palindromic Repeats (CRISPR) spacers revealed highly diverse viral assemblages and evidence of active infection. Network analysis revealed that viral host range was relatively narrow, with very few viruses infecting multiple microbial lineages. Viruses were largely endemic to individual vent sites, indicating restricted dispersal, and in some cases viral assemblages persisted over time. Thus, we show that hydrothermal vent fluids are home to novel, diverse viral assemblages that are highly localized to specific regions and taxa. ImportanceViruses play important roles in manipulating microbial communities and their evolution in the ocean, yet not much is known about viruses in deep-sea hydrothermal vents. However, viral ecology and evolution are of particular interest in hydrothermal vent habitats because of their unique nature: previous studies have indicated that most viruses in hydrothermal vents are temperate rather than lytic, and it has been established that rates of horizontal gene transfer (HGT) are particularly high among thermophilic vent microbes, and viruses are common vectors for HGT. If viruses have broad host range or are widespread across vent sites, they have increased potential to act as gene-sharing "highways" between vent sites. By examining viral diversity, distribution, and infection networks across disparate vent sites, this study provides the opportunity to better characterize and constrain the viral impact on hydrothermal vent microbial communities. We show that viruses in hydrothermal vents are diverse and apparently active, but most have restricted host range and are not widely distributed among vent sites. Thus, the impacts of viral infection are likely to be highly localized and constrained to specific taxa in these habitats.

microbiology↗

bioRxiv2017

Characterization of Thylakoid Division Using Chloroplast Dividing Mutants in Arabidopsis

Chloroplasts are double membrane bound organelles that are found in plants and algae. Their division requires a number of proteins to assemble into rings along the center of the organelle and to constrict in synchrony. Chloroplasts possess a third membrane system, the thylakoids, which house the majority of proteins responsible for the light-dependent reactions. The mechanism that allows chloroplasts to sort out and separate the intricate thylakoid membrane structures during organelle division remain unknown. By characterizing the sizes of thylakoids found in a number of different chloroplast division mutants in Arabidopsis, we show that thylakoids do not divide independently of the chloroplast division cycle. More specifically, we show that thylakoid division requires the formation of both the inner and the outer contractile rings of the chloroplast.

plant biology↗

bioRxiv2017

Adaptive gain control in the human dorsal anterior cingulate cortex

When making decisions, humans are often distracted by irrelevant information. Distraction has different impact on perceptual, cognitive and value-guided choices, giving rise to well-described behavioural phenomena such as the tilt illusion, conflict adaptation, or economic decoy effects. However, a single, unified model that can account for all these phenomena has yet to emerge. Here, we offer one such account, based on adaptive gain control, and additionally show that it successfully predicts a range of counterintuitive new behavioural phenomena on variants of a classic cognitive paradigm, the Eriksen flanker task. We also report that BOLD signals in a dorsal network prominently including the anterior cingulate cortex (dACC), index a gain-modulated decision variable predicted by the model. This work unifies the study of distraction across perceptual, cognitive and economic domains.

neuroscience↗