Biology subjects

Trinh, H.

Publications and source records attributed to Trinh, H..

8 recordsLinked to original sources

bioRxiv2025

Wide-ranging behavioral dysfunction in two mouse models of pathological human variants in the GRIK2 kainate receptor gene

De novo variants in a subset of ionotropic glutamate receptor (iGluR) genes cause nonsyndromic neurodevelopmental disorders (NDDs) in individuals. Two recurrent variants in the kainate receptor (KAR) gene GRIK2 result in the gain-of-function (GoF) substitutions p.Ala657Thr and p.Thr660Lys in a critical pore-forming domain of the GluK2 subunit. Disorders in individuals with these variants manifest as intellectual disability, developmental delay, motor impairments, and, in the case of p.Thr660Lys, epilepsy. To explore their pathogenicity and phenotypic consequences in vivo, we generated knock-in mouse models harboring orthologous Grik2 mutations. Behavioral analyses revealed a range of developmental, motor, cognitive, and naturalistic behavior impairments in both lines, with T660K mice typically exhibiting more severe phenotypes, consistent with clinical observations in humans. GluK2(T660K) mice also display interictal EEG abnormalities and handling-induced seizures. These models establish the first in vivo platforms for dissecting the underlying mechanisms of NDDs caused by a GoF mutation in the GluK2 KAR subunit and represent crucial tools for therapeutic development. HighlightsO_LIDe novo variants in the GRIK2 kainate receptor gene cause developmental disorders C_LIO_LIWe studied knockin mouse models of pathogenic p.Ala657Thr and p.Thr660Lys variants C_LIO_LIGluK2(A657T) and GluK2(T660K) mice have deficits analogous to human disorder symptoms C_LIO_LILike their human counterparts, GluK2(T660K) but not GluK2(A657T) mice have seizures C_LIO_LIGrik2 knockin mice are key tools for interrogating underlying causes of dysfunction C_LI

neuroscience↗

bioRxiv2025

Nicotinamide-loaded Peptoid Nanotubes for Energy Regeneration in Acute Brain Injury

Acute brain injuries such as perinatal asphyxia, stroke, and traumatic brain injury result in ischemia, oxidative stress, excitotoxicity, and inflammation, leading to a depletion of ATP, the brains cellular energy store. Nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular homeostasis, is crucial for energy regeneration and DNA repair in post-injury recovery. However, the therapeutic benefits of NAD+ and its precursors, such as nicotinamide (NAM), are limited by the complexity of their metabolic pathways and challenges in effective cell-specific intracellular delivery. Therefore, cellular delivery strategies are needed to capture the potential of an NAD+-regenerating therapeutic approach. In this study, we introduce a nanopeptoid delivery strategy to replenish cellular redox state and energy production in the acutely injured brain. By self-assembling peptoids into tubular structures, we created biocompatible NAM-conjugated peptoid nanotubes (NAM-PNTs) that vary in tubular length. NAM-PNTs demonstrated significant therapeutic benefits by enhancing cell viability and replenishing intracellular ATP levels within 24 hours of treatment in oxygen-glucose deprived (OGD) BV-2 cells. In organotypic brain slices, NAM-PNT treatment promoted glial proliferation, reduced pro-inflammatory cytokine levels, and increased anti-inflammatory cytokines after OGD, an ex vivo model of hypoxia-ischemia. A single systemic dose of NAM-PNTs also reduced brain tissue loss and improved neuropathology after hypoxia-ischemia in term-equivalent rats. These findings highlight the strong therapeutic potential of NAM-PNTs for cell-specific targeted delivery and energy restoration in the acutely injured neonatal brain. In the neonatal brain injury field, this is the first demonstration of a novel nanoparticle platform development from first principles design and synthesis to in vitro screening and then demonstration of efficacy in vivo.

bioengineering↗

bioRxiv2025

Preclinical evaluation of the efficacy of α-Difluoromethylornithine and Sulindac against SARS-CoV-2 infection

Despite numerous research efforts and several effective vaccines and therapies developed against COronaVIrus Disease 2019 (COVID-19), drug repurposing remains an attractive alternative to identify new treatments for SARS-CoV-2 virus variants and other viral infections that may emerge in the future. Cellular polyamines support viral propagation and tumor growth. Here we tested the antiviral activity of an irreversible inhibitor of polyamine biosynthesis, -difluoromethylornithine (DFMO) and a non-steroidal anti-inflammatory drug (NSAID) Sulindac, which have been previously evaluated for colon cancer chemoprevention. The drugs were tested as single agents and in combination in human Calu-3 lung adenocarcinoma and Caco-2 colon adenocarcinoma cell lines and the K18-hACE2 transgenic mouse model of severe COVID-19. DFMO/Sulindac combination significantly suppressed SARS-CoV-2 N1 Nucleocapsid mRNA and ACE2 mRNA levels in the infected human cell lines by interacting synergistically when cells were pretreated with drugs and additively when treatment was applied to the infected cells. The antiviral activity of DFMO and Sulindac was tested in vivo as prophylaxis (drug supplementation at the doses equivalent to the human chemoprevention trial started 7 days before infection) or as treatment (drug supplementation started 24 hours post-infection). Prophylaxis with DFMO and Sulindac as single agents significantly increased survival rates in the young male mice (p=0.01, and p=0.027, respectively), and the combination was effective in the aged male mice (p=0.042). Young female mice benefited the most from the prophylaxis with Sulindac alone (p=0.001) and DFMO/Sulindac combination (p=0.018), while aged female mice did not benefit significantly from any interventions. The treatment regime was ineffective in suppressing SARS-CoV-2 infection in K18-hACE2 mice. Overall, animal studies demonstrated the protective age- and sex-dependent antiviral efficacy of DFMO and Sulindac against SARS-CoV-2.

cell biology↗

bioRxiv2024

Transcriptomic diversity of amygdalar subdivisions across humans and nonhuman primates

The amygdaloid complex mediates learning, memory, and emotions. Understanding the cellular and anatomical features that are specialized in the amygdala of primates versus other vertebrates requires a systematic, anatomically-resolved molecular analysis of constituent cell populations. We analyzed five nuclear subdivisions of the primate amygdala with single-nucleus RNA sequencing in macaques, baboons, and humans to examine gene expression profiles for excitatory and inhibitory neurons and confirmed our results with single-molecule FISH analysis. We identified distinct subtypes of FOXP2+ interneurons in the intercalated cell masses and protein-kinase C-{delta} interneurons in the central nucleus. We also establish that glutamatergic, pyramidal-like neurons are transcriptionally specialized within the basal, lateral, or accessory basal nuclei. Understanding the molecular heterogeneity of anatomically-resolved amygdalar neuron types provides a cellular framework for improving existing models of how amygdalar neural circuits contribute to cognition and mental health in humans by using nonhuman primates as a translational bridge.

neuroscience↗

bioRxiv2024

Estimating intra-subject and inter-subject oxygen consumption in outdoor human gait using multiple neural network approaches

Oxygen consumption [Formula] is an important parameter for exercise test, such as walking and running, that can be measured using portable spirometers or metabolic analyzers. However, these devices are not feasible for regular use by consumers as they intervene with the users physical integrity, and are expensive and difficult to operate. To circumvent these drawbacks, indirect estimation of [Formula] using neural networks combined with motion parameters and heart rate measurements collected with consumer-grade sensors has been shown to yield reasonably accurate [Formula] for intra-subject estimation. However, estimating [Formula] with neural networks trained with data from other individuals than the user, known as inter-subject estimation, remains an open problem. In this paper, five types of neural network were tested in various configurations for inter-subject [Formula] estimation. To analyse predictive performance, data from 16 participants walking and running at speeds between 1.0 m/s and 3.3 m/s were used. The most promising approach was XceptionNet, which in most configurations even yielded a lower average estimation error than the LSTM neural network from an earlier study for intra-subject estimation. This suggests that XceptionNet could be embedded in portable devices for real-time estimation of oxygen consumption during walking and running.

physiology↗

bioRxiv2023

Early rise and persistent inhibition of electromyography during failed stopping

Reactively canceling movements is a vital feature of the motor system to ensure safety. This behavior can be studied in the laboratory using the stop signal task. There remains ambiguity about whether a "point-of-no-return" exists, after which a response cannot be aborted. A separate question concerns whether motor system inhibition associated with attempted stopping persists when stopping is unsuccessful. We address these two questions using electromyography (EMG) in two stop signal task experiments. Experiment 1 (n = 24) involved simple right and left index finger responses in separate task blocks. Experiment 2 (n = 28) involved a response choice between the right index and pinky fingers. To evaluate the approximate point-of-no-return, we measured EMG in responding fingers during the 100 ms preceding the stop signal and observed significantly greater EMG amplitudes during failed than successful stop trials in both experiments. Thus, EMG differentiated failed from successful stopping prior to the stop signal, regardless of whether there was a response choice. To address whether motor inhibition persists after failed stopping, we assessed EMG peak-to-offset durations and slopes (i.e., the rate of EMG decline) for go, failed stop, and successful stop (partial response EMG) trials. EMG peak-to-offset was shorter and steeper in failed stop trials compared to go and successful stop partial response EMG trials, suggesting motor inhibition persists even when failing to stop. These findings indicate EMG is sensitive to a point at which participants can no longer successfully stop an ongoing movement and suggest the peak-to-offset time of response-related EMG activity during failed stopping reflects stopping-related inhibition.

neuroscience↗

bioRxiv2021

A genetic shift in an escaped transmitted/founder virus guides combinatorial vaccine design against HIV-1

A productive HIV-1 infection in humans is often established by transmission and propagation of a single transmitted/founder (T/F) virus, which then evolves into a complex mixture of variants during the lifetime of infection. An effective HIV-1 vaccine should elicit broad immune responses in order to block the entry of diverse T/F viruses. Currently, no such vaccine exists. An in-depth study of escape variants emerging under host immune pressure during very early stages of infection might provide insights into such a HIV-1 vaccine design. Here, in a rare longitudinal study involving HIV-1 infected individuals just days after infection in the absence of antiretroviral therapy, we discovered a remarkable genetic shift that resulted in near complete disappearance of the original T/F virus and appearance of a variant with H173Y mutation in the variable V2 domain of the HIV-1 envelope protein. This coincided with the disappearance of the first wave of strictly H173-specific antibodies and emergence of a second wave of Y173-specific antibodies with increased breadth. Structural analyses indicated conformational dynamism of the envelope protein which likely allowed selection of escape variants with a conformational switch in the V2 domain from an -helix (H173) to a {beta}-strand (Y173) and induction of broadly reactive antibody responses. This differential breadth due to a single mutational change was also recapitulated in a mouse model. Rationally designed combinatorial libraries containing 54 conformational variants of V2 domain around position 173 further demonstrated increased breadth of antibody responses elicited to diverse HIV-1 envelope proteins. These results offer new insights into designing broadly effective HIV-1 vaccines.

microbiology↗

bioRxiv2021

Histone sequence variation in divergent eukaryotes facilitates diversity in chromatin packaging

The histone proteins defining nucleosome structure are highly conserved in common model organisms and are frequently portrayed as uniform chromatin building blocks. We surveyed over 1700 complete eukaryotic genomes and confirm that almost all encode recognisable canonical core histones. Nevertheless, divergent eukaryotes show unrecognised diversity in histone sequences and offer an opportunity to observe the potential for nucleosome variation. Recombinant histones for Plasmodium falciparum, Giardia lamblia, Encephalitozoon cuniculi and Leishmania major were prepared alongside those for human, Xenopus laevis and Saccharomyces cerevisiae. All could be assembled into nucleosomes in vitro on sequences known to direct positioning with metazoan histones. P. falciparum histones refolded into very stable nucleosomes consistent with a highly regulated transcriptional programme. In contrast, G. lamblia and E. cuniculi histones formed less stable nucleosomes and were prone to aggregation as H3-H4 tetramers. Inspection of the histone fold dimer interface residues suggested a potential to form tetrasomal arrays consistent with polymerisation. DNA binding preferences observed using systematic evolution of ligands by exponential enrichment (SELEX) for human, P. falciparum and E. cuniculi histone octamers were highly similar and reflect a shared capability to package diverse genomic sequences. This demonstrates that nucleosomal organisation is retained across eukaryotes and can accommodate genome variation, but histone protein sequences vary more than commonly recognised to provide the potential for diversity of chromatin features. Significance statementIt is widely assumed that eukaryotes package their genomes using equivalent nucleosome building blocks despite considerable variation in the composition and behaviour of cell nuclei. Our survey of available eukaryote genomes shows that histone proteins from divergent eukaryotes vary much more widely in sequence than is commonly recognised, even in histone fold dimer and DNA interaction interfaces. We demonstrate that divergent eukaryote histones nevertheless form nucleosomes on DNA sequences favoured in metazoans. These nucleosomes vary in stability but share broad DNA sequence preferences. This suggests that histone-dependent packaging does not constrain genome variation, and that chromatin behaviour can adapt by evolution of canonical core histone sequences in addition to other well-known mechanisms.

biochemistry↗