Biology subjects

Reddy, S.

Publications and source records attributed to Reddy, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Individualized AI-driven Neuromodulation Selectively Enhances and Reorganizes Human Tongue Sensorimotor Networks.

Precise modulation of brain networks for tongue motor and sensory control (TMSC) is critical for neruorehabilitation. Existing neuromodulation approaches use fixed targets, ignoring individual network architecture. We present an AI-driven, individualized fMRI neuromodulation (iNM) platform adaptively targeting subject-specific TMSC networks in real-time. Using a neurofunctional twin built from each participant's anatomy and function, iNM reinforces targeted activity and suppresses competing states. Unsupervised machine learning and hidden Markov modeling showed iNM increased TMSC-state occupancy from 82% to 97% and suppressed swallow-state interference by 83%. The inferior parietal lobule emerged as a sensorimotor integration hub, with increased magnitude (d' 90.4 right, 84 left) and spatial expansion (134.8% right, 81.8% left). Cortico-subcortical connectivity strengthened 53% to 74% across motor, sensory, and attention networks and persisted into non-iNM blocks. Thus, iNM may offer precision neurorehabilitation for CNS or PNS disorders, such as amyotrophic lateral sclerosis, and treatment-induced cranial neuropathy in head-and-neck-cancer survivors, respectively.

neuroscience↗

bioRxiv2026

Photoaged microplastics disrupt endothelial stretch-sensitive ion channels to impair calcium signaling and vascular integrity

Plastic-derived micro- and nanoplastics are pervasive, but how environmentally aged particles affect vascular barriers is poorly understood. We hypothesized that photoaged plastics impair endothelial force-sensing, triggering gut-brain-heart barrier failure. Ultraviolet (UV) exposure converted pristine nanoplastics into oxidized, irregular photoaged microplastic aggregates (> 1.2 {micro}m). In human aortic endothelial cells, photoaged particles increased membrane stiffness and activated transcriptional programs linked to permeability, junction disruption, inflammation, and cytoskeletal remodeling. Mechanistically, photoaged particles selectively inhibited Piezo1-mediated Ca2+ signaling and downstream Notch activity without changing PIEZO1 expression, and endothelial CRISPR inhibition of PIEZO1 recapitulated these effects. In zebrafish, photoaged plastic exposure increased gut-vascular permeability and systemic spread with brain and heart accumulation, accompanied by reduced neurovascular and myocardial Ca2+ signals, depressed cardiac contractility, and abnormal locomotor behavior. Thus, photoaged plastics compromise vascular barriers through disrupted endothelial Piezo1-Notch mechanotransduction.

cell biology↗

bioRxiv2026

β2-Adrenergic Signaling Switches from Cardioprotective to Cardiotoxic in Acute vs. Chronic Oxidative Stress

BACKGROUND AND PURPOSE{beta}-adrenergic receptors (AR) regulate both cardiac function and remodeling. Many studies suggest that, in addition to their effects on heart rate and contractility, {beta}1-ARs mediate cardiotoxic signaling, whereas {beta}2-ARs are generally cardioprotective. However, there is conflicting data on the role of {beta}2-ARs, differing dependent on the nature of the stress. Given the extremely common use of {beta}-blockers and agonists clinically, we sought to understand the differential cardioprotective/cardiotoxic effects of {beta}2-AR signaling dependent on timing (acute vs. chronic) and type of cardiotoxic stress. EXPERIMENTAL APPROACHWild-type (WT) and {beta}-AR knockout ({beta}1-KO and {beta}2-KO) mice were subjected to acute (15 mg{middle dot}kg-1 x 1 dose) or chronic (2 mg{middle dot}kg-1{middle dot}wk-1 x 7 wks) oxidative stress using doxorubicin (DOX). Survival, cardiac function and histopathology were assessed and differential signaling activation determined by Western blot and gene expression by RNA-seq. KEY RESULTSWe have shown that {beta}2-KOs manifest extreme cardiotoxicity with acute DOX (100% mortality within 30 min), supporting a strong cardioprotective role of {beta}2-signaling. In marked contrast, with chronic DOX, {beta}2-KO had enhanced survival (t[1/2] 54 d vs. 42 d in WT) and attenuated cardiac dysfunction. In {beta}2-KO, acute DOX activated stress MAPKs (p38, ERK and JNK), whereas chronic DOX did not; furthermore, in the absence of {beta}2-ARs, oxidative stress and lipid accumulation were reduced, genes regulating compensatory metabolic pathways (AMPK and insulin/PI3K) were upregulated, and genes regulating mitochondrial and contractile function were preserved, whereas they were downregulated in WT with chronic DOX. CONCLUSIONS{beta}2-AR signaling switches from being cardioprotective during acute oxidative stress, to cardiotoxic during chronic stress. Inhibition of {beta}2-AR signaling during chronic stress induces signaling and metabolic compensations that serve to reduce oxidative injury. This unexpected temporal switching has potential significant implications for all models of cardiovascular disease, as well as for the clinical use of subtype-specific {beta}-blockers. CLINICAL PERSPECTIVEO_ST_ABSWhat is new?C_ST_ABSO_LIOur finding that {beta}2-adrenergic receptor signaling can switch from being beneficial (cardioprotective) to detrimental (cardiotoxic) depending on the acuteness or chronicity of a cardiac stressor. C_LIO_LIIdentification of the mechanisms by which this temporal switch is mediated could lead to new drug development. C_LI What are the clinical implications?O_LIOur findings provide potential guidance in choosing between a {beta}1-specific vs. a {beta}1/2-non-specific drug when treating specific cardiovascular diseases based on their temporal characteristics. C_LIO_LIThe temporal protective/toxic switching that we describe could be a mechanism common to many other drugs, yet is rarely tested, suggesting the need for additional studies using temporal course as a factor. C_LI

cell biology↗

bioRxiv2026

Deciphering sepsis molecular subtypes using large-scale data to identify subtype-specific drug repurposing

Sepsis is a life-threatening dysregulated response to infection, the heterogeneity of which precludes effective targeted therapies. To address this, we created a transcriptomic atlas of publicly available adult sepsis data, on which we performed molecular subtyping and identified potential subtype-specific drug repurposing opportunities. In total, we harmonized data from 3,713 samples across 28 datasets, of which 2,251 were from sepsis patients. Using this data, we identified four molecular subtypes of sepsis (C1 - C4) by clustering the sepsis samples based on expression differences in immune-and lipid-related genes. We next identified gene signatures unique to each molecular subtype. Pathway analysis of these signatures revealed patterns of immune exhaustion and metabolic dysregulation in C1, suggesting potential benefit from corticosteroid treatment. C2 had the youngest patient population and the lowest mortality, and C2 expression patterns were often anti-correlated with those of C1. C3 was enriched for inflammatory and cellular stress pathways, while the highest mortality subtype, C4, showed evidence of immunosuppression and metabolic reprogramming. Gene and pathway-level analysis of our molecular subtypes statistically correlated with results from analysis of 28-day mortality, with the best (C2) and worst subtypes (C4) exhibiting similar molecular dysregulation as survivors and non-survivors, respectively. For each subtype, we then evaluated potential targeted therapies. Using a large-scale pharmacogenomics database, we identified drugs targeting the subtype gene signatures and assessed the potential clinical impacts of these drugs. We identified several potential candidate therapies for each molecular subtype, including possible responsiveness to Methylene Blue therapy for patients from our highest mortality subtype, C4. Notably, our drug repurposing analysis revealed a significant representation of anti-inflammatory monoclonal antibody therapies across molecular subtypes. The anti-correlated signatures in C1 and C2 suggest that monoclonal antibody therapies may not be effective for patients in both subtypes, which may explain why prior clinical trials have been unsuccessful. Altogether, our detailed molecular subtyping and analysis identify potential drug targets within each molecular subtype, with implications for future precision medicine for sepsis.

bioinformatics↗

bioRxiv2026

Ribosome Processing Factor-2 Interacts with RPL10A to Regulate Selective Translation during Plant Immunity and Drought Stress

Processing of ribosomal RNA (rRNA) is essential for ribosome biogenesis, translation, plant development, and stress adaptation. Ribosome processing factor-2 (RPF2), which plays a role in the later stages of rRNA maturation, interacts with ribosomal protein L10A (RPL10A). RPF2 overexpression in Arabidopsis and Nicotiana benthamiana showed enhanced plant growth and trichome development due to increased gibberellic acid (GA) levels. Conversely, RPF2-silenced and mutant plants had a dwarf phenotype, reduced stomatal apertures, and decreased glucosinolate accumulation. RPF2 silenced and mutant plants also showed compromised nonhost disease resistance, whereas RPF2 overexpression lines exhibited enhanced disease resistance to both host and nonhost pathogens. RPL10A and RPF2 overexpression lines were sensitive to abscisic acid (ABA) and tolerant to drought, which is attributed to their unique roles in translation regulation. Despite having larger stomatal apertures, RPF2 overexpression plants displayed low pathogen multiplication rates and reduced water loss, indicating independent resistance mechanisms associated with ribosomal functions in translation regulation. Although both RPL10A and RPF2 proteins interact with each other and are involved in translation regulation, proteomic analysis suggests that they regulate the translation of distinct sets of genes during pathogen or drought stress. These findings indicate that RPF2 and RPL10A play independent roles in the regulation of unique protein translation.

plant biology↗

bioRxiv2025

Pre-treatment Microbiome Diversity and Function is associated with Expansion of Cytotoxic and Regulatory Immune Populations after N-803 treatment in People with HIV

BackgroundN-803, an IL-15 superagonist, is currently being studied in clinical trials as a treatment to reverse HIV latency. However, its effects on the gut microbiome are not well understood. MethodsIn this longitudinal metagenomic study, we analyzed fecal microbiomes from ART-suppressed people with HIV at four different timepoints before, during, and after N-803 treatment. ResultsOverall taxonomic and functional diversity did not change significantly, yet beneficial microbial taxa and pathways were enriched after N-803. Specifically, the relative abundance of Faecalibacterium prausnitzii increased significantly after N-803, whereas histidine degradation pathways, often associated with pro-inflammatory mucosal state, decreased. A higher baseline microbial diversity correlated with stronger CD8+ and natural killer (NK) cells activation and reduced frequency of rectal HIV RNA+ cells. MaAsLin2 analyses further associated short-chain fatty acid (SCFA)-producing taxa and pathways with increased immune activation markers. ConclusionsThese results indicate that gut microbiome diversity prior to immunotherapy influences host response and suggest that microbiome-based strategies could improve efforts to cure HIV.

microbiology↗

bioRxiv2025

The human Flower isoform hFWE4 facilitates cornification in cutaneous squamous cell carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common human tumor and arises from keratinocytes that comprise the epidermis and its associated hair follicles. Remarkably, transformed keratinocytes within a cSCC retain some ability to execute the terminal differentiation program that typically generates a stratified epidermis. Instead of the polarized stratification towards the body surface seen in normal epidermis, cSCC keratinocytes differentiate concentrically inward to produce keratin pearls. It is well appreciated that cSCC differentiation status is correlated with degree of local invasion and potential for distant metastasis, with well differentiated tumors having a better prognosis. While molecular mechanisms that govern the differentiation process are incompletely understood, identifying candidate molecules associated with cSCC differentiation can provide new histologic markers for prognostic stratification. Here we demonstrate that Flower (FWE), a newly described regulator of lamellar body (LB) trafficking in normal epidermis, is specifically expressed within highly differentiated layers of cSCC. Genetic knockout of the hFWE gene dysregulates cornification and LB-related gene expression leading to abnormal keratinization patterns, while ectopic hFWE4 expression drives G1-arrest and exit from the proliferative basal keratinocyte population. Additionally, we find that poorly differentiated keratinocyte regions of human cSCC exhibit minimal FWE-positivity, while this population is readily detectable in well-differentiated regions. We propose that FWE represents a novel differentiation marker in cSCC that could be utilized for classifying differentiation status and prognostic stratifying these tumors.

cancer biology↗

bioRxiv2025

An integrated enzymatic and computational pipeline for quantifying off-target base-editing

DNA base editing is increasingly used for human genetic modification, but methods for monitoring off-target editing are nascent. Here we present a simple model-independent workflow for identifying sites of off-target base-editing in relevant cell types on a genome-wide level. We report that sites of off-target editing by the ABE8e editor could be identified using an ABE8e derivative with restored DSB cleavage activity. This allows marking of enzyme-generated double-stranded (ds) DNA breaks by incorporation of dsDNA oligonucleotides that are transfected into primary target cells. DNA sequencing at sites of oligonucleotide incorporation reported both the genomic location of off-target cleavage and the extent of base-editing nearby. We present a platform combining this cellular (BEiGUIDE-Seq) and computational workflow (CRISPRito) to generate optimized amplicon panels for convenient monitoring of off-target base editing. This work introduces a generalizable strategy to evaluate off-target edits in patient-derived cells, addressing a critical safety gap for clinical base editing.

molecular biology↗

bioRxiv2025

Generalized brain-state modeling with KenazLBM

The large-scale functional state of a human brain remains difficult to characterize, much less predict. Regardless, techniques have been engineered to electrically neuromodulate the brain to treat a subset of neurologic and psychiatric disorders with moderate efficacy. Accurate characterization of a brains instantaneous functional state has stymied the development of more effective neuromodulation paradigms. Advanced computational methods are required to address this gap and enable large-scale neuroscience. Here we define the concept of generalized brain-state modeling across humans as Large Brain-State Modeling (LBM) and present KenazLBM as the worlds first example. KenazLBM can instantaneously characterize the functional state of a persons brain with raw iEEG data, and predict future brain-states. KenazLBM was trained on over 17.9 billion unique multichannel tokens from people undergoing intracranial electroencephalography (iEEG) recordings, and has learned to interrelate brain-states between people into a common interpretable topology. Most importantly, the model generalizes to unseen subject data with significant recording channel heterogeneity from the training set. We offer KenazLBM as a first generalized brain-state model to serve as a new paradigm of basic neuroscience inquiry and potential translation into neuromodulation therapeutics.

neuroscience↗

bioRxiv2025

Epistasis between Na+/K+-ATPase Substitutions May Influence Salinity Tolerance in Steinernema Entomopathogenic Nematodes

Soil salinity varies widely across geographies both due to natural factors and human activities, including agriculture, road salt application, sea level rise, and desertification. Increases in soil salinity may affect organisms widely and particularly impact soil foodwebs. As parasites, entomopathogenic nematodes (EPNs) occupy crucial links in soil foodwebs and are important for agriculture as biological control agents of insect pests. Previous research found that the EPN Steinernema carpocapsae may exhibit higher salt tolerance than several of its congeners. We recently identified that S. carpocapsae uniquely evolved two amino acid substitutions in the first extracellular loop of the sodium pump (Na{square}/K{square}-ATPase). Here, we tested if these substitutions explain S. carpocapsaes reported lower sensitivity to salt. Our results confirm that S. carpocapsae exhibits higher salt tolerance and show it can more effectively locate and infect insect hosts than its congeners S. feltiae and S. hermaphroditum in highly saline environments. We then retraced the evolution of the two amino acid substitutions in S. carpocapsae by introducing them alone and in combination in Caenorhabditis elegans using CRISPR genome engineering. We found that C. elegans mutants with single substitutions showed improved salt tolerance. However, this improvement disappeared in the double mutant, whose sodium pump mimicked that of S. carpocapsae. This pattern of negative epistasis between the amino acid substitutions suggests they are not responsible for variation in salt tolerance between Steinernema species. Sodium pump evolution in S. carpocapsae might instead be driven by encounters with cardiac glycosides, which are released into soil by several clades of plants including milkweeds, sequestered by some of this EPNs herbivorous insect hosts, and known to target the first extracellular loop of the sodium pump. Our findings provide valuable insights into EPN adaptation to changes in environmental sodium levels and may have implications for their use in biological control.

ecology↗

bioRxiv2024

Tempo and mode of evolution across multiple traits in an adaptive radiation of birds (Vangidae)

An ongoing challenge in macroevolutionary research is identifying common drivers of diversification amid the complex interplay of many potentially relevant traits, ecological contexts, and intrinsic characteristics of clades. In this study, we used geometric morphometric and phylogenetic comparative methods to evaluate the tempo and mode of trait evolution in the adaptive radiation of Malagasy vangas and their mainland relatives. The Malagasy radiation is more diverse in both skull and foot shape. However, rather than following the classic "early burst" of diversification, trait evolution accelerated well after their arrival in Madagascar, likely driven by the evolution of new modes of foraging and especially of a few species with highly divergent morphologies. Each anatomical region showed differing evolutionary patterns, and the presence of morphological outliers impacted the results of some analyses, particularly of integration and modularity. Our results demonstrate that the adaptive radiation of Malagasy vangas has evolved exceptional ecomorphological diversity along multiple, independent trait axes, mainly driven by a late expansion in niche space due to key innovations. Our findings highlight the evolution of extreme forms as an overlooked feature of adaptive radiation warranting further study.

evolutionary biology↗

bioRxiv2024

Metagenomic Insights into the Spatio-temporal Variation of Metal and Antibiotic Resistance Genes in Lake Erie

Antibiotic resistance and metal toxicity in freshwater bodies have human health impacts and carry economic implications worldwide. The presence of metal and antibiotic resistance genes within microbial communities can be informative about both issues. The Laurentian Great Lakes contain nearly 20% of the worlds supply of freshwater; however, it is unclear how these genes are changing over time in this system. In this study, we characterized these genes in nearly two hundred metagenomes collected from multiple sites in western Lake Erie at a five-year time interval: 2014-2019. 11 metal resistance genes (MRGs) and nine antibiotic resistance genes (ARGs) were characterized and demonstrated significant changes in diversity and spatial distribution. Increased abundance was observed for genes like aac(3) and TEM-1B conferring resistance to aminoglycoside (gentamicin) and {beta}-lactam antibiotics, respectively. MRGs associated with mercury, lead, and arsenic also increased in abundance over the five years. Collectively, our data point to a notable increase in both ARGs and MRGs in Lake Erie over five years, with a specific and significant increase in the abundance of genes conferring resistance to aminoglycoside and {beta}-lactam antibiotic resistance and mercury contamination. Future integrated and systematic freshwater microbiome and public health investigations are needed to assess the potential impact on humans and environmental health from increasing microbial antibiotic and metal resistance in large freshwater reservoirs like the Great Lakes. IMPORTANCEAntibiotic and metal resistance genes (ARGs and MRGs) in microbial communities of the Laurentian Great Lakes have significant human and environmental health implications. However, an assessment of the Great Lakes microbiome for ARGs and MRGs is lacking. The abundance of 11 MRGs and 9 ARGs was characterized between 2014 and 2019 and showed significant abundance differences. Specifically, we observed an increase in genes conferring resistance to aminoglycoside (gentamicin) and {beta}-lactam antibiotics (amongst the most commonly utilized antibiotics in humans), such as aac(3) and TEM-1B, respectively. MRGs conferring resistance to mercury, lead, and arsenic also increased in abundance, with the largest increase observed for mercury resistance genes such as MerA, MerP, and MerT. Collectively, these findings point to a concerning increased abundance of both ARGs and MRGs in Lake Erie. Further studies to assess the causes for the increase and the direct impact on human and environmental health are needed.

microbiology↗

bioRxiv2024

Reversible and effective cell cycle synchronization method for studying stage-specific investigations

The cell cycle is a crucial process for cell proliferation, differentiation, and development. Numerous genes and proteins play pivotal roles at specific cell cycle stages to regulate these events precisely. Studying the stage-specific functions of the cell cycle requires accumulating cell populations at the desired cell cycle stage. Cell synchronization, achieved through the use of cell cycle kinase and protein inhibitors, is often employed for this purpose. However, suboptimal concentrations of these inhibitors can result in reduced efficiency, irreversibility, and undesirable cell cycle defects. In this study, we have optimized effective and reversible techniques to synchronize the cell cycle at each stage in human RPE1 cells, utilizing both fixed high-precision cell cycle identification methods and high-temporal live-cell imaging. These reproducible synchronization methods are invaluable for investigating the regulatory mechanisms specific to each cell cycle stage.

cell biology↗

bioRxiv2024

Mass spectrometric profiling of estrogen and estrogen metabolites in human stool and plasma partially elucidates the role of the gut microbiome in estrogen recycling

Estrogen and estrogen metabolites are commonly measured in human plasma and serum, but there exist almost no reports of estrogen measured in human stool. This methodological limitation in turn limits our understanding of the relationship between systemic and intestinal estrogen. We thus developed a highly sensitive liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method for measuring free and conjugated forms of 15 estrogens and estrogen metabolites in human stool and plasma. We first investigated human stool and plasma estrogen in healthy control males; follicular and luteal phase premenopausal females; and postmenopausal females. Most estrogens were present in the plasma and stool of all groups, and plasma estrogen levels correlated with stool estrogen levels. In stool, estrogens were higher in premenopausal females, with estrogen levels rising across the menstrual cycle. We further combined these measures with shotgun metagenomic sequencing of the stool microbiomes. The level of estrogen deconjugation enzyme gene copy number (beta-glucuronidase + arylsulfatase) was higher in premenopausal females; while the gene copy numbers of beta-glucuronidase + arylsulfatase, but not beta-glucuronidase alone, correlated with reactivated stool estrogen in all groups. Moreover, deconjugation enzyme gene copy number correlated with plasma total estrogen in males and with individual plasma estrogen metabolites in all groups. These results support the hypothesis that gut microbial beta-glucuronidase and arylsulfatase control the reactivation of gut estrogen while modulating systemic levels through the uptake and recirculation of reactivated estrogen.

molecular biology↗

bioRxiv2024

Drug-controlled CAR-T cells through the regulation of cell-cell interactions

CAR T-cell therapy is constrained by on-target, off-tumor toxicities as well as cellular exhaustion due to chronic antigen exposure. CARs comprising small-molecule controlled switches can enhance both safety and therapeutic efficacy but are limited by the scarcity of non-immunogenic protein elements responsive to non-immunosuppressive, clinically approved drugs with favorable pharmacodynamics. Here, we combine rational design and library-based optimization of a protein-protein interaction (PPI) of human origin to develop venetoclax-controlled Drug-Regulated Off-switch PPI (DROP)-CARs. DROP-CARs enable dose-dependent release of the tumor-targeting scFv and consequent T-cell dissociation from the target tumor cell. Additionally, we present proof-of-concept for a dual DROP-CAR controlled by different small molecules, as well as for logic-gated synthetic receptors enabling STAT3 signaling. We demonstrate in vitro and in vivo function of DROP-CAR T cells and conclude that the approach holds promise for clinical application.

synthetic biology↗

bioRxiv2024

The microanatomy of human skin in aging

Aging is a major driver of diseases in humans. Identifying features associated with aging is essential for designing robust intervention strategies and discovering novel biomarkers of aging. Extensive studies at both the molecular and organ/whole-body physiological scales have helped determined features associated with aging. However, the lack of meso-scale studies, particularly at the tissue level, limits the ability to translate findings made at molecular scale to impaired tissue functions associated with aging. In this work, we established a tissue image analysis workflow - quantitative micro-anatomical phenotyping (qMAP) - that leverages deep learning and machine vision to fully label tissue and cellular compartments in tissue sections. The fully mapped tissue images address the challenges of finding an interpretable feature set to quantitatively profile age-related microanatomic changes. We optimized qMAP for skin tissues and applied it to a cohort of 99 donors aged 14 to 92. We extracted 914 microanatomic features and found that a broad spectrum of these features, represented by 10 cores processes, are strongly associated with aging. Our analysis shows that microanatomical features of the skin can predict aging with a mean absolute error (MAE) of 7.7 years, comparable to state-of-the-art epigenetic clocks. Our study demonstrates that tissue-level architectural changes are strongly associated with aging and represent a novel category of aging biomarkers that complement molecular markers. Our results highlight the complex and underexplored multi-scale relationship between molecular and tissue microanatomic scales.

pathology↗

bioRxiv2024

Individualized fMRI neuromodulation enhances visuospatial perception: a guided approach targeted towards the neuro-rehabilitation of cortical blindness and deceleration of subjective cognitive impairment.

Neuromodulation is a growing precision-medicine approach to modulating neural activity that can be used to treat neuropsychiatric, and general pathophysiologic conditions. We developed individualized fMRI neuromodulation (iNM) to study the mechanisms of visuospatial perception modulation with the long-term goal of applying it in low-vision patient populations having cortical blindness or visuospatial impairment preceding subjective cognitive impairment. To determine these mechanisms, we developed a direction and coherence discrimination task to engage visual perception (VP), visual imagery (VI), selective extero-intero-ceptive attention (SEIA), and motor planning (MP) networks. Participants discriminated up and down direction, at full and subthreshold coherence under iNM or control (no iNM). We determined the blood-oxygen-level-dependent (BOLD) magnitude as area under the curve (AUC) for VI, SEIA, and MP encoded networks and used a decoder to predict the stimulus from brain maps. The increased AUC BOLD magnitude under iNM across directions and coherences ranged from: 48-76% for SEIA, 26-59% for MP, 20-47% for VI, and 100% for strong VP coherences, but decreased for weak coherences. iNM increased classification performance. Our results imply a causal role of iNM-induced visuospatial mechanisms in strengthening these networks and provide a pathway for more accurate encoding models and effective treatment.

neuroscience↗

bioRxiv2023

Faulty Metabolism: A Potential Instigator of an Aggressive Phenotype in Cdk5-dependent Medullary Thyroid Carcinoma

Mechanistic modeling of cancers such as Medullary Thyroid Carcinoma (MTC) to emulate patient-specific phenotypes is challenging. The discovery of potential diagnostic markers and druggable targets in MTC urgently requires clinically relevant animal models. Here we established orthotopic mouse models of MTC driven by aberrantly active Cdk5 using cell-specific promoters. Each of the two models elicits distinct growth differences that recapitulate the less or more aggressive forms of human tumors. The comparative mutational and transcriptomic landscape of tumors revealed significant alterations in mitotic cell cycle processes coupled with the slow-growing tumor phenotype. Conversely, perturbation in metabolic pathways emerged as critical for aggressive tumor growth. Moreover, an overlapping mutational profile was identified between mouse and human tumors. Gene prioritization revealed putative downstream effectors of Cdk5 which may contribute to the slow and aggressive growth in the mouse MTC models. In addition, Cdk5/p25 phosphorylation sites identified as biomarkers for Cdk5-driven neuroendocrine tumors (NETs) were detected in both slow and rapid onset models and were also histologically present in human MTC. Thus, this study directly relates mouse and human MTC models and uncovers vulnerable pathways potentially responsible for differential tumor growth rates. Functional validation of our findings may lead to better prediction of patient-specific personalized combinational therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/544755v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@196ed2dorg.highwire.dtl.DTLVardef@1ad2d59org.highwire.dtl.DTLVardef@7c6e84org.highwire.dtl.DTLVardef@13bd7db_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LICGRP driven aberrant Cdk5 activation develops early onset aggressive MTC C_LIO_LIGenetic alterations in mouse and human tumors disrupt common pathways C_LIO_LIAggressive tumor model characterized by alterations in metabolic pathways C_LIO_LISlow growing tumor model elicits disruption of mitotic spindle assembly C_LI

cancer biology↗