Biology subjects

Kennedy, E.

Publications and source records attributed to Kennedy, E..

15 recordsLinked to original sources

bioRxiv2026

Acute Paternal Immune Activation Shapes Embryonic Development and Protects Offspring from Viral Infection

The evolutionary arms race between host and pathogen is traditionally framed as a multigenerational paradigm, where beneficial host immune adaptations accrue in a population over time through DNA sequence variation. If pathogens exposure alters epigenetic information inherited by offspring through paternal gametes, advantageous immune traits could emerge within a single generation. We show that acute paternal immune activation (PIA) induces immune signaling in the male reproductive tract and remodels the sperm small RNA profile. Using IVF, we show that altered sperm small RNAs from immune-activated males reprograms gene expression in preimplantation embryos, eliciting sex-specific transcriptional responses. This transcriptional program is reflected in a striking inherited phenotype, as male offspring sired by PIA males exhibit enhanced survival following lethal viral challenge. These findings identify sperm small RNAs as a molecular mechanism that links PIA to embryonic development and offspring immunity, providing a comprehensive framework for how PIA shapes inherited pathogen protection.

immunology↗

bioRxiv2025

Improved Estimation of Correlation Accuracy for Machine Learning Brain-Phenotype Associations

Machine learning is used in neuroscience to examine brain-phenotype associations and facilitate individual prediction from high-dimensional brain imaging. For continuous phenotypes, Pearsons correlation between the observed and predicted phenotype is used to quantify model accuracy in testing data. However, recent research suggests millions of samples may be needed to reliably estimate the maximum achievable predictive accuracy (MAPA). We formally define the MAPA and show that Pearsons estimator is biased for this quantity and its confidence intervals fail to capture the target. We develop a semiparametric (double machine learning) one-step estimator that more accurately estimates the MAPA and yields valid confidence intervals across flexible machine learning settings. Analyzing data from the Reproducible Brain Charts dataset, we show that this estimator has smaller bias when estimating brain-phenotype associations of neuroimaging data with age and psychopathology phenotypes. We show that MAPA for psychopathology factor scores using machine learning models built on structural and functional imaging measures is not better than using demographic and nuisance covariates alone.

neuroscience↗

bioRxiv2025

Dynamics of Bacterial and Viral Transmission in Experimental Microbiota Transplantation

Mouse models are vital tools for discerning the relative contributions of host and microbial genetics to disease, often requiring the transplantation of microbiota between different mouse strains. Transfer methods include antibiotic treatment of recipients and colonization using either co-housing with donors or the transplantation of fecal or cecal donor material. However, the efficiency and dynamics of these methods in reconstituting recipients with donor microbes is not well understood. We thus directly compared co-housing, fecal transplantation, and cecal transplantation methods. Donor mice from Taconic Biosciences, possessing distinct microbial communities, served as the microbial source for recipient mice from Jackson Laboratories, which were treated with antibiotics to disrupt their native microbiota. We monitored bacterial and viral populations longitudinally over the course of antibiotics treatment and reconstitution using 16S rRNA gene sequencing, quantitative PCR, and shotgun sequencing of viral-like particles. As expected, antibiotic treatment rapidly depleted microbial biomass and diversity, with slow and incomplete natural recovery of the microbiota in non-transplanted control mice. While all transfer methods reconstituted recipient mice with donor microbiota, co-housing achieved this more rapidly for both bacterial and viral communities. This study provides valuable insights into microbial transfer methods, enhancing reproducibility and informing best practices for microbiota transplantation in mouse models.

microbiology↗

bioRxiv2025

Microbiota assembly of specific pathogen-free neonatal mice

BackgroundNeonatal mice are frequently used to model diseases that affect human infants. Microbial community composition has been shown to impact disease progression in these models. Despite this, the maturation of the early-life murine microbiome has not been well-characterized. We address this gap by characterizing the assembly of the bacterial microbiota of C57BL/6 and BALB/c litters from birth to adulthood across multiple independent litters. ResultsThe fecal microbiome of young pups is simple, dominated by only a few pioneering bacterial taxa. These taxa are present at low levels in the microbiota of multiple maternal body sites, precluding a clear identification of maternal source. The pup microbiota begins diversifying after fourteen days, coinciding with the beginning of coprophagy and the consumption of solid foods. Pup stool bacterial community composition and diversity are not significantly different from dams from day 21 onwards. Short-read shotgun sequencing-based metagenomic profiling of young pups enabled the assembly of metagenome-assembled genomes for strain-level analysis of these pioneer Ligilactobacillus, Streptococcus, and Proteus species. ConclusionsAssembly of the murine microbiome occurs over the first weeks of postnatal life and is largely complete by day 21. This detailed view of bacterial community development across multiple commonly employed mouse strains informs experimental design, allowing researchers to better target interventions before, during, or after the maturation of the bacterial microbiota. The source of pioneer bacterial strains appears heterogeneous, as the most abundant taxa identified in young pup stool were found at low levels across multiple maternal body sites, suggesting diverse routes for seeding of the murine microbiome.

microbiology↗

bioRxiv2024

Non-continuous neuromodulation in awake, unrestrained felines increases bladder capacity

ObjectiveNeuromodulation is a standard therapy for bladder symptoms such as overactive bladder. Previous studies have demonstrated that non-continuous stimulation (NCS) can increase bladder capacity and that bladder pressure can be estimated from dorsal root ganglia (DRG) neural activity in anesthetized animal models. Our goal is to determine if NCS elicits similar bladder capacity effects as continuous stimulation (CS) and if bladder pressure can be estimated from DRG signals in an awake, unrestrained animal model. ApproachWe performed aseptic, chronic implant surgeries with seven adult, male felines. Three animals were used to establish procedures, three for experimental testing, and one did not yield data. Bipolar stimulating electrodes were placed on the pudendal nerve and sacral nerve on the same side. Microelectrode arrays were inserted in two ipsilateral sacral DRG. Two single-lumen catheters were implanted in the bladder dome for recording bladder pressure and infusing saline. Fixed-sequence, repeated bladder fills were performed in four awake felines to evaluate the bladder capacity during no-stimulation (NS), NCS, and CS at either the pudendal or sacral nerve. NCS was performed based on increases in bladder pressure estimated from DRG recordings or when 50% of the average NS bladder capacity was reached. Main resultsWe observed similar bladder capacity increases for NCS (122 {+/-} 31% of NS control) as for CS (121 {+/-} 33%) in the four animals. NCS paradigms reduced stimulation time by 46% on average. Median correlation coefficients of 0.46 and 0.64 (maximum 0.93) between the predicted and measured bladder pressure were obtained for awake trials with DRG bladder units in two animals. SignificanceThis study demonstrated the feasibility of using NCS to increase bladder capacity in awake, unrestrained felines and for decoding bladder pressure from DRG recordings. Further studies are needed to optimize NCS timing for clinical translation.

bioengineering↗

bioRxiv2023

Bridging Big Data: Procedures for Combining Non-equivalent Cognitive Measures from the ENIGMA Consortium

Investigators in neuroscience have turned to Big Data to address replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. These efforts unveil new questions about integrating data arising from distinct sources and instruments. We focus on the most frequently assessed cognitive domain - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated global raw data from 53 studies totaling N = 10,505 individuals. A mega-analysis was conducted using empirical bayes harmonization to remove site effects, followed by linear models adjusting for common covariates. A continuous item response theory (IRT) model estimated each individuals latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance while preserving covariate effects, and our conversion tool is freely available online. This demonstrates that large-scale data sharing and harmonization initiatives can address reproducibility and integration challenges across the behavioral sciences. TeaserWe present a global effort to devise harmonization procedures necessary to meaningfully leverage big data.

neuroscience↗

bioRxiv2022

Brain-Controlled Electrical Stimulation Restores Continuous Finger Function

Brain-machine interfaces have shown promise in extracting upper extremity movement intention from the thoughts of nonhuman primates and people with tetraplegia. Attempts to restore a users own hand and arm function have employed functional electrical stimulation (FES), but most work has restored discrete grasps. Little is known about how well FES can control continuous finger movements. Here, we use a low-power brain-controlled functional electrical stimulation (BCFES) system to restore continuous volitional control of finger positions to a monkey with a temporarily paralyzed hand. In a one-dimensional, continuous, finger-related target acquisition task, the monkey improved his success rate to 83% (1.5s median acquisition time) when using the BCFES system during temporary paralysis from 8.8% (9.5s median acquisition, equivalent to chance) when attempting to use his temporarily paralyzed hand. With two monkeys under general anesthesia, we found FES alone could control the monkeys fingers to rapidly reach targets in a median 1.1s but caused oscillation about the target. Finally, when attempting to perform a virtual two-finger continuous target acquisition task in brain-control mode following temporary hand paralysis, we found performance could be completely recovered by executing recalibrated feedback-intention training one time following temporary paralysis. These results suggest that BCFES can restore continuous finger function during temporary paralysis using existing low-power technologies and brain-control may not be the limiting performance factor in a BCFES neuroprosthesis.

neuroscience↗

bioRxiv2022

Manipulating the 3D organization of the largest synthetic yeast chromosome

Whether synthetic genomes can power life has attracted broad interest in the synthetic biology field, especially when the synthetic genomes are extensively modified with thousands of designer features. Here we report de novo synthesis of the largest eukaryotic chromosome thus far, synIV, a 1,454,621-bp Saccharomyces cerevisiae chromosome resulting from extensive genome streamlining and modification. During the construction of synIV, we developed megachunk assembly combined with a hierarchical integration strategy, which significantly increased the accuracy and flexibility of synthetic chromosome construction and facilitated chromosome debugging. In addition to the drastic sequence changes made to synIV by rewriting it, we further manipulated the three-dimensional structure of synIV in the yeast nucleus to explore spatial gene regulation within the nuclear space. Surprisingly, we found few gene expression changes, suggesting that positioning inside the yeast nucleoplasm plays a minor role in gene regulation. Lastly, we tethered synIV to the inner nuclear membrane via its hundreds of loxPsym sites and observed transcriptional repression of the entire chromosome, demonstrating chromosome-wide transcription manipulation without changing the DNA sequences. Our manipulation of the spatial structure of the largest synthetic yeast chromosome shed light on higher-order architectural design of the synthetic genomes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/487066v2_ufig1.gif" ALT="Figure 1"> View larger version (64K): org.highwire.dtl.DTLVardef@18bf586org.highwire.dtl.DTLVardef@1a471d5org.highwire.dtl.DTLVardef@12d7690org.highwire.dtl.DTLVardef@1c32510_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIDe novo synthesis of the largest eukaryotic chromosome, synIV C_LIO_LISynIV shows similar 3D structure to wild-type IV, despite thousands of changes made to it C_LIO_LI"Inside-out" repositioning of synIV in nucleus shows minor transcriptional changes C_LIO_LIMultipoint tethering synIV to inner nuclear membrane represses transcription of whole chromosome C_LI

synthetic biology↗

bioRxiv2021

Tibial nerve stimulation increases vaginal blood perfusion and bone mineral density and yield load in ovariectomized rats

Introduction and HypothesisHuman menopause transition and post-menopausal syndrome, driven by reduced ovarian activity and estrogen levels, are associated with an increased risk for symptoms including but not limited to sexual dysfunction, metabolic disease, and osteoporosis. Current treatments are limited in efficacy and may have adverse consequences, so investigation for additional treatment options is necessary. Previous studies have demonstrated that tibial nerve stimulation (TNS) or electro-acupuncture near the tibial nerve are minimally invasive treatments that increase vaginal blood perfusion or serum estrogen in the rat model. We hypothesized that TNS would protect against harmful reproductive and systemic changes associated with menopause. MethodsWe examined the effects of twice weekly TNS (0.2 ms pulse width, 20 Hz, 2x motor threshold) under ketamine-xylazine anesthesia in ovariectomized (OVX) female Sprague Dawley rats on menopause-associated physiological parameters including serum estradiol, body weight, blood glucose, bone health, and vaginal blood flow. Rats were split into three groups (n = 10 per group): 1) intact control (no stimulation), 2) OVX control (no stimulation), and 3) OVX stimulation (treatment group). ResultsTNS did not affect serum estradiol levels, body weight, or blood glucose. TNS transiently increased vaginal blood perfusion during stimulation for up to 5 weeks after OVX and increased areal bone mineral density and yield load of the right femur (side of stimulation) compared to the unstimulated OVX control. ConclusionTNS may ameliorate some symptoms associated with menopause. Additional studies to elucidate the full potential of TNS on menopause-associated symptoms under different experimental conditions are warranted. SummaryPercutaneous tibial nerve stimulation increases vaginal blood perfusion, areal bone mineral density, and femur yield load in an ovariectomized rat model of menopause.

physiology↗

bioRxiv2020

Metabolic reprogramming and host-immune response against Crimean-Congo Hemorrhagic Fever Viruses

The pathogenesis and host-viral interactions of the Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV) are convoluted and not well evaluated. Application of the multi-omics system biology approaches including biological network analysis in elucidating the complex host-viral response, allow for interrogating the viral pathogenesis. The present study aimed to fingerprint the system-level alterations during acute CCHFV-infection and the cellular immune responses during productive CCHFV-replication in vitro. We used system-wide network-based system biology analysis of peripheral blood mononuclear cells (PBMCs) from a longitudinal cohort of CCHF patients during the acute phase of infection and after one year of recovery (convalescent phase) and untargeted quantitative proteomics analysis of the most permissive CCHFV-infected Huh7 and SW13 cells. In the RNAseq analysis of the PBMCs, comparing the acute and convalescent-phase, we observed system-level hosts metabolic reprogramming towards central carbon and energy metabolism (CCEM) with distinct upregulation of oxidative phosphorylation (OXPHOS) during CCHFV-infection. Upon application of network-based system biology methods, negative coordination of the biological signaling systems like FOXO/Notch axis and Akt/mTOR/HIF-1 signaling with metabolic pathways during CCHFV-infection were observed. The temporal quantitative proteomics in Huh7 showed a dynamic change in the CCEM over time and was in agreement with the cross-sectional proteomics in SW13 cells. By blocking the two key CCEM pathways, glycolysis and glutaminolysis, viral replication was inhibited in vitro. Activation of key interferon stimulating genes during infection suggested the role of type I and II interferon-mediated antiviral mechanisms both at system-level and during progressive replication. Significance StatementA combination of multi-modal systems-wide host-immune response and in vitro temporal analysis identified molecular re-arrangement in CCEM and fingerprinting the interferon-mediated antiviral mechanism during CCHFV-infection. Using the newly gained insights, we then modulated the key pathways of CCEM by drugs and inhibited the productive CCHFV-replication in in vitro infection models. Our study thus provides a comprehensive, system-level picture of the regulation of cellular and metabolic pathways during productive CCHFV-infection for the first time that aids in identifying novel therapeutic targets and treatment strategies.

microbiology↗

bioRxiv2020

High burden of Mycoplasma genitalium and other reproductive tract infections among pregnant women in Papua New Guinea

There is a pressing need for detailed knowledge of the range of pathogens, extent of co-infection and clinical impact of reproductive tract infections (RTIs) among pregnant women. Here, we report on RTIs (Mycoplasma genitalium, Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis, Treponema pallidum subspecies pallidum, bacterial vaginosis and vulvovaginal candidiasis) and other sexual and reproductive health indicators among 699 pregnant women in Papua New Guinea (PNG). We found widespread M. genitalium infection (12.5% of women), the first time this pathogen has been reported in PNG, with no evidence of macrolide resistance. Most pregnant women (76.2%) had at least one RTI, most of which are treatable. Excluding syphilis, sexually-transmitted infections were detected in 37.8% women. Syndromic management of infections is greatly inadequate and there was remarkably little use of contraception; 98.4% report never having used barrier contraception. This work has implications for improving maternal and child health in PNG. ARTICLE SUMMARY LINEThis first report of Mycoplasma genitalium in Papua New Guinea finds a high burden (12.5%) among 699 pregnant women. Additionally, more than one in two women were positive for a treatable reproductive tract infection associated with poor health outcomes.

microbiology↗

bioRxiv2020

Twist, Snail, and Sox9 form an allosterically regulated complex, the EMTosome, on a bipartite E-box site.

Epithelial-Mesenchymal transition (EMT) of primary tumor cells is a critical trans-differentiation event that contributes to dissemination and metastasis. The process of EMT is controlled by specific DNA-binding transcription factors (TFs) that reprogram the tumor transcriptome. In particular, the canonical EMT-TFs Twist and Snail can induce an EMT program when overexpressed in cancer cells, and both are found upregulated in metastatic cancers. Twist and Snail bind DNA directly, by recognition to variants of the E-Box sequence CANNTG. However, it is unclear how this binding is regulated. We have used a biochemical approach to dissect DNA binding and protein-protein interactions that occur amongst these proteins. We find that Twist preferentially recognizes a dyad repeat of E-boxes that are not directly bound by Snail. Our data suggest that Twist use its WR domain to recruit Snail into a binding complex through the Snail zinc-finger motifs. We analyzed Twist-Snail complexes in the breast carcinoma cell line SUM1315 and found evidence that it contains an additional protein partner, Sox9. Notably, we report that a native Twist complex can be displaced from its dyad binding site by consensus DNA binding sites for Snail and Sox9 even though these proteins do not contact the Twist dyad site. Taken together, our findings suggest that Snail and Sox9 interact with Twist to regulate its DNA binding ability via protein-protein interactions, thereby allosterically regulating Twist DNA binding. We designate this ternary complex EMTosome. These results may inform efforts to therapeutically target the EMT program in order to target cancer metastasis.

cancer biology↗

bioRxiv2019

Urodynamic parameters and anesthetic depth vary depending on anesthetic agent (alfaxalone, dexmedetomidine, propofol) at doses necessary to facilitate preclinical testing

Urodynamic studies, used to understand bladder function, diagnose bladder disease, and develop treatments for dysfunctions, are ideally performed with awake subjects. However, in animal models, especially cats (a common model of spinal cord injury and associated bladder pathology), anesthesia is often required for these procedures and can be a research confounder. This study compared the effects of select agents (dexmedetomidine, alfaxalone, propofol, isoflurane, and -chloralose) on urodynamic ({Delta}pressure, bladder capacity, bladder compliance, non-voiding contractions, bladder pressure slopes) and anesthetic (change in heart rate [{Delta}HR], average heart rate [HR], reflexes, induction/recovery times) parameters in repeated cystometrograms across five adult male cats. {Delta}pressure was greatest with propofol, bladder capacity was highest with -chloralose, non-voiding contractions were greatest with -chloralose. Propofol and dexmedetomidine had the highest bladder pressure slopes during the initial and final portions of the cystometrograms respectively. Cats progressed to a deeper plane of anesthesia (lower HR, smaller {Delta}HR, decreased reflexes) under dexmedetomidine, compared to propofol and alfaxalone. Time to induction was shortest with propofol, and time to recovery was shortest with dexmedetomidine. These agent-specific differences in urodynamic and anesthetic parameters in cats will facilitate appropriate study-specific anesthetic choices.

physiology↗

bioRxiv2019

The rodent vaginal microbiome across the estrous cycle and the effect of genital nerve electrical stimulation

Treatment options are limited for the approximately 40% of postmenopausal women worldwide who suffer from female sexual dysfunction (FSD). Neural stimulation has shown potential as a treatment for genital arousal FSD, however the mechanisms for its improvement are unknown. One potential cause of some cases of genital arousal FSD are changes to the composition of the vaginal microbiota, which is associated with vulvovaginal atrophy. The primary hypothesis of this study was that neural stimulation may induce healthy changes in the vaginal microbiome, thereby improving genital arousal FSD symptoms. In this study we used healthy rats, which are a common animal model for sexual function, however the rat vaginal microbiome is understudied. Thus this study also sought to examine the composition of the rat vaginal microbiota. Treatment rats (n=5) received 30 minutes of cutaneous electrical stimulation targeting the genital branch of the pudendal nerve, and Control animals (n=4) had 30-minute sessions without stimulation. Vaginal lavage samples were taken during a 14-day baseline period including multiple estrous periods and after twice-weekly 30-minute sessions across a six-week trial period. Analysis of 16S rRNA gene sequences was used to characterize the rat vaginal microbiota in baseline samples and determine the effect of stimulation. We found that the rat vaginal microbiota is dominated by Proteobacteria, Firmicutes, and Actinobacteria, which changed in relative abundance during the estrous cycle and in relationship to each other. While the overall stimulation effects were unclear in these healthy rats, some Treatment animals had less alteration in microbiota composition between sequential samples than Control animals, suggesting that stimulation may help stabilize the vaginal microbiome. Future studies may consider additional physiological parameters, in addition to the microbiome composition, to further examine vaginal health and the effects of stimulation.

microbiology↗

bioRxiv2019

Encoding information in synthetic metabolomes

Biomolecular information systems offer numerous potential advantages over conventional semiconductor technologies. Downstream from DNA, the metabolome is an information-rich molecular system with diverse chemical dimensions which could be harnessed for information storage and processing. As a proof of principle of postgenomic data storage, here we demonstrate a workflow for representing abstract data in synthetic metabolomes. Our approach leverages robotic liquid handling for writing digital information into chemical mixtures, and mass spectrometry for extracting the data. We present several kilobyte-scale image datasets stored in synthetic metabolomes, which are decoded with accuracy exceeding 98-99% using multi-mass logistic regression. Cumulatively, >100,000 bits of digital image data was written into metabolomes. These early demonstrations provide insight into the benefits and limitations of postgenomic chemical information systems.

synthetic biology↗