Biology subjects

Jordan, T.

Publications and source records attributed to Jordan, T..

11 recordsLinked to original sources

bioRxiv2026

Relationship between X chromosome mosaicism, neuroanatomy and cognitive performance in females

Females have two X chromosomes, one of which is inactivated early in development with specific regions and genes escaping inactivation. Thus, X chromosome loss putatively results in decreased dosage of X chromosome escapee and pseudoautosomal genes, impacting downstream pathways. Evidence from Turner syndrome indicates that X chromosome monosomy results in consistent neuroanatomical and cognitive phenotypes. However, it remains unclear whether mosaic karyotypes, with mixed proportions of 45X and 46XX cells, attenuate these phenotypes. We examined whether X chromosome mosaicism is predicted by neuroanatomical and cognitive features. Higher proportion of 46XX cells was significantly predicted by structural properties in somatosensory, motor, visual, and language brain areas, and by performance in visuospatial, fine-motor, and language tasks. Thus, mosaicism partially rescues phenotypes linked to full 45X monosomy and may explain the role of the X chromosome not only across heterogeneous phenotypic expression in females, but also in sex differences observed in neuropsychiatric conditions.

neuroscience↗

bioRxiv2024

Effects of oral contraceptive pills on brain networks: A replication and extension

Neuroimaging research has identified significant effects of oral contraceptive pills (OCPs) on brain networks. A wide variety of approaches have been employed, largely in observational samples, with few converging results. This study therefore was designed to test for replication and extend this previous work using a randomized, double-blind, placebo-controlled crossover trial of the effects of OCPs on brain networks. Using functional MRI, we focused on brain regions identified in prior studies. Our analyses did not strictly replicate previously reported effects of OCPs on functional connectivity. Exploratory analyses suggested that traditional seed-based approaches may miss broader, network-level effects of OCPs on brain circuits. We applied data-driven, multivariate techniques to assess these network-level changes, A deeper understanding of neural effects of OCPs can be important in helping patients make informed decisions regarding contraception, mitigating unwanted side effects. Such information can also identify potentially confounding effects of OCPs in other neuroimaging investigations.

neuroscience↗

bioRxiv2024

Connectivity in the Dorsal Visual Stream is Enhanced in Action Video Game Players

Action video games foster competitive environments that demand rapid spatial navigation and decision-making. Action video gamers often exhibit faster response times and slightly improved accuracy in vision-based sensorimotor tasks. However, the underlying functional and structural changes in the two visual streams of the brain that may be contributing to these cognitive improvements have been unclear. Using functional and diffusion MRI data, this study investigated the differences in connectivity between gamers who play action video games and nongamers in the dorsal and ventral visual streams. We found that action video gamers have enhanced functional and structural connectivity, especially in the dorsal visual stream. Specifically, there is heightened functional connectivity--both undirected and directed--between the left Superior Occipital Gyrus and the left Superior Parietal Lobule during a moving-dots discrimination decision-making task. This increased connectivity correlates with response time in gamers. The structural connectivity, as quantified by diffusion fractional anisotropy and quantitative anisotropy measures of the axonal fiber pathways between the same regions was also enhanced for gamers compared to nongamers. These findings provide valuable insights into how action video gaming can induce targeted neuroplastic changes, enhancing structural and functional connectivity between specific brain regions in the visual processing pathways. These connectivity changes in the dorsal visual stream underpin the superior performance of action video gamers compared to non-gamers in tasks requiring rapid and accurate vision-based decision-making. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=169 SRC="FIGDIR/small/615213v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1ebf169org.highwire.dtl.DTLVardef@1363d13org.highwire.dtl.DTLVardef@1e3c08eorg.highwire.dtl.DTLVardef@176e719_HPS_FORMAT_FIGEXP M_FIG C_FIG Impact StatementUnderstanding the neural mechanisms underlying how observed cognitive alterations due to video game playing are achieved has potential implications for future cognitive training, rehabilitation, and education. The structural and functional MRI analysis in this study provides a quantitative basis by which the underlying neural connectivity changes due to video game playing in the visual streams may be assessed and linked to observed behavioral differences. These methods are extendible and provide insight into underlying neural network enhancements associated with improved cognitive performance due to video game playing. The findings of this study support enhanced functional and structural connectivity in the dorsal visual stream among gamers due to video game playing in the behavioral paradigm of vision-based sensorimotor decision-making. Functional connectivity measures that were considered were significantly correlated with the participants response times.

neuroscience↗

bioRxiv2024

Rapid Parallel Visual Presentation Provides a New Perspective on Relative Clause Processing in Mandarin Chinese

A fundamental question in language processing research is the degree to which the acceptability and ease of interpretation of a sentence are affected by the moment-by-moment memory encoding and retrieval processes needed to process it in time, vs. the properties of the linguistic representation itself, such as syntactic complexity. This manuscript investigates relative clauses, a crucial testing ground for theories of language processing, using parallel presentation, a technique in which the key elements of the target syntactic dependency are displayed to the visual system at the same time. Compared to serial presentation, parallel presentation mitigates the extent to which complex memory operations must be deployed to process the structure word-by-word. We report on an electroencephalography (EEG) experiment in Mandarin Chinese. Participants were presented with sentences which contained either a subject- or object-modifying subject- or object-extracted relative clause. Sentence presentation was split across two separate screens, with each screen being displayed only for 166ms on average. We find a behavioral preference for subject-extracted relative clauses and distinct EEG signatures for subject- and object-extracted relative clauses. Together, these results - on account of the parallel presentation scheme applied here - provide support for the independent contribution of linguistic representation in processing difficulty and the perspective that relative clause processing involves more than the factors that word by word accounts of this phenomenon would suggest. Further, the EEG result contributes to a growing body of electrophysiology literature attempting to illuminate the processing mechanisms deployed in the context of parallel presentation.

neuroscience↗

bioRxiv2024

An in vivo screen for proteolytic switches that can mediate Notch activation

Notch proteins are single pass transmembrane receptors activated by sequential extracellular and intramembrane cleavages that release their cytosolic domains to function as transcription factors in the nucleus. Upon binding, Delta/Serrate/LAG-2 (DSL) ligands activate Notch by exerting a "pulling" force across the intercellular ligand/receptor bridge. This pulling force is generated by Epsin-mediated endocytosis of ligand into the signal-sending cell, and results in the extracellular cleavage of the force-sensing Negative Regulatory Region (NRR) of the receptor by an ADAM10 protease [Kuzbanian (Kuz) in Drosophila]. Here, we have used chimeric Notch and DSL proteins to screen for other domains that can function as ligand-dependent proteolytic switches in place of the NRR in the developing Drosophila wing. While most of the tested domains are either refractory to cleavage or constitutively cleaved, we identify several that mediate Notch activation in response to ligand. These NRR analogues derive from widely divergent source proteins and have strikingly different predicted structures. Yet, almost all depend on force exerted by Epsin-mediated ligand endocytosis and cleavage catalyzed by Kuz. We posit that the sequence space of protein domains that can serve as force-sensing proteolytic switches in Notch activation is unexpectedly large, a conclusion that has implications for the mechanism of target recognition by Kuz/ADAM10 proteases and is consistent with a more general role for force dependent ADAM10 proteolysis in other cell contact-dependent signaling mechanisms. Our results also validate the screen for increasing the repertoire of proteolytic switches available for synthetic Notch (synNotch) therapies and tissue engineering. One sentence summaryA scalable in vivo screen for Epsin and ADAM10 dependent proteolytic switches that can mediate Notch activation in response to force.

cell biology↗

bioRxiv2024

Rapid visual form-based processing of (some) grammatical features in parallel reading: An EEG study in English

Theories of language processing - and typical experimental methodologies - emphasize the word-by-word processing of sentences. This paradigm is good for approximating speech or careful text reading, but arguably, not for the common, cursory glances used while reading short sentences (e.g., cellphone notifications, social media posts). How can we interpret a sentence in a single glance? In an electroencephalography (EEG) study, brain responses to grammatical sentences (the dogs chase a ball) presented for 200ms diverged from non-lexical consonant strings (thj rjxb zkhtb w lhct) [~]160ms post-sentence onset and from scrambled constructions (a dogs chase ball the) [~]250ms post-sentence onset, demonstrating - at different time points - rapid recognition and cursory analysis of linguistic stimuli. In the grammatical sentences, unigram probability correlated with EEG data [~]150-300ms post-sentence onset, and probability of the word given its context estimated by BERT correlated with EEG data after [~]700-800ms. EEG responses did not diverge between grammatical sentences and their counterparts with ungrammatical agreement (the dogs chases a ball), although EEG responses did diverge for plural vs. singular morphology at [~]200ms. These results suggest that at-a-glance reading is possible, based on coactivation of individual lexical items, morphological structures, and constituent structure at [~]200-300ms, but that words are not integrated into a coherent syntactic/semantic analysis, as evidenced by the substantially later responses to BERT probability and the absence of sensitivity to agreement errors.

neuroscience↗

bioRxiv2023

Pyruvate Kinase Activity Regulates Cystine Starvation Induced Ferroptosis through Malic Enzyme 1 in Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with high mortality and limited efficacious therapeutic options. PDAC cells undergo metabolic alterations to survive within a nutrient-depleted tumor microenvironment. One critical metabolic shift in PDAC cells occurs through altered isoform expression of the glycolytic enzyme, pyruvate kinase (PK). Pancreatic cancer cells preferentially upregulate pyruvate kinase muscle isoform 2 isoform (PKM2). PKM2 expression reprograms many metabolic pathways, but little is known about its impact on cystine metabolism. Cystine metabolism is critical for supporting survival through its role in defense against ferroptosis, a non-apoptotic iron-dependent form of cell death characterized by unchecked lipid peroxidation. To improve our understanding of the role of PKM2 in cystine metabolism and ferroptosis in PDAC, we generated PKM2 knockout (KO) human PDAC cells. Fascinatingly, PKM2KO cells demonstrate a remarkable resistance to cystine starvation mediated ferroptosis. This resistance to ferroptosis is caused by decreased PK activity, rather than an isoform-specific effect. We further utilized stable isotope tracing to evaluate the impact of glucose and glutamine reprogramming in PKM2KO cells. PKM2KO cells depend on glutamine metabolism to support antioxidant defenses against lipid peroxidation, primarily by increased glutamine flux through the malate aspartate shuttle and utilization of ME1 to produce NADPH. Ferroptosis can be synergistically induced by the combination of PKM2 activation and inhibition of the cystine/glutamate antiporter in vitro. Proof-of-concept in vivo experiments demonstrate the efficacy of this mechanism as a novel treatment strategy for PDAC. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/557984v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@fa23c2org.highwire.dtl.DTLVardef@41c01dorg.highwire.dtl.DTLVardef@abc283org.highwire.dtl.DTLVardef@6f53ef_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIPKM2KO in pancreatic ductal adenocarcinoma (PDAC) cells produces enhanced defense against cystine starvation induced ferroptosis. C_LIO_LIPharmacologic activation of pyruvate kinase (PK) activity promotes ferroptosis under cystine starvation, while inhibition promotes ferroptosis survival in PDAC cells. C_LIO_LIDecrease in PK activity reprograms glutamine metabolism to increase use of malic enzyme 1 and promote survival under cystine starvation in PDAC cells. C_LIO_LICystine starvation and activation of pyruvate kinase synergistically decreases progression of pancreatic cancer in vivo. C_LI

cancer biology↗

bioRxiv2023

Unraveling Neural Complexity: Exploring Brain Entropy to Yield Mechanistic Insight in Neuromodulation Therapies for Tobacco Use Disorder

Neuromodulation therapies, such as repetitive transcranial magnetic stimulation (rTMS), have shown promise as treatments for tobacco use disorder (TUD). However, the underlying mechanisms of these therapies remain unclear, which may hamper optimization and personalization efforts. In this study, we investigated alteration of brain entropy as a potential mechanism underlying the neural effects of noninvasive brain stimulation by rTMS in people with TUD. We employed sample entropy (SampEn) to quantify the complexity and predictability of brain activity measured using resting-state fMRI data. Our study design included a randomized single-blind study with 42 participants who underwent 2 data collection sessions. During each session, participants received high-frequency (10Hz) stimulation to the dorsolateral prefrontal cortex (dlPFC) or a control region (visual cortex), and resting-state fMRI scans were acquired before and after rTMS. Our findings revealed that individuals who smoke exhibited higher baseline SampEn throughout the brain as compared to previously-published SampEn measurements in control participants. Furthermore, high-frequency rTMS to the dlPFC but not the control region reduced SampEn in the insula and dlPFC, regions implicated in TUD, and also reduced self-reported cigarette craving. These results suggest that brain entropy may serve as a potential biomarker for effects of rTMS, and provide insight into the neural mechanisms underlying rTMS effects on smoking cessation. Our study contributes to the growing understanding of brain-based interventions for TUD by highlighting the relevance of brain entropy in characterizing neural activity patterns associated with smoking. The observed reductions in entropy following dlPFC-targeted rTMS suggest a potential mechanism for the therapeutic effects of this intervention. These findings support the use of neuroimaging techniques to investigate the use of neuromodulation therapies for TUD.

neuroscience↗

bioRxiv2023

Emergent spatiotemporal patterning of synthetic Notch signal transduction in vivo

Cell-cell communication through direct contact, or juxtacrine signaling, is important in development, disease, and many areas of physiology. Synthetic forms of juxtacrine signaling can be precisely controlled and operate orthogonally to native processes, making them a powerful reductionist tool with which to address fundamental questions in cell-cell communication in vivo. Here we investigate how cell-cell contact length and tissue growth dynamics affect juxtacrine signal responses through implementing a custom synthetic gene circuit in Drosophila wing imaginal discs alongside mathematical modeling to determine synthetic Notch (synNotch) activation patterns. We find that the area of contact between cells largely determines the extent of syn-Notch activation, leading to the prediction that the shape of the interface between signal-sending and signal-receiving cells will impact the magnitude of the synNotch response. Notably, synNotch outputs form a graded spatial profile that extends several cell diameters from the signal source, providing evidence that the response to juxtacrine signals can persist in cells as they proliferate away from source cells, or that cells remain able to communicate directly over several cell diameters. Our model suggests the former mechanism may be sufficient, since it predicts graded outputs without diffusion or long-range cell-cell communication. Overall, we identify that cell-cell contact area together with output synthesis and decay rates likely govern the pattern of synNotch outputs in both space and time during tissue growth, insights that may have broader implications for juxtacrine signaling in general.

biophysics↗

bioRxiv2020

Topoisomerase 1 inhibition therapy protects against SARS-CoV-2-induced inflammation and death in animal models.

The ongoing pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is currently affecting millions of lives worldwide. Large retrospective studies indicate that an elevated level of inflammatory cytokines and pro-inflammatory factors are associated with both increased disease severity and mortality. Here, using multidimensional epigenetic, transcriptional, in vitro and in vivo analyses, we report that Topoisomerase 1 (Top1) inhibition suppresses lethal inflammation induced by SARS-CoV-2. Therapeutic treatment with two doses of Topotecan (TPT), a FDA-approved Top1 inhibitor, suppresses infection-induced inflammation in hamsters. TPT treatment as late as four days post-infection reduces morbidity and rescues mortality in a transgenic mouse model. These results support the potential of Top1 inhibition as an effective host-directed therapy against severe SARS-CoV-2 infection. TPT and its derivatives are inexpensive clinical-grade inhibitors available in most countries. Clinical trials are needed to evaluate the efficacy of repurposing Top1 inhibitors for COVID-19 in humans.

microbiology↗

bioRxiv2019

Molecular profiling of lymphovascular invasive cancer cells in TNBC using G&T-seq

Lymphovascular invasion (LVI) is a critical step in the metastatic process but have received relatively little attention due to the technical challenges associated with their isolation. In this study, we used laser capture microdissection (LCM) to isolate 97 cancer cell clusters from pathological frozen sections within lymphatic vessels, primary tumor tissue, and axillary lymph nodes of a triple negative breast cancer (TNBC) patient. Simultaneous genome and transcriptome amplification and sequencing (G&T-seq) performed on these clusters permitted a comprehensive depiction of the genomic and transcriptional profiles of cancer cells associated with LVI. Combination phylogeny analysis pointed to three evolutionarily distinct pathways of tumor clone development and metastasis in this patient, each of which was associated with a unique mRNA signature, and correlated to disparate overall survival outcomes. Moreover, hub gene evaluation found extensive down regulation of ribosomal protein mRNA to be a potential marker of poor prognosis in breast cancer patients.

cancer biology↗