Biology subjects

Smith, D. R.

Publications and source records attributed to Smith, D. R..

At least 19 recordsLinked to original sources

bioRxiv2026

Organelle intergenic DNA is preferentially distributed between opposite-polarity gene pairs.

Across eukaryotes, mitochondrial and plastid genomes vary enormously in size and noncoding content. This variation is often attributed to diverging mutation rates, DNA repair mechanisms, and the power of genetic drift. Although these processes can help explain how much noncoding DNA an organelle genome may retain, they do not explain how this noncoding DNA is distributed throughout the genome. We analyzed over 2.6 million intergenic regions (IGRs) from ~37,000 mitochondrial and plastid genomes to test whether gene-pair polarity marks local differences in the distribution of organelle intergenic DNA. Taxonomy-structured mixed models, controlling for flanking-gene length and type, showed that IGRs between opposite-polarity gene pairs were 1.1-3.2-fold longer than those between same-polarity genes. IGRs between convergent (+-) and divergent (-+) gene pairs showed distinct residual-dispersion patterns, indicating that they are not homogeneous in their length distribution. The prevalence of opposite-polarity gene pairs showed no consistent relationship with organelle genome size or intergenic DNA fraction. Ultimately then, gene-pair polarity consistently marks where organelle intergenic DNA is preferentially located.

evolutionary biology↗

bioRxiv2026

Elevated mutation in haploid yeast driven by translesion synthesis

The impact of selection versus genetic drift on the evolution of mutation patterns is unclear. In Saccharomyces cerevisiae, which is predominantly diploid in nature, there is evidence that haploid cells have a higher mutation rate than diploids, suggesting that a haploid-specific mutator phenotype may have evolved due to the limited opportunity for selection to act on this rare cell type. Mutation in haploids was primarily elevated in late-replicating regions of the genome, implicating error-prone translesion synthesis (TLS) repair. Additional research has demonstrated that removing REV1, a gene responsible for initiating TLS, causes a reduction in haploid mutation rate. To assess whether the preferential use of this error-prone repair pathway by haploids explains the difference in genome-wide mutation patterns between cell types, we deleted REV1 in both diploid and haploid S. cerevisiae and estimated their mutation rates using a mutation accumulation experiment. Consistent with a previous study, we found a 50% higher single nucleotide mutation rate in REV1+ haploids than in REV1+ diploids. Deleting the REV1 gene caused this difference to vanish, with mutation rates in haploid and diploid rev1{Delta} lines converging on 2.4 x 10-10. Our results suggest that the mutagenic effect of translesion synthesis is much stronger in haploids, reflecting a limited opportunity for selection to act on mutation rates in rarer cells or smaller populations. We also find evidence that REV1 plays an important role in mitochondrial genome maintenance in both cell types.

evolutionary biology↗

bioRxiv2026

Single-cell characterization of skin response to a bite by West Nile virus-infected mosquito reveals fibroblast-mediated barrier to transmission

Cutaneous events at the mosquito bite site that determine orthoflavivirus transmission efficiency remain largely uncharacterized. Here, we report single-cell RNA-sequencing of skin from immunocompetent mice bitten by West Nile virus-infected mosquitoes, capturing early response at a critical transmission bottleneck. Fibroblasts were the dominant cells exposed to infectious saliva. While neutrophils and Folr2+ macrophages diminished, monocyte-derived and antigen-presenting macrophages, and lymphocytes became more abundant. Cell-cell communication analysis revealed the central roles of fibroblasts and myeloid cells in induced immune-related signaling. Transcriptional profiling defined cell type-specific responses to infectious bite integrating immune modulation, skin repair and metabolic remodeling. Using in vivo gene silencing, we demonstrated that fibroblast-expressed LRRC15 (leucine rich repeat-containing 15) functions as a cutaneous restriction factor, limiting viral replication in skin, viral dissemination to draining lymph nodes, and disease severity. Collectively, our analyses provide cellular and molecular understanding of bite-initiated arboviral transmission, establishing skin-resident fibroblasts as frontline defender cells. HIGHLIGHTSO_LISingle-cell profiling captures early cutaneous response to West Nile virus-infected mosquito bites with cell type resolution. C_LIO_LISkin-resident fibroblasts are the dominant frontline cells exposed to infectious mosquito saliva. C_LIO_LIInfectious bite reconfigures cutaneous immune cells, and activates multi-directional signaling between immune and structural skin cell types. C_LIO_LIBite-induced fibroblast-expressed LRRC15 restricts viral transmission and attenuates disease severity. C_LI

zoology↗

bioRxiv2025

Chimeric Antigen Receptors Transmit Co-stimulatory Domain Dependent Piconewton Forces to their Target

Chimeric antigen receptor (CAR) T cells promote tumor-specific cytotoxicity through engagement of a recombinant, synthetic receptor with target ligands expressed on cancer cells. Native T cells are mechanically active, both transmitting and sensing forces exceeding 19 piconewtons (pN) via transmembrane receptors, including the T cell receptor (TCR). Emerging evidence implicates mechanoactivity in CAR T cell biology, but CAR-transmitted T cell forces have not been directly measured. Here, we utilize DNA-based molecular tension probes (MTPs) conjugated to CAR target ligands, providing evidence of actin-polymerization dependent forces exceeding 4.7-19 pN borne by the CAR. We demonstrate force transmission by three clinically relevant CARs (CD123, CD33, and CD19), suggesting that these forces are generalizable across CAR targets and constructs. Additionally, we identify intracellular co-stimulatory domains as the main determinants of CAR-mediated forces, because first-generation CARs lacking co-stimulatory domains do not transmit measurable forces to their ligand. Finally, we demonstrate that CAR forces temporally precede Ca2+ signaling and are spatially correlated with phosphorylation of classical TCR-signaling machinery, indicating a link between CAR T cell forces and early biochemical signaling. Our study introduces CAR-mediated mechanobiology as a key correlate of early CAR T cell activation events. Significance StatementChimeric antigen receptor (CAR) T cell therapies have revolutionized treatment for several hematological malignancies. CARs are recombinant receptors containing domains derived from the T cell receptor complex machinery and other co-stimulatory proteins. Mechanical forces are believed to be important in T cell activation and antigen recognition. The role of mechanobiology in CAR T cell immunotherapy remains poorly understood. Here, using DNA-based molecular tension probes conjugated to CAR ligands, we provide direct evidence that CARs bear actin polymerization-dependent piconewton forces during antigen engagement that precede early signaling events. These forces depend on CAR co-stimulatory domains, and first-generation CARs lacking these domains fail to transmit detectable force. These findings suggest mechanobiology may be a key, tunable parameter for next-generation CAR T cells.

immunology↗

bioRxiv2025

How to prepare the input data and run MCScanX efficiently?

The protocol by Wang et al. is particularly useful as it outlines the steps for efficiently identifying colinear blocks in intra-and inter-species BLASTP outputs by using MCScanX. We recently discovered that the protocol lacks the pre-processing steps for checking if there are multiple isoforms derived from alternative splicing. Conserved sequences derived from alternative splicing can have similar functional domains, to avoid mis-prediction of gene duplicates, especially for the genome data from NCBI or other online resources. Without this step, the number of duplicate genes will be overrepresented. Besides we shared some useful experience to faster preparing the input data and easier running MCScanX. This is including alternative options to prepare the .gff input file and iterated all-against-all BLASTP processing. Lastly, we want to raise awareness of the potential challenges when preparing the input files and highlight potential issues when using the protocol.

bioinformatics↗

bioRxiv2025

Protocol for GDT, Gene Dictionary Tool, to create and implement a gene dictionary across annotated genomes

The Gene Dictionary Tool is a protocol for the creation and implementation of gene dictionaries across annotated genomes. Through a Python CLI (Command Line Interface), the user identifies what annotations are missing in the inputted dictionary. Via two Jupyter Notebooks, the user builds a gene dictionary based on attributes retrieved from inputted GFF3 files. The final output, a .gdict file, is Findable, Accessible, Interoperable, and Reusable (FAIR). We showcase GDTs functionalities by creating a gene dictionary for fungal mitochondrial genomes.

bioinformatics↗

bioRxiv2025

Germline polymorphism in the immunoglobulin kappa and lambda loci explain variation in the expressed light chain antibody repertoire

Variation in antibody (Ab) responses contributes to variable disease outcomes and therapeutic responsiveness, the determinants of which are incompletely understood. This study demonstrates that polymorphisms in immunoglobulin (IG) light chain loci dictate the composition of the Ab repertoire, establishing fundamental baseline differences that preclude functional Ab-mediated responses. Using long-read genomic sequencing of the IG kappa (IGK) and IG lambda (IGL) loci, we comprehensively resolved genetic variation, including novel structural variants, single nucleotide variants, and gene alleles. By integrating these genetic data with Ab repertoire profiling, we found that all forms of IG germline variation contributed to inter-individual gene usage differences for >70% of light chain genes in the repertoire, directly impacting the amino acids of expressed light chain transcripts, including complementarity determining region domains. The genomic locations of usage - associated variants in both intergenic and coding regions indicated that IG polymorphisms modulate gene usage via diverse mechanisms, likely including the modulation of V(D)J recombination, heavy and light chain pairing biases, and transcription/translation. Finally, relative to IGL, IGK was characterized by more extensive linkage disequilibrium and genetic co-regulation of gene usage, illuminating differential regulatory and evolutionary features between the two light chain loci. These results firmly establish the critical contribution of IG light chain polymorphism in Ab repertoire diversity, with important implications for investigating Ab responses in health and disease.

immunology↗

bioRxiv2025

Antimuscarinic drugs exert β-arrestin-biased agonism at the muscarinic acetylcholine type 1 receptor

Previous studies indicate that both pirenzepine (PZ), a selective orthosteric muscarinic acetylcholine type 1 receptor (M1R) antagonist, and muscarinic toxin 7 (MT7), a negative M1R allosteric modulator (NAM), act via M1R to promote neuritogenesis in cultured adult rodent primary dorsal root ganglia (DRG) sensory neurons, in part, through {beta}-arrestin-dependent activation of extracellular signal-regulated protein kinase 1/2 (ERK1/2). Furthermore, these antagonists reverse nerve degeneration in a variety of rodent models of peripheral neuropathy through multiple complementary pathways. To understand the therapeutic effects and mechanism of M1R antagonist-induced ERK1/2 phosphorylation, we tested the hypothesis that PZ and MT7 possess {beta}-arrestin-biased agonism at M1R to drive activation of ERK and enhance neurite outgrowth. Treatment for up to 30 min with PZ and MT7 dose-dependently recruited {beta}-arrestin2 to M1R (analyzed using nano-BRET) and increased ERK phosphorylation in both HEK293 cells and DRG neurons. DRG neurons of different sub-types express M1R, and ERK activation by MT7 was only observed in M1R-positive neurons. These novel pharmacological effects occurred in the absence of activation of G protein signaling or receptor internalization. PZ phosphorylated M1R at six specific serine/threonine residues (T230, S251, T254, S321, T354, S356) of intracellular loop 3 (ICL3) and deletion mutation of these sites suppressed PZ and MT7 induction of {beta}-arrestin binding to M1R and inhibited ERK activation. With regard to PZ signaling, alanine substitution at S251 and T254 was sufficient to impede {beta}-arrestin binding and ERK activation. {beta}-arrestin-biased activity of PZ and MT7 involved the mobilization of casein kinase 2 (CK2) and this occurred in the absence of Gq or G protein receptor kinase (GRK) activity. Pharmacological or siRNA-based inhibition of CK2 blocked PZ-induction of {beta}-arrestin association, ERK activation and neurite outgrowth in DRG neurons. In conclusion, PZ/MT7 activated M1R toward the {beta}-arrestin signaling pathway in both HEK293 cells and DRG neurons to augment ERK activation and neurite outgrowth via engagement of CK2. One-sentence summaryAntimuscarinic drugs act as {beta}-arrestin-biased agonists via casein kinase 2 activation to promote ERK1/2 phosphorylation and neurite outgrowth O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/649213v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1bb8da7org.highwire.dtl.DTLVardef@510218org.highwire.dtl.DTLVardef@608d69org.highwire.dtl.DTLVardef@e40d9e_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstract.C_FLOATNO Schematic presentation of the effect of muscarinic ligands at M1R associated signaling pathway. (A) Muscarine/carbachol acts as a balanced ligand by engaging both Gq and -arrestin signaling pathways and treatment with pirenzepine/MT7 blocks these effects. (B) Pirenzepine/MT7 acts as a -arrestin biased ligand by 1) phosphorylating of ICL3 region of M1R via CK2 (but not GRKs), 2) no activation of G protein signaling, 3) recruitment of -arrestin 2 and 4) ERK1/2 activation leading to neurite outgrowth in DRG sensory neurons. This figure was generated by BioRender under license number EK285MUOPQ. C_FIG

pharmacology and toxicology↗

bioRxiv2024

Antimicrobial cetylpyridinium chloride suppresses mast cell function by targeting tyrosine phosphorylation of Syk kinase

Cetylpyridinium chloride (CPC) is a quaternary ammonium antimicrobial used in numerous personal care products, human food, cosmetic products, and cleaning solutions. Yet, there is minimal published data on CPC effects on eukaryotes, immune signaling, and human health. Previously, we showed that low-micromolar CPC inhibits rat mast cell function by inhibiting antigen (Ag)-stimulated Ca2+ mobilization, microtubule polymerization, and degranulation. In this study, we extend the findings to human mast cells (LAD2) and present data indicating that CPCs mechanism of action centers on its positively-charged quaternary nitrogen in its pyridinium headgroup. CPCs inhibitory effect is independent of signaling platform receptor architecture. Tyrosine phosphorylation events are a trigger of Ca2+ mobilization necessary for degranulation. CPC inhibits global tyrosine phosphorylation in Ag-stimulated mast cells. Specifically, CPC inhibits tyrosine phosphorylation of specific key players Syk kinase and LAT, a substrate of Syk. In contrast, CPC does not affect Lyn kinase phosphorylation. Thus, CPCs root mechanism is electrostatic disruption of particular tyrosine phosphorylation events essential for signaling. This work outlines the biochemical mechanisms underlying the effects of CPC on immune signaling and allows the prediction of CPC effects on cell types, like T cells, that share similar signaling elements.

pharmacology and toxicology↗

bioRxiv2024

Sphingomyelins in mosquito saliva modify the host lipidome to enhance transmission of flaviviruses by promoting viral protein levels

Mosquito saliva plays a determining role in flavivirus transmission. Here, we discover and elucidate how salivary lipids enhance transmission. Building upon our discovery of salivary extracellular vesicles (EV), we determined that lipids within mosquito EVs, and neither within human EVs nor virions, enhance infection for flaviviruses in primary cell types relevant for transmission. Mechanistically, mosquito EV-lipids specifically promote viral protein levels by reducing ER-associated degradation. Infection enhancement is caused by sphingomyelins within mosquito salivary EVs that elevate sphingomyelin concentration within host cells. Transmission assays showed that mosquito EV-lipids exacerbate disease severity. Our study reveals that EV-associated sphingomyelins within mosquito saliva enhance transmission for multiple flaviviruses by reconfiguring the host lipidome to promote viral protein levels and the resulting skin infection. Our findings open a new dimension centered on lipids in the interplay between hosts, mosquitoes and flaviviruses that determine transmission, unveiling lipids as a new pan-flavivirus target. HighlightsO_LILipids within mosquito extracellular vesicles (EVs) enhance infection in primary skin and immune cells for multiple flaviviruses. C_LIO_LIMosquito EV-lipids increase flaviviral protein levels by dampening ER-associated degradation. C_LIO_LISphingomyelins within salivary EVs are responsible for the infection enhancement by altering host lipidome. C_LIO_LICo-injection of mosquito EV-lipids exacerbate disease severity. C_LI

pathology↗

bioRxiv2024

Mechanical Properties of White Matter Tracts in Aging Assessed via Anisotropic MR Elastography

Magnetic resonance elastography (MRE) is a promising neuroimaging technique to probe tissue microstructure, which has revealed widespread softening with loss of structural integrity in the aging brain. Traditional MRE approaches assume mechanical isotropy. However, white matter is known to be anisotropic from aligned, myelinated axonal bundles, which can lead to uncertainty in mechanical property estimates in these areas when using isotropic MRE. Recent advances in anisotropic MRE now allow for estimation of shear and tensile anisotropy, along with substrate shear modulus, in white matter tracts. The objective of this study was to investigate age-related differences in anisotropic mechanical properties in human brain white matter tracts for the first time. Anisotropic mechanical properties in all tracts were found to be significantly lower in older adults compared to young adults, with average property differences ranging between 0.028-0.107 for shear anisotropy and between 0.139-0.347 for tensile anisotropy. Stiffness perpendicular to the axonal fiber direction was also significantly lower in older age, but only in certain tracts. When compared with fractional anisotropy measures from diffusion tensor imaging, we found that anisotropic MRE measures provided additional, complementary information in describing differences between the white matter integrity of young and older populations. Anisotropic MRE provides a new tool for studying white matter structural integrity in aging and neurodegeneration.

neuroscience↗

bioRxiv2024

Phylogeography of the Giant Honeybees Based on Mitochondrial Gene Sequences

AO_SCPLOWBSTRACTC_SCPLOWWe carried out a phylogenetic analysis of the giant honeybees using mitochondrial COI and COII gene sequences analyzed with maximum likelihood methods. Our goal was to resolve phylogenetic relationships among Apis laboriosa, and the Apis dorsata subspecies: A. d. dorsata, A. d. binghami, and A. d. breviligula, the last two of which have been proposed as full species by several authors. We obtained strong support for four clades within A. dorsata: the three subspecies mentioned above, and a fourth from south India, but our analysis did not resolve the phylogenetic relationships among the four clades within A. dorsata in the broad sense. Recognition of these distinct lineages is important for conservation planning, so that their individual ecologies and migration patterns can be taken into account.

genetics↗

bioRxiv2024

ComI inhibits transformation in Bacillus subtilis by selectively killing competent cells

Many bacteria build elaborate molecular machines to import DNA via natural competence, yet this activity is often not identified until strains have been handled and domesticated in laboratory settings. For example, one of the best studied Gram-positive model organisms, Bacillus subtilis, has a non-transformable ancestor. Transformation in the ancestral strain is inhibited by a transmembrane peptide, ComI, which is encoded on an extrachromosomal plasmid. Although ComI was shown to be necessary and sufficient to inhibit transformation when produced at high levels under an inducible promoter, the mechanism by which ComI inhibits transformation is unknown. Here, we examine the native regulation and mechanism of transformation inhibition by ComI. We find that under native regulation, ComI expression is restricted in the absence of the plasmid. In the presence of the plasmid, we find that ComI is preferentially expressed in cells that are differentiating into a competent state. The subcellular localization of ComI, however, does not depend on any other competence proteins and permeabilization activity is concentration dependent. Thus over time, the competent cells gradually producing ComI, are permeabilized and killed. Based on these observations we propose a new model for the mechanism of ComI, suggesting a response to competence activation that selectively eliminates the competent subpopulation. ImportanceNatural transformation mechanisms have been studied across several bacterial systems, but few examples of inhibition exist. This work investigates the mechanism of action of a plasmid-encoded transmembrane inhibitor of natural transformation. The data reveal that the peptide can cause cell permeabilization. Permeabilization is synergistic with entry of Bacillus subtilis into the "competent" state, such that cells with ability to be transformed are preferentially killed. These findings reveal a self-preservation mechanism coupled to the physiological state of the cells that ensures the population can maintain unaltered plasmid and its predicted prophage.

microbiology↗

bioRxiv2023

Developmental Manganese Exposure Causes Lasting Attention Deficits Accompanied by Dysregulation of mTOR Signaling and Catecholaminergic Gene Expression in Brain Prefrontal Cortex

Elevated manganese (Mn) exposure is associated with attentional deficits in children, and is an environmental risk factor for attention deficit hyperactivity disorder (ADHD). We have shown that developmental Mn exposure causes lasting attention and sensorimotor deficits in a rat model of early childhood Mn exposure, and that these deficits are associated with a hypofunctioning catecholaminergic system in the prefrontal cortex (PFC), though the mechanistic basis for these deficits is not well understood. To address this, male Long-Evans rats were exposed orally to Mn (50 mg/kg/d) over PND 1-21 and attentional function was assessed in adulthood using the 5-Choice Serial Reaction Time Task. Targeted catecholaminergic system and epigenetic gene expression, followed by unbiased differential DNA methylation and gene regulation expression transcriptomics in the PFC, were performed in young adult littermates. Results show that developmental Mn exposure causes lasting focused attention deficits that are associated with reduced gene expression of tyrosine hydroxylase, dopamine transporter, and DNA methyltransferase 3a. Further, developmental Mn exposure causes broader lasting methylation and gene expression dysregulation associated with epigenetic regulation, inflammation, cell development, and hypofunctioning catecholaminergic neuronal systems. Pathway enrichment analyses uncovered mTOR and Wnt signaling pathway genes as significant transcriptomic regulators of the Mn altered transcriptome, and Western blot of total, C1 and C2 phospho-mTOR confirmed mTOR pathway dysregulation. Our findings deepen our understanding of the mechanistic basis of how developmental Mn exposure leads to lasting catecholaminergic dysfunction and attention deficits, which may aid future therapeutic interventions of environmental exposure associated disorders. Significance StatementAttention deficit hyperactivity disorder (ADHD) is associated with environmental risk factors, including exposure to neurotoxic agents. Here we used a rodent model of developmental manganese (Mn) exposure producing lasting attention deficits to show broad epigenetic and gene expression changes in the prefrontal cortex, and to identify disrupted mTOR and Wnt signaling pathways as a novel mechanism for how developmental Mn exposure may induce lasting attention and catecholaminergic system impairments. Importantly, our findings establish early development as a critical period of susceptibility to lasting deficits in attentional function caused by elevated environmental toxicant exposure. Given that environmental health threats disproportionately impact communities of color and low socioeconomic status, our findings can aid future studies to assess therapeutic interventions for vulnerable populations.

pharmacology and toxicology↗

bioRxiv2023

Methylphenidate alleviates attentional and sensorimotor dysfunction induced by developmental manganese exposure: Assessment of catecholaminergic receptor involvement

Environmental manganese (Mn) exposure is associated with impaired attention and psychomotor functioning, as well as impulsivity/hyperactivity in children and adolescents. We have shown previously that developmental Mn exposure can cause these same dysfunctions in a rat model. Methylphenidate (MPH) lessens impairments in attention, impulse control, and sensorimotor function in children, but it is unknown whether MPH ameliorates these dysfunctions when induced by developmental Mn exposure. Here, we sought to (1) determine whether oral MPH treatment ameliorates the lasting attention and sensorimotor impairments caused by developmental Mn exposure, and (2) elucidate the mechanism(s) of Mn neurotoxicity and MPH effectiveness. Rats were given 50 mg Mn/kg/d orally over PND 1-21 and assessed as adults in a series of attention, impulse control and sensorimotor tasks during oral MPH treatment (0, 0.5, 1.5, or 3.0 mg/kg/d). Subsequently, selective catecholaminergic receptor antagonists were administered to gain insight into the mechanism(s) of action of Mn and MPH. Developmental Mn exposure caused persistent attention and sensorimotor impairments. MPH treatment at 0.5 mg/kg/d completely ameliorated the Mn attentional dysfunction, whereas the sensorimotor deficits were ameliorated by the 3.0 mg/kg/d MPH dose. Notably, the MPH benefit on attention was only apparent after prolonged treatment, while MPH efficacy for the sensorimotor deficits emerged early in treatment. Selectively antagonizing D1, D2, or 2A receptors had no effect on the Mn-induced attentional dysfunction or MPH efficacy in this domain. However, antagonism of D2R attenuated the Mn sensorimotor deficits, whereas the efficacy of MPH to ameliorate those deficits was diminished by D1R antagonism. These findings demonstrate that MPH is effective in alleviating the lasting attention and sensorimotor dysfunction caused by developmental Mn exposure, and they clarify the mechanisms underlying developmental Mn neurotoxicity and MPH efficacy. Given that the cause of attention and psychomotor deficits in children is often unknown, these findings have implications for the treatment of environmentally-induced attentional and psychomotor dysfunction in children more broadly. HighlightsO_LIDevelopmental Mn exposure impaired attention and sensorimotor function C_LIO_LIMPH ameliorated the Mn deficits, but the effective dose varied by functional domain C_LIO_LIThe MPH benefit on attention was only apparent after prolonged treatment C_LIO_LINo specific catecholaminergic receptor singly mediates Mn-induced inattention or MPH efficacy in this domain C_LIO_LIDopamine 1 and 2 receptors moderated Mn sensorimotor deficits and MPH efficacy in this domain C_LIO_LIMPH can improve behavioral dysfunction induced by an environmental toxicant C_LI

animal behavior and cognition↗

bioRxiv2023

Maternal choline supplementation: A potential therapy for developmental Manganese exposure?

Studies in children have reported associations between elevated manganese (Mn) exposure and ADHD-related symptoms of inattention, impulsivity/hyperactivity, and psychomotor impairment. Maternal choline supplementation (MCS) during pregnancy/lactation may hold promise as a protective strategy because it has been shown to lessen cognitive dysfunction caused by numerous early insults. Our objectives were to determine whether (1) developmental Mn exposure alters behavioral reactivity/emotion regulation, in addition to impairing learning, attention, impulse control, and sensorimotor function, and (2) MCS protects against these Mn-induced impairments. Pregnant Long-Evans rats were given standard diet, or a diet supplemented with additional choline throughout gestation and lactation (G3 - PND 21). Male offspring were exposed orally to 0 or 50 mg Mn/kg/day over PND 1-21. In adulthood, animals were tested in a series of learning, attention, impulse control, and sensorimotor tasks. Mn exposure caused lasting dysfunction in attention, reactivity to errors and reward omission, learning, and sensorimotor function, recapitulating the constellation of symptoms seen in ADHD children. MCS lessened Mn-induced attentional dysfunction and partially normalized reactivity to committing an error or not receiving an expected reward but provided no protection against Mn-induced learning or sensorimotor dysfunction. In the absence of Mn exposure, MCS produces lasting offspring benefits in learning, attention, and reactivity to errors. To conclude, developmental Mn exposure produces a constellation of deficits consistent with ADHD symptomology, and MCS offered some protection against the adverse Mn effects, adding to the evidence that maternal choline supplementation is neuroprotective for offspring and improves offspring cognitive functioning. HighlightsO_LIDevelopmental Mn exposure causes lasting dysfunction consistent with ADHD symptomology. C_LIO_LIMaternal choline supplementation (MCS) protects against Mn-induced deficits in attention and behavioral reactivity. C_LIO_LIMCS in control animals produces lasting benefits to offspring in learning, attention, and error reactivity. C_LIO_LIThese data support efforts to increase choline intake during pregnancy, particularly for individuals at risk of neurotoxicant exposure. C_LI

animal behavior and cognition↗

bioRxiv2023

Neuro-Environmental Interactions: a time sensitive matter

The assessment of resting state (rs) neurophysiological dynamics relies on the control of sensory, perceptual, and behavioral environments to minimize variability and rule-out confounding sources of activation during testing conditions. Here, we investigated how temporally-distal environmental inputs, specifically metal exposures experienced up to several months prior to scanning, affect functional dynamics measured using rs functional magnetic resonance imaging (rs-fMRI). We implemented an interpretable XGBoost-Shapley Additive Explanation (SHAP) model that integrated information from multiple exposure biomarkers to predict rs dynamics in typically developing adolescents. In 124 participants (53% females, ages: 13-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study, we measured concentrations of six metals (manganese, lead, chromium, cupper, nickel and zinc) in biological matrices (saliva, hair, fingernails, toenails, blood and urine) and acquired rs-fMRI scans. Using graph theory metrics, we computed global efficiency (GE) in 111 brain areas (Harvard Oxford Atlas). We used a predictive model based on ensemble gradient boosting to predict GE from metal biomarkers, adjusting for age and biological sex. Model performance was evaluated by comparing predicted versus measured GE. SHAP scores were used to evaluate feature importance. Measured versus predicted rs dynamics from our model utilizing chemical exposures as inputs were significantly correlated (p< 0.001, r = 0.36). Lead, chromium, and copper contributed most to the prediction of GE metrics. Our results indicate that a significant component of rs dynamics, comprising approximately 13% of observed variability in GE, is driven by recent metal exposures. These findings emphasize the need to estimate and control for the influence of past and current chemical exposures in the assessment and analysis of rs functional connectivity.

neuroscience↗

bioRxiv2022

HSDatabase - a database of highly similar duplicate genes from plants, animals, and algae.

Gene duplication is an important evolutionary mechanism capable of providing new genetic material, which can help organisms adapt to various environmental conditions. Recent studies, for example, have indicated that highly similar duplicated genes (HSDs) are involved in adaptation to extreme conditions via gene dosage. However, HSDs in most genomes remain uncharacterized. Here, we collected and curated HSDs in nuclear genomes from a diversity of species and indexed them in an online, open-access sequence repository called HSDatabase. Currently, this database contains 117,864 curated HSDs from 40 eukaryotic genomes, and it includes information on the total HSD number, gene copy number/length, and alignments of gene copies. HSDatabase also allows users to download sequences of gene copies, access genome browsers, and link out to other databases, such as Pfam and KEGG. Whats more, a built-in Basic Local Alignment Search Tool (BLAST) option is available to conveniently explore potential homologous sequences of interest within and across species. HSDatabase is presented with a user-friendly interface and provides easy access to the source data. It can be used on its own for comparative analyses of gene duplicates or in conjunction with HSDFinder, a newly developed bioinformatics tool for identifying, annotating, categorizing, and visualizing HSDs. Database URLhttp://hsdfinder.com/database/

bioinformatics↗