Biology subjects

Nguyen, K. K.

Publications and source records attributed to Nguyen, K. K..

9 recordsLinked to original sources

bioRxiv2026

Real-time reorienting during episodic retrieval rescues memories from suboptimal arousal-attentional states

Successful knowledge expression varies with one's arousal-attentional (A-A) state at the moment just prior to attempting to remember. Yet, whether such states causally affect retrieval remains unclear. Here we introduce PRISM (Pupil-based Real-time Intervention System for Memory), a closed-loop paradigm that continuously monitors pupil size to track A-A states in real time and, during suboptimal states (SOS), delivers a visual reorienting cue in the moment before a retrieval attempt. In 67 participants performing a goal-directed source memory and item recognition task, we show that pupil-defined SOS just prior to retrieval impair both item recognition and source recollection relative to optimal state (OS) trials. Critically, delivering a brief visual reorienting trigger cue on SOS trials in real time rescues item memory, but not source memory, raising item memory to a level not credibly different from real-time OS trials and providing causal evidence that phasic attentional reorienting during A-A-defined suboptimal states facilitates memory access at retrieval. Offline spline-detrending analysis confirms that the A-A state-memory relationship is robust to slow physiological drift. It also shows that the trigger benefit was credible for marginally suboptimal (drift-driven) SOS trials and smaller and less certain for deeply suboptimal (drift-resistant) SOS trials, consistent with a zone-of-recoverability account, although the difference between the two SOS subtypes was not credible. Furthermore, among deeply suboptimal trials the A-A-boosting trigger cue improved memory for low-A-A SOS (i.e., pupillary constriction) but not high-A-A SOS (i.e., pupillary dilation) trials, consistent with the classic inverted-U relationship between arousal and performance, although the difference between the two directions was not credible. Together, these findings causally link phasic arousal-attentional reorienting at retrieval to memory rescue and suggest that the depth and direction of suboptimality shape whether such rescue succeeds, connecting the readiness-to-remember framework to the classic arousal-performance inverted-U relationship. Moreover, these findings provide a further foundation for adaptive closed-loop technologies that would tailor intervention to the depth and direction of momentary arousal-attentional states, facilitating memory expression in real time.

neuroscience↗

bioRxiv2026

Elevated polyadenylated histone gene transcription in human cancer

Histone production is tightly restricted to S-phase to prevent genomic instability, yet human cancers with an overabundance of RNA Polymerase II (RNAPII) at histone genes are associated with aggressive cancers. To better understand histone gene overexpression in cancer, we applied a quantitative PCR assay to measure total replication-coupled histone output across the histone gene clusters using cell line models. We observed pervasive accumulation of polyadenylated histone transcripts, supported by analysis of >1,400 RNA-sequencing datasets in human cancers, with more than 70% of patients showing tumor specific increases. This alternative processing preferentially enriches for histone H2B, which lacks replication independent variants, across >8,300 tumors comprising diverse cancer types and transcriptional subtypes. We also found that disruption of nuclear components required to maintain RNAPII levels at the histone genes increased polyadenylated histone transcripts. Our results suggest that S-phase-dependent histone genes are subject to unscheduled gap phase transcription in human cancer.

cancer biology↗

bioRxiv2026

N-terminal Trimming Supports Proteostasis Under Secretory Protein Mislocalization Stress

Secretory proteins that fail to enter the endoplasmic reticulum (ER) are mislocalized to the cytosol, where they threaten cellular proteostasis. How cells manage these mislocalized proteins remains poorly understood. Here, we show that inefficient Sec61 translocon activity induces a transcriptional stress response, which is enhanced by blocking NRF-1-dependent adaptation of proteasomal capacity. To maintain proteasomal capacity, thermodynamically stable mislocalized proteins persist in the cytosol of HepG2 and HEK293T cells, while mislocalized proteins that are inherently more aggregation-prone are preferentially ubiquitinated and degraded. This triaging process is accomplished through N-terminal trimming of the signal sequence of thermodynamically stable proteins, which simultaneously reduces their aggregation and prevents proteasomal degradation. These findings reveal a stability-dependent cytosolic triaging mechanism that matches substrate burden to proteasome capacity when ER import is challenged.

cell biology↗

bioRxiv2026

The Cost to Scroll: Short-form Video Use and Episodic Memory

Short-form video platforms expose users to rapid streams of novel content; these features are posited to place heavy demands on cognitive processes. In a preregistered online study, we used device-reported screen time to examine whether short-form video use is associated with sustained attention and episodic memory in participants aged 18-24 yrs (N = 502). During a sustained attention task, participants made indoor/outdoor decisions on scene stimuli, with 90% frequent trials and 10% infrequent trials; the subsequent surprise recognition test assessed memory for these items. Among participants with device-reported TikTok or Instagram use (N = 398), short-form video use was not associated with attention performance. By contrast, greater short-form video use was associated with poorer episodic memory; this relationship was driven by poorer recognition of infrequent-category items. These findings connect heavier short-form video consumption with poorer episodic memory in young adults, showing how daily digital habits co-vary with memory function.

neuroscience↗

bioRxiv2026

Aclarubicin disrupts RNA polymerase II progression at replication-coupled histone genes

Anthracyclines are highly effective chemotherapeutic agents that cause DNA and chromatin damage. One member of the anthracyclines, aclarubicin, has recently gained therapeutic interest due to its ability to kill cancer cells through chromatin-based mechanisms, thus avoiding the off-target effects associated with DNA damage. Despite this, the molecular mechanism of action leading to aclarubicin-induced chromatin damage remains elusive. Here we performed Cleavage Under Targets and Tagmentation (CUT&Tag) of RNA polymerase II (Pol II) and other transcriptional regulators in human cells during aclarubicin treatment. We found that aclarubicin strongly disrupts the replication-coupled histone genes, resulting in a nonproductive accumulation of Pol II-transcription machinery here beyond the levels at other genes. We attribute this sensitivity to the dense Pol II loading and rapid transcription of the histone genes, which intensify the chromatin-disrupting effects of aclarubicin at these loci. Together, our findings support the effectiveness of aclarubicin as an anticancer drug and point to the histone gene cluster as a promising target for therapeutic intervention.

molecular biology↗

bioRxiv2023

GPCR binding and JNK3 activation by arrestin-3 have different structural requirements

Arrestins bind active phosphorylated G protein-coupled receptors (GPCRs). Among the four mammalian subtypes, only arrestin-3 facilitates the activation of JNK3 in cells. In available structures, Lys-295 in the lariat loop of arrestin-3 and its homologue Lys-294 in arrestin-2 directly interact with the activator-attached phosphates. We compared the role of arrestin-3 conformational equilibrium and of Lys-295 in GPCR binding and JNK3 activation. Several mutants with enhanced ability to bind GPCRs showed much lower activity towards JNK3, whereas a mutant that does not bind GPCRs was more active. Subcellular distribution of mutants did not correlate with GPCR recruitment or JNK3 activation. Charge neutralization and reversal mutations of Lys-295 differentially affected receptor binding on different backgrounds, but had virtually no effect on JNK3 activation. Thus, GPCR binding and arrestin-3-assisted JNK3 activation have distinct structural requirements, suggesting that facilitation of JNK3 activation is the function of arrestin-3 that is not bound to a GPCR.

cell biology↗

bioRxiv2022

Hspa13 Regulates Endoplasmic Reticulum and Cytosolic Proteostasis Through Modulation of Protein Translocation

Most eukaryotic secretory proteins are co-translationally translocated through Sec61 into the endoplasmic reticulum (ER). Because these proteins have evolved to fold in the ER, their mistargeting is associated with toxicity. Genetic experiments have implicated the ER Hsp70 Hspa13/STCH as involved in processing of nascent secretory proteins. Herein, we evaluate the role of Hspa13 in protein import and the maintenance of cellular proteostasis. We find that Hspa13 interacts primarily with the Sec61 translocon and its associated factors. Hspa13 overexpression inhibits translocation of the secreted protein transthyretin (TTR), leading to accumulation and aggregation of immature TTR in the cytosol. ATPase inactive mutants of Hspa13 further inhibit translocation and maturation of secretory proteins. While Hspa13 overexpression inhibits cell growth and ER quality control, HSPA13 knockout destabilizes proteostasis and increases sensitivity to ER disruption. Thus, we propose that Hspa13 regulates import through the translocon to maintain both ER and cytosolic protein homeostasis. The raw mass spectrometry data associated with this manuscript has been deposited in the PRIDE archive and can be accessed at PXD033498.

cell biology↗

bioRxiv2021

Monitoring Protein Import into the Endoplasmic Reticulum in Living Cells with Proximity Labeling

The proper trafficking of eukaryotic proteins is essential to cellular function. Genetic, environmental, and other stresses can induce protein mistargeting, and in turn threaten cellular protein homeostasis. Current methods for measuring protein mistargeting are difficult to translate to living cells, and thus the role of cellular signaling networks in stress-dependent protein mistargeting processes, such as ER pre-emptive quality control (ER pQC), are difficult to parse. Herein, we use genetically encoded peroxidases to characterize protein import into the endoplasmic reticulum (ER). We show that the ERHRP/cytAPEX pair provides good selectivity and sensitivity for identifying protein mistargeting, using the known ER pQC substrate transthyretin (TTR). Although ERHRP labeling induces formation of detergent-resistant TTR aggregates, this is minimized by using low ERHRP expression, without loss of labeling efficiency. cytAPEX labeling recovers TTR that is mistargeted as a consequence of Sec61 inhibition or ER stress-induced ER pQC. Furthermore, we demonstrate that stress-free activation of the ER stress-associated transcription factor ATF6 recapitulates the TTR import deficiency of ER pQC. Hence, proximity labeling is an effective strategy for characterizing factors that influence ER protein import in living cells.

molecular biology↗

bioRxiv2020

A continuously self-sterilizing form of copper capable of 99% SARS-CoV-2 deactivation in 30 seconds.

The coronavirus disease 2019 (COVID-19) has created an acute worldwide demand for sustained broadband pathogen suppression in households, hospitals, and public spaces. The US recently passed a new sad milestone of 500,000 deaths due to COVID-19, the highest rate anywhere in the world. In response, we have created a rapid-acting, self-sterilizing PPE configurations capable of killing SARS-CoV-2 and other microbes in seconds. The highly active material destroys pathogens faster than any conventional copper configuration. The material maintains its antimicrobial efficacy over sustained use and is shelf stable. We have performed rigorous testing in accordance with guidelines from U.S. governing authorities and believe that the material could offer broad spectrum, non-selective defense against most microbes via integration into masks and other protective equipment. SummaryA novel configuration of copper offering continued fast-acting protection against viruses and bacteria, including SARS-CoV-2.

immunology↗