Recent ucr_som_cgni_oapolicydeposits items

Contributions of Gray Matter Microstructure to Differences in Fluid Cognition and Episodic Memory Across the Healthy Adult Lifespan

Thu, 11 Jun 2026 00:00:00 +0000

Cognitive decline, in healthy older adults without cognitive impairment or dementia, has been associated with numerous microstructural alterations in brain tissue using magnetic resonance imaging (MRI). Prior studies have primarily linked age-related cognitive decline to alterations in white matter tissue, but methodological advances in diffusion-weighted imaging (dMRI) data acquisition and modeling now allow for these analyses to be extended to gray matter tissue. Here, using a sample of 152 healthy adults (18-88 years of age), we used a multicompartment dMRI model to assess (1) age-related differences in gray matter microstructure of functionally defined networks and (2) whether microstructural alterations accounted for age-related differences in episodic memory and speed-dependent fluid cognition. We observed significant age-related alterations in gray matter tissue in the form of nonlinear, age-related increases and decreases in intracellular and dispersed diffusion, respectively,...

The QuadMax Task: Parametrically Manipulating Associative Memory Load across the Adult Lifespan

Thu, 11 Jun 2026 00:00:00 +0000

Adults of all ages are worse at recognizing pairs of items that were previously seen together relative to the individual items, and this paired-associative memory deficit is exacerbated in aging. Less is known about memory for higher associative loads, which place greater demands on binding processes that link items into a cohesive memory trace, among other processes (e.g., working memory, recollection). In this study, adults across the lifespan (n = 250, 18-78 years) completed a novel recognition task in which they studied word pairs, triplets, and quadruplets and were tested on their memory for repeated, recombined, and novel word sets. Associative memory deficits were seen in adults of all ages as fewer correct responses to repeated sets (hits), more incorrect responses to recombined sets (recombined false alarm, FA), and larger differences between these measures (associative memory) at higher set sizes. In addition, older adults had worse associative memory...

The QuadMax Task: A Novel Parametric Manipulation of Associative Memory Load in Adults Across the Lifespan

Thu, 11 Jun 2026 00:00:00 +0000

Adults of all ages are worse at remembering which pairs of items were previously seen together relative to memory for the individual items, and this paired-associative memory deficit is exacerbated in aging. Less is known about memory for higher-order associations, including whether they place greater demands on the binding processes that link information into a cohesive memory trace. In this study, adults across the lifespan (Experiment 1: n = 250, 18-78 years) and in extreme age groups (Experiment 2: n = 64, 18-25 and 64-78 years) completed a novel recognition task in which they studied word pairs, triplets, and quadruplets and were later tested on their memory for repeated, recombined, and novel word sets. Associative memory deficits were seen in both experiments as the difference between correct responses to repeated (hits) and incorrect responses to recombined (recombined false alarm, FA) sets that decreased from pairs to quadruplets. In addition, older age groups had...

Connectome-based predictive modeling of grip strength: a marker of physical frailty

Thu, 11 Jun 2026 00:00:00 +0000

Introduction: Frailty is characterized by a persistent and progressive decline in functional capacity, leading to increased vulnerability to stressors and a heightened risk of adverse health outcomes, both physically and mentally. Despite frailty's prevalence in older adults, there is limited research on its neural substrates. Methods: In this study, we used connectome-based predictive modeling (CPM) to find a linear relationship between task-based connectomes taken from tasks that involved similar handgrip manipulations and a separate measure of physical frailty: the maximum grip strength in older adults. Results: We observed that the task-based connectomes were able to explain individual differences in grip strength, with the Subcortical and Cerebellum network, particularly the caudate nucleus functional connectivity, being the strongest predictor. Discussion: These findings demonstrate that task-based functional connectomes can serve as personalized markers for predicting individual...

Examining iron‐related off‐target binding effects of 18F‐AV1451 PET in the cortex of Aβ+ individuals

Thu, 11 Jun 2026 00:00:00 +0000

The presence of neurofibrillary tangles containing hyper-phosphorylated tau is a characteristic of Alzheimer's disease (AD) pathology. The positron emission tomography (PET) radioligand sensitive to tau neurofibrillary tangles (¹⁸F-AV1451) also binds with iron. This off-target binding effect may be enhanced in older adults on the AD spectrum, particularly those with amyloid-positive biomarkers. Here, we examined group differences in ¹⁸F-AV1451 PET after controlling for iron-sensitive measures from magnetic resonance imaging (MRI) and its relationships to tissue microstructure and cognition in 40 amyloid beta positive (Aβ+) individuals, 20 amyloid beta negative (Aβ-) with MCI and 31 Aβ- control participants. After controlling for iron, increased ¹⁸F-AV1451 PET uptake was found in the temporal lobe and hippocampus of Aβ+ participants compared to Aβ- MCI and control participants. Within the Aβ+ group, significant correlations were seen between ¹⁸F-AV1451...

Locus Coeruleus Engagement Drives Network Connectivity Dynamics In Humans And Rats

Thu, 11 Jun 2026 00:00:00 +0000

Locus Coeruleus Engagement Drives Network Connectivity Dynamics In Humans And Rats

Neuroimaging Measures of Iron and Gliosis Explain Memory Performance in Aging

Thu, 11 Jun 2026 00:00:00 +0000

Abstract Evidence from animal and histological studies have indicated that accumulation of iron in the brain results in reactive gliosis that contributes to cognitive deficits. The current study extends these findings to human cognitive aging and suggests that magnetic resonance imaging (MRI) techniques like quantitative relaxometry can be used to study iron and its effects in vivo . The effects of iron on microstructure and memory performance were examined using a combination of quantitative relaxometry and multi-compartment diffusion imaging in 35 young (21.06 ± 2.18 years) and 28 older (72.58 ± 6.47 years) adults, who also completed a memory task. Replicating past work, results revealed age-related increases in iron content (R 2 *) and diffusion, and decreases in memory performance. Independent of age group, iron content was significantly related to restricted (intracellular) diffusion in regions with low-moderate iron (hippocampus, caudate) and to all diffusion metrics in...

Aging of gray matter microstructure: A brain-wide characterization of, age group differences using NODDI

Thu, 11 Jun 2026 00:00:00 +0000

This study aimed to provide a complete characterization of age group differences in cortical lobar, hippocampal, and subcortical gray matter microstructure using a multi-compartment diffusion-weighted MRI (DWI) approach with parameters optimized for gray matter (Neurite Orientation Dispersion and Density Imaging, NODDI). 76 younger (undergraduate students) and 64 older (surrounding communities) adults underwent diffusion-, T1-, and susceptibility-weighted MRI. Results revealed eight unique patterns across the 12 regions of interest in the relative direction and magnitude of age effects across NODDI metrics, which were grouped into three prominent patterns: cortical gray matter had predominantly higher free diffusion in older than younger adults, the hippocampus and amygdala had predominantly higher dispersion of diffusion and intracellular diffusion in older than younger adults, and the putamen and globus pallidus had lower dispersion of diffusion in older than younger adults....

Age group differences in learning-related activity reflect task stage, not learning stage

Thu, 11 Jun 2026 00:00:00 +0000

Healthy aging is accompanied by declines in the ability to learn associations between events, even when their relationship cannot be described. Previous functional magnetic resonance imaging (fMRI) studies have attributed these implicit associative learning (IAL) deficits to differential engagement of the hippocampus and basal ganglia in older relative to younger adults in early and late stages of the task, respectively. However, these task stages have been confounded with age group differences in learning performance that emerge later and to a lesser degree in older adults. To disentangle the effects of task stage from learning stage (i.e., when there is significant evidence of learning) on age group differences in the neural substrates of IAL, we acquired fMRI data while 28 younger (20.8 ± 2.3 years) and 22 older (73.6 ± 6.8 years) healthy adults completed the Triplets Learning Task, in which the location of two cues predicted the location of a target with high (HF) or low...

Associations between iron and mean kurtosis in iron-rich grey matter nuclei in aging.

Thu, 11 Jun 2026 00:00:00 +0000

OBJECTIVE: Elevated kurtosis values have been observed in subcortical grey matter structures of patients with neurodegenerative diseases. Here, we examined relationships between iron measures and kurtosis in iron-rich subcortical grey matter structures.Please check and confirm the affiliation 4 for the author "Xiaoping P. Hu".Affiliation 4 for Xiaoping P. Hu was incorrect since he is not associated with that department. We have removed this affiliation. Thanks! MATERIALS AND METHODS: Multi-shell diffusion and multi-echo gradient echo acquisitions were used to derive mean kurtosis and iron measures (R₂* and magnetic susceptibility), respectively, in subcortical grey matter nuclei and white matter tracts in a discovery cohort (110 healthy older and 63 younger adults) and replication cohort (72 healthy older adults).Please confirm if the author names are presented accurately and in the correct sequence (Ilana J. Bennett and Xiaoping P. Hu). Also, kindly confirm the...

Handgrip strength relates to corticospinal tract microstructure in older adults

Thu, 11 Jun 2026 00:00:00 +0000

Handgrip strength relates to corticospinal tract microstructure in older adults

Iron content affects age group differences in associative learning-related fMRI activity

Thu, 11 Jun 2026 00:00:00 +0000

Brain regions accumulate different amounts of iron with age, with older adults having higher iron in the basal ganglia (globus pallidus, putamen, caudate) relative to the hippocampus. This has important implications for functional magnetic resonance imaging (fMRI) studies in aging as the presence of iron may influence both neuronal functioning as well as the measured fMRI (BOLD) signal, and these effects will vary across age groups and brain regions. To test this hypothesis, the current study examined the effect of iron on age group differences in task-related activity within each basal nuclei and the hippocampus. Twenty-eight younger and 22 older adults completed an associative learning task during fMRI acquisition. Iron content (QSM, R₂*) was estimated from a multi-echo gradient echo sequence. As previously reported, older adults learned significantly less than younger adults and age group differences in iron content were largest in the basal ganglia (putamen, caudate)....

TGFβ signaling is required during human and chick Neural Crest formation

Sun, 7 Jun 2026 00:00:00 +0000

Neural crest (NC) cells are multipotent cells unique to vertebrates that arise early in development, at the edge of the neural plate, and subsequently undergo an epithelial to mesenchymal transition, migrate throughout the body, and differentiate into many different derivatives, contributing to the formation of many organs and systems. NC induction research from multiple modeling organisms has identified critical roles for a few signaling pathways, including Wnt, BMP, FGF, Notch/ Delta, Indian Hedgehog, and Endothelin signaling (Prasad et al., 2019). Given the limitations of human embryo studies, pluripotent stem cell models of human NC formation have provided a resourceful alternative (Lee et al., 2007). Intriguingly, while TGFβ inhibition had not been identified as a signaling requirement for NC formation in any in vivo model organism, several pluripotent stem cell (PSC) models of human NC induction rely on TGFβ inhibition (Chambers et al., 2009). To address this issue, we evaluate...

ThIEF: Finding Genome-wide Trajectories of Epigenetics Marks

Thu, 21 May 2026 00:00:00 +0000

We address the problem of comparing multiple genome-wide maps representing nucleosome positions or specific histone marks. These maps can originate from the comparative analysis of ChIP-Seq/MNase-Seq/FAIRE-Seq data for different cell types/tissues or multiple time points. The input to the problem is a set of maps, each of which is a list of genomics locations for nucleosomes or histone marks. The output is an alignment of nucleosomes/histone marks across time points (that we call trajectories), allowing small movements and gaps in some of the maps. We present a tool called ThIEF (TrackIng of Epigenetic Features) that can efficiently compute these trajectories. ThIEF comes into two "flavors": ThIEF:Iterative finds the trajectories progressively using bipartite matching, while ThIEF:LP solves a k-partite matching problem on a hyper graph using linear programming. ThIEF:LP is guaranteed to find the optimal solution, but it is slower than ThIEF:Iterative. We demonstrate the utility...

Associations between iron and mean kurtosis in iron-rich grey matter nuclei in aging

Mon, 18 May 2026 00:00:00 +0000

ObjectiveElevated kurtosis values have been observed in subcortical grey matter structures of patients with neurodegenerative diseases. Here, we examined relationships between iron measures and kurtosis in iron-rich subcortical grey matter structures.Please check and confirm the affiliation 4 for the author "Xiaoping P. Hu".Affiliation 4 for Xiaoping P. Hu was incorrect since he is not associated with that department. We have removed this affiliation. Thanks! Materials and methodsMulti-shell diffusion and multi-echo gradient echo acquisitions were used to derive mean kurtosis and iron measures (R2* and magnetic susceptibility), respectively, in subcortical grey matter nuclei and white matter tracts in a discovery cohort (110 healthy older and 63 younger adults) and replication cohort (72 healthy older adults).Please confirm if the author names are presented accurately and in the correct sequence (Ilana J. Bennett and Xiaoping P. Hu). Also, kindly confirm the details in the...

Endothelial Adgrl2 expression and alternative splicing controls the cerebrovasculature.

Thu, 9 Apr 2026 00:00:00 +0000

Central nervous system development requires parallel but interrelated processes of neural circuit assembly and vascularization. Intersecting between these two processes is the cell-adhesion G-protein coupled receptor Adgrl2. In select neuronal populations, Adgrl2 is localized and control the assembly of specific synaptic sites. In non-neuronal brain cells, Adgrl2 is restricted in expression to endothelial cells. Testing for Adgrl2 function in these cells in mice (of either sex), here we find that endothelial cell specific Adgrl2 deletion results in an impairment in cerebrovascular integrity. To understand how it might be possible for Adgrl2 to function independently in neuronal and endothelial contexts, we surveyed Adgrl2 transcripts within these cell classes. By analyzing single-cell RNA sequencing datasets, we find that Adgrl2 mRNA is subject to robust cell type-specific alternative splicing that results in distinct isoforms...

Connectome-based predictive modelling predicts frailty levels in older adults

Thu, 26 Mar 2026 00:00:00 +0000

Frailty is characterized by a persistent and progressive decline in physiological reserves, leading to increased vulnerability to stressors and a heightened risk of adverse health outcomes, both physically and mentally. Despite frailty's prevalence in older adults, there is limited research on its neural substrates, especially using task-based brain functional connectivity. In this study, we used connectome-based predictive modelling (CPM) to find a linear relationship between task-based connectomes - taken from tasks that involved similar handgrip manipulations - and a separate measure of frailty: the maximum grip strength in older adults. We observed that the task-based connectomes were able to explain individual differences in grip strength, with the Subcortical and Cerebellum network, particularly the caudate nucleus, functional connectivity being the strongest predictor. These findings demonstrate that task-based functional connectomes can serve as personalized markers that...

Babesia hegotelforum sp. nov., a zoonotic Babesia species previously referred to as Babesia sp. MO1.

Thu, 12 Mar 2026 00:00:00 +0000

A zoonotic Babesia species previously referred to as Babesia sp. MO1 is formally described and named here as Babesia hegotelforum sp. nov. This taxon is distinct from Babesia divergens based on genome-wide sequence divergence, phylogenetic placement, host associations, and clinical presentation. The parasite infects erythrocytes of humans, and eastern cottontail rabbits (Sylvilagus floridanus), and is transmitted by Ixodes dentatus. The holotype consists of a Giemsa-stained thin blood smear and cryopreserved infected erythrocytes from the cloned isolate BML-Bh-B12 at ≤10 passages in continuous in vitro culture. Paratype material includes five additional clones (BML-Bh-H1, BML-Bh-F12, BML-Bh-H6, BML-Bh-A3, and BML-Bh-F1) derived from BEI Resources strain NR-50441, along with the original mixed isolate NR-50441. This species description meets the requirements of the International Code of Zoological...

Proposed Key Characteristics of Neurotoxic Chemicals

Wed, 11 Mar 2026 00:00:00 +0000

A critical component of evaluating whether a chemical can cause human neurotoxicity is hazard identification, which typically involves a comprehensive literature search to identify and synthesize epidemiological, animal, and mechanistic data for the chemical of interest. The key characteristics (KCs) concept has proven to be a useful tool for searching, organizing, and evaluating mechanistic data for hazard identification. KCs are the established chemical and biological properties of known human neurotoxic agents based on understanding of their mechanisms of neurotoxicity. KCs were originally developed for carcinogens but have now also been published for endocrine- and metabolism-disruptors and various organ-selective toxic chemicals. To identify KCs associated with neurotoxic chemicals, an expert committee was convened to consider current mechanistic understanding of chemicals known to be neurotoxic in humans with the goal of identifying established molecular and cellular actions...

Fuel-driven filamentous phage nanomotors

Thu, 26 Feb 2026 00:00:00 +0000

Virus-based nanocarriers have shown great potential for noninvasive delivery of drugs, diagnostics, and imaging agents to hard-to-reach anatomical locations. Yet, they largely depend on diffusion for transport, often lacking the force to actively penetrate biological barriers, and navigation to guide therapeutic agents. In these studies, the M13 bacteriophage, a linearly shaped virus, was converted from passive nanocarrier to actively propelled, fuel-driven nanomotor. Using the distinctive low symmetry of its capsid, a single Pt nanoparticle was added to one end of the M13 virus to form a tadpole-like structure. The Pt/M13 head/tail nanomotors exhibited notably enhanced diffusion in the presence of hydrogen peroxide fuel, and significantly improved uptake by SVOK3 ovarian cancer cells in vitro. Given the successes of the M13 bacteriophage as a nanocarrier, the demonstration of this simple, but comparatively mobile M13-based nanomotor platform represents an important step...

Two cytochrome P450 epoxidases mediate juvenile hormone biosynthesis in Drosophila melanogaster

Thu, 29 Jan 2026 00:00:00 +0000

Juvenile hormones (JHs) mediate various biological processes such as development and reproduction in insects. Although pleiotropic functions of JHs are well investigated in the fruit fly Drosophila melanogaster, their biosynthetic mechanisms are less well understood, partly because many JH biosynthetic enzymes still remain unidentified in this important model species. Here we report that two cytochrome P450 (CYP) epoxidases mediate JH biosynthesis in D. melanogaster. In addition to previously reported Cyp6g2, a second epoxidase, Cyp6a13, also functions in the corpus allatum, the major JH biosynthetic endocrine gland. Combined mutations of the genes encoding these enzymes cause developmental and reproductive defects, which can be rescued by JH application. JH biosynthetic functions of these genes were further confirmed by using a heterologous expression system and ex vivo tissue culture. Collectively, our results indicate that these two CYP epoxidases function cooperatively to...

Entorhinal cortex layer III Adgrl2 expression controls topographical circuit connectivity required for sequence learning

Thu, 29 Jan 2026 00:00:00 +0000

The entorhinal cortex and hippocampus are interconnected brain regions required for episodic learning and memory. For this functional encoding, correct assembly of specific synaptic connections across this circuit is critical during development. To guide the connection specificity between neurons, a multitude of circuit building molecular components are required, including the latrophilin family of adhesion G protein-coupled receptors (Lphn1-3; gene symbols Adgrl1-3). Within this genetic family, Adgrl2 exhibits a unique topographical and cell-type specific expression patterning in the entorhinal cortex and hippocampus that mirrors connectivity. To investigate the role of Adgrl2 in a cell-type specific fashion for this circuit, we here created a transgenic mouse (Adgrl2fl/fl;pOxr1-Cre) with targeted and selective Adgrl2 deletion in medial entorhinal cortex layer III neurons (MECIII). Using these mice, we find two major input/output circuitry pathways to be topographically shifted...

Adhesion G protein-coupled receptors

Thu, 29 Jan 2026 00:00:00 +0000

Adhesion G protein-coupled receptors (aGPCRs) constitute a structurally and functionally distinct group within the superfamily of GPCRs. In 2015, the International Union of Pharmacology invited the Adhesion GPCR Consortium to publish a comprehensive review about aGPCRs and to establish a unified nomenclature. Since then, substantial progress has been made in delineating the biological roles, molecular architecture, biochemical properties, expression profiles, ligand repertoire, and activation and signaling strategies of aGPCRs. Commensurate with these advances, their relevance to human pathophysiology has become increasingly evident. In a coordinated effort, the Adhesion GPCR Consortium has reviewed recent progress in the field and provides a comprehensive assessment of the current understanding of aGPCR biology here. This includes a focus on human and mammalian aGPCRs, their evolutionary origins, methodological approaches and model systems for their investigation, as well as...

Identifying indicators of consciousness in AI systems

Thu, 15 Jan 2026 00:00:00 +0000

Rapid progress in artificial intelligence (AI) capabilities has drawn fresh attention to the prospect of consciousness in AI. There is an urgent need for rigorous methods to assess AI systems for consciousness, but significant uncertainty about relevant issues in consciousness science. We present a method for assessing AI systems for consciousness that involves exploring what follows from existing or future neuroscientific theories of consciousness. Indicators derived from such theories can be used to inform credences about whether particular AI systems are conscious. This method allows us to make meaningful progress because some influential theories of consciousness, notably including computational functionalist theories, have implications for AI that can be investigated empirically.

A cholesterol-responsive hepatic tRNA-derived small RNA regulates cholesterol homeostasis and atherosclerosis development

Mon, 22 Dec 2025 00:00:00 +0000

Transfer RNA-derived small RNAs (tsRNAs) have emerged as crucial players in diverse biological processes. Yet, their involvement in lipid metabolism and cardiovascular disease remains elusive. Using an advanced PANDORA-seq method, we identify tsRNA-Glu-CTC as the most abundant tsRNA in mouse liver. Intriguingly, tsRNA-Glu-CTC is cholesterol responsive. Overexpression of tsRNA-Glu-CTC elicits hypercholesterolemia and hepatic steatosis, whereas its knockdown protects against diet-induced hypercholesterolemia and atherosclerosis in mice. Mechanistically, tsRNA-Glu-CTC regulates key hepatic lipogenic genes including Srebp2, a master regulator of lipid metabolism. tsRNA-Glu-CTC interacts with SREBP2 to regulate its own transcription through an E-box motif. We further identify site-specific RNA modifications of endogenous tsRNA-Glu-CTC by a mass spectrometry-based MLC-seq and demonstrate the modified tsRNA-Glu-CTC as a more potent regulator of cholesterol homeostasis compared to its...

Durable humoral immunity and long-term protection induced by a Crimean-Congo hemorrhagic fever virus replicon particle vaccine in mice

Mon, 8 Dec 2025 00:00:00 +0000

A Crimean-Congo hemorrhagic fever virus replicon particle vaccine was evaluated for long-term immunity and efficacy in mice. IgG responses persisted up to 18 months, with similar titers across dosing strategies through 12 months. Protective efficacy reached ≥75% at 6 months (prime-only) and up to 12 months (prime-boost). Booster dosing enhanced antibody avidity, effector function, and improved long-term protection. These findings support durable immunity from single or boosted vaccination.

Precocene-I mediated reduction of juvenile hormone titers and ovarian activity is ephemeral in a bumble bee

Thu, 4 Dec 2025 00:00:00 +0000

Juvenile hormones (JHs) are key insect endocrine signals regulating pre-adult development and adult life history strategies, physiology, and behavior. The importance of this endocrine signal has led to the development of insecticides targeting JH signaling pathways. While effective against target pests, they can also affect beneficial insects, such as pollinators and natural pest enemies, many of which are hymenopterans. Research on JH, which is crucial for understanding the physiology, behavior, and organization of social insects, requires effective means to manipulate JH signaling pathways. A common method for reducing JH titers includes applying the phytotoxin precocene-I (P-I), which abolishes JH biosynthesis in the corpora allata (CA). However, achieving consistently effective topical treatments has proven challenging. Here, we investigated the dynamics of the effect of P-I manipulations on JH titers and reproductive development in orphan worker groups of a key pollinator...

A conserved long-range RNA interaction in SARS-CoV-2 recruits ADAR1 to enhance virus proliferation

Thu, 23 Oct 2025 00:00:00 +0000

Long-range RNA-RNA pairing impacts the genome structure and function of SARS-CoV-2 variants. To understand the structure and function relationships of different SARS-CoV-2 variants that have emerged during the COVID-19 pandemic, we perform high-throughput structure probing and modelling of the genomic structures of the wildtype (WT), Alpha, Beta, Delta and Omicron variants of SARS-CoV-2. We observe that genomes of SARS-CoV-2 variants are generally structurally conserved, and that single-nucleotide variations and interactions with RNA binding proteins can impact RNA structures across the viruses. Importantly, using proximity ligation sequencing, we identify many conserved ultra-long-range RNA-RNA interactions, including one that spans more than 17 kb in both the WT virus and the Omicron variant. We show that mutations that disrupt this 17 kb long-range interaction reduce viral fitness at later stages of its infection cycle, while compensatory mutations partially restore virus fitness....

Effect of Oceanic Islands on an Insect Symbiont Genome in Transition to a Host-Restricted Lifestyle

Fri, 29 Aug 2025 00:00:00 +0000

Islands offer unique opportunities to study adaptive radiations and their impacts on host genome evolution. In Hawaiian Pariaconus psyllids, all species harbor the ancient nutritional symbiont Carsonella, while only free-living and open-gall species on younger islands host a second stable cosymbiont, Makana. In contrast, a third cosymbiont, Malihini, appears to be in an early stage of host restriction and genome degradation, making it a valuable model for understanding symbiont evolution during island radiations. Here, we examine Malihini genome evolution across multiple Pariaconus lineages using 16S rRNA sequencing, metagenomics, phylogenetic reconstruction, and microscopy. We find that Malihini is codiversifying with its hosts on the oldest island Kaua'i (kamua group; open- and closed-gall makers) and on the younger islands only in free-living species (bicoloratus group). Comparison of five Malihini genomes-including three newly assembled in this study-shows ongoing genome reduction...

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

Thu, 28 Aug 2025 00:00:00 +0000

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⁺/K⁺-ATPase). Here, we tested if these substitutions explain S. carpocapsae's reported lower sensitivity to salt. Our results confirm that S. carpocapsae exhibits higher salt tolerance and show it can more effectively locate and infect...

Rapid, sensitive, and species-independent detection of Crimean Congo hemorrhagic fever virus nucleoprotein and GP38 antibodies

Thu, 14 Aug 2025 00:00:00 +0000

BACKGROUND: Crimean-Congo hemorrhagic fever virus (CCHFV), a zoonotic agent in the Nairoviridae family (genus Orthonairovirus), is a high-priority pathogen. CCHFV infection causes Crimean-Congo hemorrhagic fever (CCHF), a human disease with case fatality rates of up to 40%. Serological surveillance of CCHFV in animals and humans is crucial for ecological studies and public health. METHODS: We developed CCHFV mix-and-read assays utilizing split-NanoLuc technology (NanoBiT) to detect anti-CCHFV antibodies against the nucleoprotein (NP) stalk region and the GP38 glycoprotein. These species- and isotype-agnostic assays provide results in ∼30 min. Using serum samples from RT-PCR-confirmed CCHF cases collected during and after hospitalization, we investigated anti-NP and anti-GP38 antibody development. The performance of the mix-and-read assays was compared to the NP-based IDScreen® CCHF commercial assay using human sera, and cross-reactivity potential was evaluated using a diverse...

Long-Term Effects of Moderate Concussive Brain Injury During Adolescence on Synaptic and Tonic GABA Currents in Dentate Granule Cells and Semilunar Granule Cells

Thu, 14 Aug 2025 00:00:00 +0000

Progressive physiological changes in the hippocampal dentate gyrus circuits following traumatic brain injury (TBI) contribute to temporal evolution of neurological sequelae. Although early posttraumatic changes in dentate synaptic and extrasynaptic GABA currents have been reported, and whether they evolve over time and remain distinct between the two projection neuron classes, granule cells and semilunar granule cells, have not been evaluated. We examined long-term changes in tonic GABA currents and spontaneous inhibitory postsynaptic currents (sIPSCs) and in dentate projection neurons 3 months after moderate concussive fluid percussion injury (FPI) in adolescent rats. Granule cell tonic GABA current amplitude remained elevated up to 1 month after FPI, but decreased to levels comparable with age-matched controls by 3 months postinjury. Granule cell sIPSC frequency, which we previously reported to be increased 1 week after FPI, remained higher than in age-matched controls at 1...

Neuroendocrinology and the Genetics of Obesity

Mon, 4 Aug 2025 00:00:00 +0000

The increase in the incidence of obesity has coincided with changes in lifestyle, diet, and environment. Comorbidities associated with obesity include cardiovascular disease, diabetes, musculoskeletal disorders, stroke, and thromboembolism, affecting public health. The effect of increased weight has recently become even more obvious, since obesity has been significantly associated with increased severity and higher mortality among COVID-19 patients. The need to decrease rates of obesity prompted a surge in the use of glucagon-like peptide-1 agonist medications. Twin studies, however, determined that increased weight has a large genetic component, estimating the heritability of obesity to be 45% to 70%. Surprisingly, obesity due to known single gene mutation comprises only 5% to 10% of individuals, who mostly exhibit early-onset severe obesity. Genome-wide linkage studies and association studies identified more than 250 genes associated with obesity, but each of these has a relatively...

Inhibition of alloparental behavior by acute stress in virgin male California mice (Peromyscus californicus)

Thu, 17 Jul 2025 00:00:00 +0000

In many biparental mammals, such as California mice (Peromyscus californicus), fathers display affiliative behavior toward unfamiliar infants whereas reproductively naïve adult males show highly variable responses. Sources of this variability are not well understood, but evidence suggests that stress can either enhance or inhibit alloparental care. We evaluated immediate and delayed effects of acute stress on pup-directed behavior in adult virgin male California mice. Mice underwent three 10-minute tests with unfamiliar pups at 48-hour intervals. Stressed mice (N=22) received a subcutaneous oil injection immediately before tests 1 and 2, whereas controls (N=22) were left undisturbed. In controls, but not stressed mice, latency to approach the pup decreased and duration of alloparental behavior increased across the three tests. At each time point, stressed males were less likely than controls to perform alloparental behavior. Controls spent significantly more time performing alloparental...

Parenthood and gene expression of oxytocin receptors and vasopressin receptors in sensory cortices of the male California mouse (Peromyscus californicus)

Thu, 17 Jul 2025 00:00:00 +0000

The onset of parental care is associated with shifts in parents' perception of sensory stimuli from infants, mediated by neural plasticity in sensory systems. In new mothers, changes in auditory and olfactory processing have been linked to plasticity at several points along both sensory pathways, including cortical changes that are modulated, at least in part, by oxytocin. In males of biparental species, vasopressin, in addition to oxytocin, is important for modulating parental behavior; however, little is known about sensory plasticity in new fathers. We examined variation in the mRNA expression of oxytocin and vasopressin receptors (Oxtr and Avpr1a) in sensory cortices of virgin males, paired nonbreeding males, and new fathers in the biparental California mouse (Peromyscus californicus), and variation among cortices using the visual cortex for comparison. Reproductive status did not affect gene expression for either receptor, but compared to the visual cortex, expression of...

The parental umwelt: Effects of parenthood on sensory processing in rodents

Thu, 17 Jul 2025 00:00:00 +0000

An animal's umwelt, comprising its perception of the sensory environment, which is inherently subjective, can change across the lifespan in accordance with major life events. In mammals, the onset of motherhood, in particular, is associated with a neural and sensory plasticity that alters a mother's detection and use of sensory information such as infant-related sensory stimuli. Although the literature surrounding mammalian mothers is well established, very few studies have addressed the effects of parenthood on sensory plasticity in mammalian fathers. In this review, we summarize the major findings on the effects of parenthood on behavioural and neural responses to sensory stimuli from pups in rodent mothers, with a focus on the olfactory, auditory, and somatosensory systems, as well as multisensory integration. We also review the available literature on sensory plasticity in rodent fathers. Finally, we discuss the importance of sensory plasticity for effective parental care,...

Neural responses to pup calls and pup odors in California mouse fathers and virgin males

Thu, 17 Jul 2025 00:00:00 +0000

The onset of mammalian maternal care is associated with plasticity in neural processing of infant-related sensory stimuli; however, little is known about sensory plasticity associated with fatherhood. We quantified behavioral and neural responses of virgin males and new fathers to olfactory and auditory stimuli from young, unfamiliar pups in the biparental California mouse (Peromyscus californicus). Each male was exposed for 10 min to one of four combinations of a chemosensory stimulus (pup-scented or unscented cotton [control]) and an auditory stimulus (pup vocalizations or white noise [control]). Behavior did not differ between fathers and virgins during exposure to sensory stimuli or during the following hour; however, males in both groups were more active both during and after exposure to pup-related stimuli compared to control stimuli. Fathers had lower expression of Fos in the main olfactory bulbs (MOB) but higher expression in the medial preoptic area (MPOA) and bed...

Reasoning Goals and Representational Decisions in Computational Cognitive Neuroscience: Lessons From the Drift Diffusion Model

Thu, 3 Jul 2025 00:00:00 +0000

Computational cognitive models are powerful tools for enhancing the quantitative and theoretical rigor of cognitive neuroscience. It is thus imperative that model users-researchers who develop models, use existing models, or integrate model-based findings into their own research-understand how these tools work and what factors need to be considered when engaging with them. To this end, we developed a philosophical toolkit that addresses core questions about computational cognitive models in the brain and behavioral sciences. Drawing on recent advances in the philosophy of modeling, we highlight the central role of model users' reasoning goals in the application and interpretation of formal models. We demonstrate the utility of this perspective by first offering a philosophical introduction to the highly popular drift diffusion model (DDM) and then providing a novel conceptual analysis of a long-standing debate about decision thresholds in the DDM. Contrary to most existing work,...

Cerebrovascular alterations in a mouse model of late-onset Alzheimer’s disease

Wed, 18 Jun 2025 00:00:00 +0000

Significance: Alzheimer's disease (AD) is an age-related neurodegenerative disorder with cerebrovascular alterations contributing to cognitive decline. Assessing cerebrovascular changes in mouse models that mimic the human condition of late-onset, sporadic AD is important for better human applicability. Aim: To assess cerebrovascular changes in three mouse models: (1) 3xTg-AD; (2) the humanized amyloid-beta knock-in ( -KI) mouse model of late-onset, sporadic AD; and (3) age-matched wild-type mice. Approach: We measured resting-state cerebral blood flow (CBF) and neurovascular coupling (NVC) using laser speckle imaging (LSI) and performed ex vivo analyses of gene expression and cerebrovascular structure using bulk ribonucleic acid sequencing and confocal microscopy, respectively. Results: Our study identifies specific cerebrovascular alterations in the -KI mouse model, including increased resting-state CBF, a shift toward smaller blood vessel diameters,...

Functional characterization of eicosanoid signaling in Drosophila development

Thu, 22 May 2025 00:00:00 +0000

20-carbon fatty acid-derived eicosanoids are versatile signaling oxylipins in mammals. In particular, a group of eicosanoids termed prostanoids are involved in multiple physiological processes, such as reproduction and immune responses. Although some eicosanoids such as prostaglandin E2 (PGE2) have been detected in some insect species, molecular mechanisms of eicosanoid synthesis and signal transduction in insects have not been thoroughly investigated. Our phylogenetic analysis indicated that, in clear contrast to the presence of numerous receptors for oxylipins and other lipid mediators in humans, the Drosophila genome only possesses a single ortholog of such receptors, which is homologous to human prostanoid receptors. This G protein-coupled receptor, named Prostaglandin Receptor or PGR, is activated by PGE2 and its isomer PGD2 in Drosophila S2 cells. PGR mutant flies die as pharate adults with insufficient tracheal development, which can be rescued by supplying high oxygen....

Steroid hormone signaling: What we can learn from insect models

Thu, 22 May 2025 00:00:00 +0000

Ecdysteroids are a group of steroid hormones in arthropods with pleiotropic functions throughout their life history. Ecdysteroid research in insects has made a significant contribution to our current understanding of steroid hormone signaling in metazoans, but how far can we extrapolate our findings in insects to other systems, such as mammals? In this chapter, we compare steroid hormone signaling in insects and mammals from multiple perspectives and discuss similarities and differences between the two lineages. We also highlight a few understudied areas and remaining questions of steroid hormone biology in metazoans and propose potential future research directions.

PTPN2 Regulates Iron Handling Protein Expression in Inflammatory Bowel Disease Patients and Prevents Iron Deficiency in Mice

Sat, 26 Apr 2025 00:00:00 +0000

Anemia is the most common extraintestinal manifestation of inflammatory bowel disease (IBD). Iron deficiency is the most frequent cause of anemia in IBD; however, the mechanisms involved are still poorly understood. Here, we investigated the role of the IBD risk gene, protein tyrosine phosphatase non-receptor type 2 (PTPN2), in regulating iron homeostasis. Proteomic analyses were performed on serum from IBD patients genotyped for the IBD-associated loss-of-function rs1893217 PTPN2 variant. Constitutive Ptpn2 wild type (WT), heterozygous (Het), and knockout (KO) mice were analyzed for iron content, blood parameters, and expression of iron handling proteins. Iron absorption was assessed through radiotracer assays. Serum proteomic analyses revealed that the "iron homeostasis signaling pathway" was the main pathway downregulated in Crohn's disease (CD) patients carrying the PTPN2 risk allele, independent of disease activity. Ptpn2-KO mice showed...

Molecular basis for the calcium-dependent activation of the ribonuclease EndoU

Mon, 14 Apr 2025 00:00:00 +0000

Ribonucleases (RNases) are ubiquitous enzymes that process or degrade RNA, essential for cellular functions and immune responses. The EndoU-like superfamily includes endoribonucleases conserved across bacteria, eukaryotes, and certain viruses, with an ancient evolutionary link to the ribonuclease A-like superfamily. Both bacterial EndoU and animal RNase A share a similar fold and function independently of cofactors. In contrast, the eukaryotic EndoU catalytic domain requires divalent metal ions for catalysis, possibly due to an N-terminal extension near the catalytic core. In this study, we use biophysical and computational techniques along with in vitro assays to investigate the calcium-dependent activation of human EndoU. We determine the crystal structure of EndoU bound to calcium and find that calcium binding remote from the catalytic triad triggers water-mediated intramolecular signaling and structural changes, activating the enzyme through allostery. Calcium binding involves...

Whole-brain causal discovery using fMRI

Fri, 11 Apr 2025 00:00:00 +0000

Despite significant research, discovering causal relationships from fMRI remains a challenge. Popular methods such as Granger causality and dynamic causal modeling fall short in handling contemporaneous effects and latent common causes. Methods from causal structure learning literature can address these limitations but often scale poorly with network size and need acyclicity. In this study, we first provide a taxonomy of existing methods and compare their accuracy and efficiency on simulated fMRI from simple topologies. This analysis demonstrates a pressing need for more accurate and scalable methods, motivating the design of Causal discovery for Large-scale Low-resolution Time-series with Feedback (CaLLTiF). CaLLTiF is a constraint-based method that uses conditional independence between contemporaneous and lagged variables to extract causal relationships. On simulated fMRI from the macaque connectome, CaLLTiF achieves significantly higher accuracy and scalability than all tested...

Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2 Gene

Fri, 11 Apr 2025 00:00:00 +0000

BACKGROUND & AIMS: Coronavirus disease (COVID-19), caused by severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2), triggered a global pandemic with severe medical and socioeconomic consequences. Although fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases. The aim of our study was to investigate whether the autoimmunity risk gene, PTPN2, which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake. METHODS: Using samples from PTPN2 genotyped patients with inflammatory bowel disease, PTPN2-deficient mice, and human intestinal and lung epithelial cell lines, we investigated...

Mixed-Methods Approach: Impact of Clinical Consenter Diversity on Clinical Trials Enrollment

Fri, 11 Apr 2025 00:00:00 +0000

BACKGROUND: Clinical trials should benefit all people. Consequently, the National Cancer Institute expects cancer centers to accrue individuals to clinical trials in proportion to the cancer burden experienced by populations that live in their respective catchment areas; unfortunately, many cancer centers fail to meet this expectation. The person who gives consent for individuals in clinical trials frequently has significant contact with potential trial participants. We hypothesized that the race, ethnicity, and language of the consenter may have an important bearing on whether an individual chooses to participate in a clinical trial. METHODS: We used mixed methods to investigate the impact of the socio-cultural background of the consenter on the decision of a potential research subject to participate in a clinical trial. Between 01/2018 and 02/2020, 205 women were approached in the sequential order they appeared in our breast clinic; of the 181 participants who agreed to complete...

Chronic Wound Initiation: Single-Cell RNAseq of Cutaneous Wound Tissue and Contributions of Oxidative Stress to Initiation of Chronicity

Wed, 2 Apr 2025 00:00:00 +0000

Chronic wounds (CWs) in humans affect millions of people in the US alone, cost billions of dollars, cause much suffering, and still there are no effective treatments. Patients seek medical care when wound chronicity is already established, making it impossible to investigate factors that initiate chronicity. In this study, we used a diabetic mouse model of CWs that mimics many aspects of chronicity in humans. We performed scRNAseq to compare the cell composition and function during the first 72 h post-injury and profiled 102,737 cells into clusters of all major cell types involved in healing. We found two types of fibroblasts. Fib 1 (pro-healing) was enriched in non-CWs (NCWs) whereas Fib 2 (non-healing) was in CWs. Both showed disrupted proliferation and migration, and extracellular matrix (ECM) deposition in CWs. We identified several subtypes of keratinocytes, all of which were more abundant in NCWs, except for Channel-related keratinocytes, and showed altered migration, apoptosis,...

Demyelination and neurodegeneration early in experimental autoimmune encephalomyelitis contribute to functional deficits in the anterior visual pathway

Tue, 1 Apr 2025 00:00:00 +0000

Impaired visual function is a prevalent feature of optic neuritis (ON) in multiple sclerosis (MS). Abnormal visual evoked potential (VEP) findings of increased latencies, reduced amplitudes and abnormal waveforms as well as decreased retinal nerve fiber layer (RNFL) assessed by optical coherence tomography (OCT) are hallmarks of ON-induced visual dysfunction. Here we utilized the experimental autoimmune encephalomyelitis (EAE) mouse model of MS to investigate the functional and pathological progression during early (before any clinical symptoms), peak (initial maximal clinical symptoms), and late (chronic disease for > 3 weeks) disease stages. Demyelination and initial stages of axon damage were observed in early EAE. Significant demyelination, inflammation, increased axon damage and impaired P1/N2 amplitudes and latencies by VEP were seen in middle and late EAE groups. A decrease in RNFL thickness by OCT was observed only during late EAE. NanoString analysis of optic...

Replication Studies of Alkyl Phosphotriester Lesions in Human Cells

Tue, 1 Apr 2025 00:00:00 +0000

Alkyl phosphotriester (alkyl-PTE) lesions in DNA are shown to be poorly repaired; however, little is known about how these lesions impact DNA replication in human cells. Here, we investigated how the S_P and R_P diastereomers of four alkyl-PTE lesions (alkyl = Me, Et, nPr, or nBu) at the TT site perturb DNA replication in HEK293T cells. We found that these lesions moderately impede DNA replication and that their replicative bypass is accurate. Moreover, CRISPR-Cas9-mediated depletion of Pol η or Pol ζ resulted in significantly attenuated bypass efficiencies for both diastereomers of nPr- and nBu-PTE adducts, and the S_P diastereomer of Et-PTE. Diminished bypass efficiencies were also detected for the R_p diastereomer of nPr- and nBu-PTE lesions upon ablation of Pol κ. Together, our study uncovered the impact of the alkyl-PTE lesions on DNA replication in human cells and...

Determination of Trends Underlying Aspartic Acid Isomerization in Intact Proteins Reveals Unusually Rapid Isomerization of Tau

Tue, 1 Apr 2025 00:00:00 +0000

Spontaneous chemical modifications in long-lived proteins can potentially change protein structure in ways that impact proteostasis and cellular health. For example, isomerization of aspartic acid interferes with protein turnover and is anticorrelated with cognitive acuity in Alzheimer's disease. However, few isomerization rates have been determined for Asp residues in intact proteins. To remedy this deficiency, we used protein extracts from SH-SY5Y neuroblastoma cells as a source of a complex, brain-relevant proteome with no baseline isomerization. Cell lysates were aged in vitro to generate isomers, and extracted proteins were analyzed by data-independent acquisition (DIA) liquid chromatography-mass spectrometry (LC-MS). Although no Asp isomers were detected at day 0, isomerization increased over time and was quantifiable for 105 proteins by day 50. Data analysis revealed that the isomerization rate is influenced by both primary sequence and secondary structure, suggesting...

On the Feasibility of SERS-Based Monitoring of Drug Loading Efficiency in Exosomes for Targeted Delivery

Wed, 26 Mar 2025 00:00:00 +0000

Cancer, a significant cause of mortality, necessitates improved drug delivery strategies. Exosomes, as natural drug carriers, offer a more efficient, targeted, and less toxic drug delivery system compared to direct dispersal methods via ingestion or injection. To be successfully implemented as drug carriers, efficient loading of drugs into exosomes is crucial, and a deeper understanding of the loading mechanism remains to be solved. This study introduces surface-enhanced Raman scattering (SERS) to monitor drug loading efficacy at the single vesicle level. By enhancing the Raman signal, SERS overcomes limitations in Raman spectroscopy. A gold nanopyramids array-based SERS substrate assesses exosome heterogeneity in drug-loading capabilities with the help of single-layer graphene for precise quantification. This research advances targeted drug delivery by presenting a more efficient method of evaluating drug-loading efficiency into individual exosomes through SERS-based monitoring....

Chronic, Low-Dose Methamphetamine Reveals Sexual Dimorphism of Memory Performance, Histopathology, and Gene Expression Affected by HIV-1 Tat Protein in a Transgenic Model of NeuroHIV

Thu, 13 Mar 2025 00:00:00 +0000

Methamphetamine (METH) use is frequent among people with HIV (PWH) and appears to increase the risk of neuronal injury and neurocognitive impairment (NCI). This study explored in vivo the effects of a 12 week (long-term), low-dose METH regimen in a transgenic animal model of neuroHIV with inducible expression of HIV-1 transactivator of transcription (Tat). Seven months after transient Tat induction and five months after METH exposure ended, we detected behavioral changes in the Barnes maze (BM) spatial memory task in the Tat and METH groups but not the combined Tat + METH group. The novel object recognition (NOR) task revealed that Tat extinguished discrimination in female animals with and without METH, although METH alone slightly improved NOR. In contrast, in males, Tat, METH, and Tat + METH all compromised NOR. Neuropathological examination detected sex-dependent and brain region-specific changes of pre-synaptic terminals, neurites, and activation of astrocytes and microglia....

Quantitative Proteomics Identifies Profilin‑1 as a Pseudouridine-Binding Protein

Sat, 1 Mar 2025 00:00:00 +0000

Pseudouridine (Ψ) is the most abundant RNA modification in nature; however, not much is known about the biological functions of this modified nucleoside. Employing an unbiased quantitative proteomics method, we identified multiple candidate reader proteins of Ψ in RNA, including a cytoskeletal protein profilin-1 (PFN1). We demonstrated that PFN1 binds directly and selectively to Ψ-containing RNA. Additionally, we discovered approximately 4000 binding sites of PFN1 in human cells, including a known dyskerin (DKC1)-installed Ψ site in TPI1 mRNA, which encodes triosephosphate isomerase. Moreover, we showed that PFN1 and DKC1 are crucial for regulating the stability and translation efficiency of TPI1 mRNA through modulating PFN1-Ψ interaction. Together, we identified PFN1 as a reader protein of Ψ in RNA and illustrated a potential role of PFN1-Ψ interaction in post-transcriptional regulation. These findings provide new insights into the functions of Ψ in RNA biology...

The Toxoplasma rhoptry protein ROP55 is a major virulence factor that prevents lytic host cell death

Thu, 27 Feb 2025 00:00:00 +0000

Programmed-cell death is an antimicrobial defense mechanism that promotes clearance of intracellular pathogens. Toxoplasma counteracts host immune defenses by secreting effector proteins into host cells; however, how the parasite evades lytic cell death and the effectors involved remain poorly characterized. We identified ROP55, a rhoptry protein that promotes parasite survival by preventing lytic cell death in absence of IFN-γ stimulation. RNA-Seq analysis revealed that ROP55 acts as a repressor of host pro-inflammatory responses. In THP-1 monocytes ΔROP55 infection increased NF-κB p65 nuclear translocation, IL-1β production, and GSDMD cleavage compared to wild type or complemented parasites. ΔROP55 infection also induced RIPK3-dependent necroptosis in human and mouse primary macrophages. Moreover, ΔROP55 parasites were significantly impaired in virulence in female mice and prevented NF-κB activation and parasite clearance in mBMDM. These findings place ROP55 as a major virulence...

Entomopathogenic Nematode Species Vary in Their Behavior and Virulence in Response to Cardiac Glycosides Within and Around Insect Hosts

Mon, 17 Feb 2025 00:00:00 +0000

Plants produce defensive toxins to deter herbivores. In response, some specialized herbivores evolved resistance and even the capacity to sequester toxins, affecting interactions at higher trophic levels. Here, we test the hypothesis that potential natural enemies of specialized herbivores are differentially affected by plant toxins depending on their level of adaptation to the plant-herbivore system. We focus on toxic cardiac glycosides (CGs) from milkweeds (Asclepias spp.), which inhibit animal Na+/K+-ATPases, and two CG-resistant insects, the large milkweed bug Oncopeltus fasciatus and a CRISPR-edited Drosophila melanogaster. Both have CG-resistant Na+/K+-ATPases through a set of key amino acid substitutions, which facilitate CG sequestration. We conducted infection experiments with entomopathogenic nematodes (Steinernema carpocapsae, S. feltiae, and S. hermaphroditum) as natural enemies on host insects containing mixtures of milkweed-derived CGs or purified CGs (ouabain, digoxin,...

Can a Hybrid Line Break a Selection Limit on Behavioral Evolution in Mice?

Mon, 17 Feb 2025 00:00:00 +0000

Artificial selection yielded four replicate high runner (HR) lines of mice that reached apparent selection limits (~ threefold increase in wheel revolutions per day vs. four control lines), despite maintenance of additive genetic variance. After 68 generations, we used animal models to test for changes in additive-genetic variances and covariance of the two measured components (average speed and duration) of running distance. We also attempted to break the selection limit by crossing two HR lines, then continuing directional selection on this hybrid line and on the two parental lines for nine generations. The genetic correlation between speed and duration was positive in the base population, but evolved to be negative in the two parental HR lines. Although heritability for both speed and duration (but not distance) increased in the hybrid line, their genetic correlation remained negative. Hybrid F1 mice from generation 68 parents showed heterosis for running distance, which was...

Targeting Anaerobic Respiration in Pseudomonas aeruginosa with Chlorate Improves Healing of Chronic Wounds

Tue, 11 Feb 2025 00:00:00 +0000

Objective: Pseudomonas aeruginosa is an opportunistic pathogen that can establish chronic infections and form biofilm in wounds. Because the wound environment is largely devoid of oxygen, P. aeruginosa may rely on anaerobic metabolism, such as nitrate respiration, to survive in wounds. While nitrate reductase (Nar) typically reduces nitrate to nitrite, it can also reduce chlorate to chlorite, which is a toxic oxidizing agent. Therefore, chlorate can act as a prodrug to specifically eradicate hypoxic/anoxic, nitrate-respiring P. aeruginosa populations, which are often tolerant to conventional antibiotic treatments. Approach: Using a diabetic mouse model for chronic wounds, we tested the role that anaerobic nitrate respiration plays in supporting chronic P. aeruginosa infections. Results: P. aeruginosa forms biofilm deep within the wound where the environment is anoxic. Daily treatment of P. aeruginosa-infected wounds...

Maternal probiotic supplementation protects against PBDE-induced developmental, behavior and metabolic reprogramming in a sexually dimorphic manner: Role of gut microbiome

Mon, 10 Feb 2025 00:00:00 +0000

Polybrominated diphenyl ethers (PBDEs) are endocrine-disrupting persistent organic pollutants (POPs) used as flame retardants in a wide range of commercial applications. We have previously reported neurobehavioral and metabolic reprogramming produced by developmental PBDEs. PBDEs perturb the microbiome, an influencer of life-long health, while probiotic supplementation with Limosilactobacillus reuteri (LR) can avert neurobehavioral and endocrine disruption. We, therefore, tested the hypothesis that perinatal maternal LR supplementation would protect gut microbiome richness and diversity, developmental milestones, adult neurobehavior and metabolic homeostasis in PBDE-exposed offspring. C57BL/6N dams were orally exposed to a commercial penta-mixture of PBDEs, DE-71, at 0.1 mg/kg/day, or corn oil vehicle (VEH/CON) during gestation and lactation. Mice offspring received DE-71 or VEH/CON with or without co-administration of LR (ATCC-PTA-6475) indirectly via their mother from gestational...

Engineering the Ratios of Nanoparticles Dispersed in Triphasic Nanocomposites for Biomedical Applications

Thu, 30 Jan 2025 00:00:00 +0000

Polymer/ceramic nanocomposites integrated the advantages of both polymers and ceramics for a wide range of biomedical applications, such as bone tissue repair. Here, we reported triphasic poly(lactic-co-glycolic acid) (PLGA, LA/GA = 90:10) nanocomposites with improved dispersion of hydroxyapatite (HA) and magnesium oxide (MgO) nanoparticles using a process that integrated the benefits of ultrasonic energy and dual asymmetric centrifugal mixing. We characterized the microstructure and composition of the nanocomposites and evaluated the effects of the HA/MgO ratios on degradation behavior and cell-material interactions. The PLGA/HA/MgO nanocomposites were composed of 70 wt % PLGA and 30 wt % nanoparticles made of 20:10, 25:5, and 29:1% by weight of HA and MgO, respectively. The results showed that the nanocomposites had a homogeneous nanoparticle distribution and as-designed elemental composition. The cell study indicated that reducing the MgO content in the triphasic nanocomposite...

Task relevant autoencoding enhances machine learning for human neuroscience

Thu, 30 Jan 2025 00:00:00 +0000

In human neuroscience, machine learning can help reveal lower-dimensional neural representations relevant to subjects’ behavior. However, state-of-the-art models typically require large datasets to train, and so are prone to overfitting on human neuroimaging data that often possess few samples but many input dimensions. Here, we capitalized on the fact that the features we seek in human neuroscience are precisely those relevant to subjects’ behavior rather than noise or other irrelevant factors. We thus developed a Task-Relevant Autoencoder via Classifier Enhancement (TRACE) designed to identify behaviorally-relevant target neural patterns. We benchmarked TRACE against a standard autoencoder and other models for two severely truncated machine learning datasets (to match the data typically available in functional magnetic resonance imaging [fMRI] data for an individual subject), then evaluated all models on fMRI data from 59 subjects who observed animals and objects. TRACE outperformed...

Superstable lipid vacuoles endow cartilage with its shape and biomechanics

Wed, 29 Jan 2025 00:00:00 +0000

Conventionally, the size, shape, and biomechanics of cartilages are determined by their voluminous extracellular matrix. By contrast, we found that multiple murine cartilages consist of lipid-filled cells called lipochondrocytes. Despite resembling adipocytes, lipochondrocytes were molecularly distinct and produced lipids exclusively through de novo lipogenesis. Consequently, lipochondrocytes grew uniform lipid droplets that resisted systemic lipid surges and did not enlarge upon obesity. Lipochondrocytes also lacked lipid mobilization factors, which enabled exceptional vacuole stability and protected cartilage from shrinking upon starvation. Lipid droplets modulated lipocartilage biomechanics by decreasing the tissue's stiffness, strength, and resilience. Lipochondrocytes were found in multiple mammals, including humans, but not in nonmammalian tetrapods. Thus, analogous to bubble wrap, superstable lipid vacuoles confer skeletal tissue with cartilage-like properties without "packing...

Obesity Alters POMC and Kisspeptin Neuron Cross Talk Leading to Reduced Luteinizing Hormone in Male Mice

Wed, 22 Jan 2025 00:00:00 +0000

Obesity is associated with hypogonadism in males, characterized by low testosterone and sperm number. Previous studies determined that these stem from dysregulation of hypothalamic circuitry that regulates reproduction, by unknown mechanisms. Herein, we used mice fed chronic high-fat diet, which mimics human obesity, to determine mechanisms of impairment at the level of the hypothalamus, in particular gonadotropin-releasing hormone (GnRH) neurons that regulate luteinizing hormone (LH), which then regulates testosterone. Consistent with obese humans, we demonstrated lower LH, and lower pulse frequency of LH secretion, but unchanged pituitary responsiveness to GnRH. LH pulse frequency is regulated by pulsatile GnRH secretion, which is controlled by kisspeptin. Peripheral and central kisspeptin injections, and DREADD-mediated activation of kisspeptin neurons, demonstrated that kisspeptin neurons were suppressed in obese mice. Thus, we investigated regulators of kisspeptin secretion....

Global atlas of predicted functional domains in Legionella pneumophila Dot/Icm translocated effectors

Mon, 20 Jan 2025 00:00:00 +0000

Legionella pneumophila utilizes the Dot/Icm type IVB secretion system to deliver hundreds of effector proteins inside eukaryotic cells to ensure intracellular replication. Our understanding of the molecular functions of the largest pathogenic arsenal known to the bacterial world remains incomplete. By leveraging advancements in 3D protein structure prediction, we provide a comprehensive structural analysis of 368 L. pneumophila effectors, representing a global atlas of predicted functional domains summarized in a database (https://pathogens3d.org/legionella-pneumophila). Our analysis identified 157 types of diverse functional domains in 287 effectors, including 159 effectors with no prior functional annotations. Furthermore, we identified 35 cryptic domains in 30 effector models that have no similarity with experimentally structurally characterized proteins, thus, hinting at novel functionalities. Using this analysis, we demonstrate the activity of thirteen functional domains,...

Sensory regulation of meal sorting in Aedes aegypti mosquitoes

Mon, 20 Jan 2025 00:00:00 +0000

Meal sorting in mosquitoes is a phenomenon whereby ingested blood and sugar meals are directed to different destinations in the alimentary canal. We undertake a systematic analysis and show that entry of blood in the midgut is influenced by blood components, temperature, and feeding mode, while sugar solutions are directed to the crop in a dose-dependent manner. Sweet and nutritive sugars, like sucrose and maltose, enter the crop more efficiently compared to non-sweet or non-nutritive sugars. Additionally, the robustness of meal sorting declines with mosquito age and is compromised in mutants of candidate thermoreceptors. Proper blood meal sorting is crucial for optimal egg production, as disruption of this process by adding sucrose results in reduced fecundity. Furthermore, certain amino acids essential for vitellogenesis are preferentially directed to the midgut. Our findings provide new insights into the meal sorting mechanism, with implications for mosquito reproduction and...

Alleviation of extensive visual pathway dysfunction by a remyelinating drug in a chronic mouse model of multiple sclerosis

Fri, 17 Jan 2025 00:00:00 +0000

Visual deficits are among the most prevalent symptoms in patients with multiple sclerosis (MS). To understand deficits in the visual pathway during MS and potential treatment effects, we used experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. The afferent visual pathway was assessed in vivo using optical coherence tomography (OCT), electroretinography (ERG), and visually evoked cortical potentials (VEPs). Inflammation, demyelination, and neurodegeneration were examined by immunohistochemistry ex vivo. In addition, an immunomodulatory, remyelinating agent, the estrogen receptor β ligand chloroindazole (IndCl), was tested for its therapeutic potential in the visual pathway. EAE produced functional deficits in visual system electrophysiology, including suppression of ERG and VEP waveform amplitudes and increased signal latencies. Therapeutic IndCl rescued overall visual system latency by VEP but had little impact on amplitude or ERG findings...

The role of long noncoding RNAs in malaria parasites

Wed, 8 Jan 2025 00:00:00 +0000

The human malaria parasites, including Plasmodium falciparum, persist as a major cause of global morbidity and mortality. The recent stalling of progress toward malaria elimination substantiates a need for novel interventions. Controlled gene expression is central to the parasite's numerous life cycle transformations and adaptation. With few specific transcription factors (TFs) identified, crucial roles for chromatin states and epigenetics in parasite transcription have become evident. Although many chromatin-modifying enzymes are known, less is known about which factors mediate their impacts on transcriptional variation. Like those of higher eukaryotes, long noncoding RNAs (lncRNAs) have recently been shown to have integral roles in parasite gene regulation. This review aims to summarize recent developments and key findings on the role of lncRNAs in P. falciparum.

Cancer mutations rewire the RNA methylation specificity of METTL3-METTL14

Sat, 4 Jan 2025 00:00:00 +0000

Chemical modification of RNAs is important for posttranscriptional gene regulation. The METTL3-METTL14 complex generates most N⁶-methyladenosine (m⁶A) modifications in messenger RNAs (mRNAs), and dysregulated methyltransferase expression has been linked to cancers. Here we show that a changed sequence context for m⁶A can promote oncogenesis. A gain-of-function missense mutation from patients with cancer, METTL14^R298P, increases malignant cell growth in culture and transgenic mice without increasing global m⁶A levels in mRNAs. The mutant methyltransferase preferentially modifies noncanonical sites containing a GGAU motif, in vitro and in vivo. The m⁶A in GGAU context is detected by the YTH family of readers similarly to the canonical sites but is demethylated less efficiently by an eraser, ALKBH5. Combining the biochemical and structural data, we provide a model for how the cognate RNA sequences are selected...

Synthesis and Molecular Properties of Nerve Agent Reactivator HLö‑7 Dimethanesulfonate

Tue, 24 Dec 2024 00:00:00 +0000

The threat of a deliberate release of chemical nerve agents has underscored the need to continually improve field effective treatments for these types of poisonings. The oxime containing HLö-7 is a potential second-generation therapeutic reactivator. A synthetic process for HLö-7 is detailed with improvements to the DIBAL reduction and ion exchange steps. HLö-7 was visualized for the first time within the active site of human acetylcholinesterase and its relative ex vivo potency confirmed against various nerve agents using a phrenic nerve hemidiaphragm assay.

Variations of neuronal properties in the region of locus coeruleus of mice

Thu, 19 Dec 2024 00:00:00 +0000

Neurons in the locus coeruleus (LC) have been traditionally viewed as a homogenous population. Recent studies begin to reveal their heterogeneity at multiple levels, ranging from molecular compositions to projection targets. To further uncover variations of neuronal properties in the LC, we took a genetic-based tagging approach to identify these neurons. Our data revealed diverse spike waveforms among neurons in the LC region, including a considerable fraction of narrow-spiking units. While all wide-spiking units possessed the regular waveform polarity (negative-positive deflection), the narrow units can be further divided based on opposing waveform polarities. Under anesthesia, wide units emitted action potential at a higher rate than the narrow units. Under wakefulness, only one subtype of narrow units exhibited fast-spiking phenotype. These neurons also had long latencies to optogenetic stimulation. In-situ hybridization further supported the existence of a small population...

A Sexually Dimorphic Role for Intestinal Cannabinoid Receptor Subtype-1 in the Behavioral Expression of Anxiety

Fri, 13 Dec 2024 00:00:00 +0000

Background: Increasing evidence suggests that the endocannabinoid system (ECS) in the brain controls anxiety and may be a therapeutic target for the treatment of anxiety disorders. For example, both pharmacological and genetic disruption of cannabinoid receptor subtype-1 (CB₁R) signaling in the central nervous system is associated with increased anxiety-like behaviors in rodents, while activating the system is anxiolytic. Sex is also a critical factor that controls the behavioral expression of anxiety; however, roles for the ECS in the gut in these processes and possible differences between sexes are largely unknown. Objective: In this study, we aimed to determine if CB₁Rs in the intestinal epithelium exert control over anxiety-like behaviors in a sex-dependent manner. Methods: We subjected male and female mice with conditional deletion of CB₁Rs in the intestinal epithelium (intCB₁^-/-) and controls (intCB₁^+/+)...

Replicon particle vaccination induces non-neutralizing anti-nucleoprotein antibody-mediated control of Crimean-Congo hemorrhagic fever virus

Mon, 9 Dec 2024 00:00:00 +0000

Crimean-Congo hemorrhagic fever virus (CCHFV) can cause severe human disease and is considered a WHO priority pathogen due to the lack of efficacious vaccines and antivirals. A CCHF virus replicon particle (VRP) has previously shown protective efficacy in a lethal Ifnar-/- mouse model when administered as a single dose at least 3 days prior to challenge. Here, we determine that non-specific immune responses are not sufficient to confer short-term protection, since Lassa virus VRP vaccination 3 days prior to CCHFV challenge was not protective. We also investigate how CCHF VRP vaccination confers protective efficacy by examining viral kinetics, histopathology, clinical analytes and immunity early after challenge (3 and 6 days post infection) and compare to unvaccinated controls. We characterize how these effects differ based on vaccination period and correspond to previously reported CCHF VRP-mediated protection. Vaccinating Ifnar-/- mice with CCHF VRP 28, 14, 7, or 3 days prior...

Elovanoids, a Novel Class of Lipid Mediators, Are Neuroprotective in a Traumatic Brain Injury Model in Rats

Mon, 9 Dec 2024 00:00:00 +0000

BACKGROUND: In the United States, traumatic brain injury (TBI) contributes significantly to mortality and morbidity. Elovanoids (ELVs), a novel class of homeostatic lipid mediators we recently discovered and characterized, have demonstrated neuroprotection in experimental stroke models but have never been tested after TBI. METHODS: A moderate fluid-percussion injury (FPI) model was used on male rats that were treated with ELVs by intravenous (IV) or intranasal (IN) delivery. In addition, using liquid chromatography-mass spectrometry (LC-MS/MS), we examined whether ELVs could be detected in brain tissue after IN delivery. RESULTS: ELVs administered intravenously 1 h after FPI improved behavior on days 2, 3, 7, and 14 by 20, 23, 31, and 34%, respectively, and preserved hippocampal CA3 and dentate gyrus (DG) volume loss compared to the vehicle. Whole-brain tractography revealed that ELV-IV treatment increased corpus callosum white matter fibers at the injury site. In comparison to...

Structural characterization of protective non-neutralizing antibodies targeting Crimean-Congo hemorrhagic fever virus

Mon, 9 Dec 2024 00:00:00 +0000

Crimean-Congo Hemorrhagic Fever Virus (CCHFV) causes a life-threatening disease with up to a 40% mortality rate. With no approved medical countermeasures, CCHFV is considered a public health priority agent. The non-neutralizing mouse monoclonal antibody (mAb) 13G8 targets CCHFV glycoprotein GP38 and protects mice from lethal CCHFV challenge when administered prophylactically or therapeutically. Here, we reveal the structures of GP38 bound with a human chimeric 13G8 mAb and a newly isolated CC5-17 mAb from a human survivor. These mAbs bind overlapping epitopes with a shifted angle. The broad-spectrum potential of c13G8 and CC5-17 and the practicality of using them against Aigai virus, a closely related nairovirus were examined. Binding studies demonstrate that the presence of non-conserved amino acids in Aigai virus corresponding region prevent CCHFV mAbs from binding Aigai virus GP38. This information, coupled with in vivo efficacy, paves the way for future mAb therapeutics effective...

Exploring Noncovalent Protease Inhibitors for the Treatment of Severe Acute Respiratory Syndrome and Severe Acute Respiratory Syndrome-Like Coronaviruses

Sat, 7 Dec 2024 00:00:00 +0000

Over the last 20 years, both severe acute respiratory syndrome coronavirus-1 and severe acute respiratory syndrome coronavirus-2 have transmitted from animal hosts to humans causing zoonotic outbreaks of severe disease. Both viruses originate from a group of betacoronaviruses known as subgroup 2b. The emergence of two dangerous human pathogens from this group along with previous studies illustrating the potential of other subgroup 2b members to transmit to humans has underscored the need for antiviral development against them. Coronaviruses modify the host innate immune response in part through the reversal of ubiquitination and ISGylation with their papain-like protease (PLpro). To identify unique or overarching subgroup 2b structural features or enzymatic biases, the PLpro from a subgroup 2b bat coronavirus, BtSCoV-Rf1.2004, was biochemically and structurally evaluated. This evaluation revealed that PLpros from subgroup 2b coronaviruses have narrow substrate specificity for...

Polyphenols as alternative treatments of COVID-19

Sat, 7 Dec 2024 00:00:00 +0000

Although scientists around the world have put lots of effort into the development of new treatments for COVID-19 since the outbreak, no drugs except Veklury (remdesivir) have been approved by FDA. There is an urgent need to discover some alternative antiviral treatment for COVID-19. Because polyphenols have been shown to possess antiviral activities, here we conducted a large-scale virtual screening for more than 400 polyphenols. Several lead compounds such as Petunidin 3-O-(6″-p-coumaroyl-glucoside) were identified to have promising binding affinities and convincing binding mechanisms. Analyzing the docking results and ADME properties sheds light on the potential efficacy of the top-ranked drug candidates and pinpoints the key residues on the target proteins for the future of drug development.

The structural and biochemical impacts of monomerizing human acetylcholinesterase

Fri, 6 Dec 2024 00:00:00 +0000

Serving a critical role in neurotransmission, human acetylcholinesterase (hAChE) is the target of organophosphate nerve agents. Hence, there is an active interest in studying the mechanism of inhibition and recovery of enzymatic activity, which could lead to better countermeasures against nerve agents. As hAChE is found in different oligomeric assemblies, certain approaches to studying it have been problematic. Herein, we examine the biochemical and structural impact of monomerizing hAChE by using two mutations: L380R/F535K. The activities of monomeric hAChE L380R/F535K and dimeric hAChE were determined to be comparable utilizing a modified Ellman's assay. To investigate the influence of subunit-subunit interactions on the structure of hAChE, a 2.1 Å X-ray crystallographic structure was determined. Apart from minor shifts along the dimer interface, the overall structure of the hAChE L380R/F535K mutant is similar to that of dimeric hAChE. To probe whether the plasticity of the...

Changes in immune cell populations during acclimatization to high altitude.

Fri, 6 Dec 2024 00:00:00 +0000

The immune response to acute hypoxemia may play a critical role in high-altitude acclimatization and adaptation. However, if not properly controlled, hypoxemia-induced inflammation may exacerbate high-altitude pathologies, such as acute mountain sickness (AMS), or other hypoxia-related clinical conditions. Several studies report changes in immune cell subsets at high altitude. However, the mechanisms underlying these changes, and if these alterations are beneficial or maladaptive, remains unknown. To address this, we performed multiparameter flow cytometry on peripheral blood mononuclear cells (PBMCs) collected throughout 3 days of high-altitude acclimatization in healthy sea-level residents (n = 20). Additionally, we conducted in vitro stimulation assays to test if high-altitude hypoxia exposure influences responses of immune cells to subsequent inflammatory stimuli. We found several immune populations were altered at high altitude, including monocytes, T cells, and B cells....

Identifying Drug Candidates for COVID-19 with Large-Scale Drug Screening

Fri, 6 Dec 2024 00:00:00 +0000

Papain-like protease (PL^pro) is critical to COVID-19 infection. Therefore, it is a significant target protein for drug development. We virtually screened a 26,193 compound library against the PL^pro of SARS-CoV-2 and identified several drug candidates with convincing binding affinities. The three best compounds all had better estimated binding energy than those of the drug candidates proposed in previous studies. By analyzing the docking results for the drug candidates identified in this and previous studies, we demonstrate that the critical interactions between the compounds and PL^pro proposed by the computational approaches are consistent with those proposed by the biological experiments. In addition, the predicted binding energies of the compounds in the dataset showed a similar trend as their IC₅₀ values. The predicted ADME and drug-likeness properties also suggested that these identified compounds can be used for COVID-19 treatment.

The SARS-CoV‑2 SSHHPS Recognized by the Papain-like Protease

Fri, 6 Dec 2024 00:00:00 +0000

Viral proteases are highly specific and recognize conserved cleavage site sequences of ∼6-8 amino acids. Short stretches of homologous host-pathogen sequences (SSHHPS) can be found spanning the viral protease cleavage sites. We hypothesized that these sequences corresponded to specific host protein targets since >40 host proteins have been shown to be cleaved by Group IV viral proteases and one Group VI viral protease. Using PHI-BLAST and the viral protease cleavage site sequences, we searched the human proteome for host targets and analyzed the hit results. Although the polyprotein and host proteins related to the suppression of the innate immune responses may be the primary targets of these viral proteases, we identified other cleavable host proteins. These proteins appear to be related to the virus-induced phenotype associated with Group IV viruses, suggesting that information about viral pathogenesis may be extractable directly from the viral genome sequence. Here we identify...

Eusociality and Senescence: Neuroprotection and Physiological Resilience to Aging in Insect and Mammalian Systems.

Fri, 6 Dec 2024 00:00:00 +0000

Are eusociality and extraordinary aging polyphenisms evolutionarily coupled? The remarkable disparity in longevity between social insect queens and sterile workers-decades vs. months, respectively-has long been recognized. In mammals, the lifespan of eusocial naked mole rats is extremely long-roughly 10 times greater than that of mice. Is this robustness to senescence associated with social evolution and shared mechanisms of developmental timing, neuroprotection, antioxidant defenses, and neurophysiology? Focusing on brain senescence, we examine correlates and consequences of aging across two divergent eusocial clades and how they differ from solitary taxa. Chronological age and physiological indicators of neural deterioration, including DNA damage or cell death, appear to be decoupled in eusocial insects. In some species, brain cell death does not increase with worker age and DNA damage occurs at similar rates between queens and workers. In comparison, naked mole rats exhibit...

Inflammation associated with monocyte/macrophage activation and recruitment corresponds with lethal outcome in a mouse model of Crimean-Congo haemorrhagic fever

Fri, 6 Dec 2024 00:00:00 +0000

Crimean-Congo haemorrhagic fever virus (CCHFV) causes human disease ranging from subclinical to a fatal haemorrhagic syndrome. Determinants of CCHF pathogenesis are largely unknown and animal models that recapitulate human disease are limited. A recently described mouse model uses a monoclonal antibody (mAb 5A3) targeting the interferon (IFN) alpha/beta receptor to suppress type I IFN responses, making animals transiently susceptible to infection. To advance utility of this model, we investigated effects of challenge route, timing of 5A3 delivery, mouse sex and age, and virus strain on clinical course and outcome. C57BL/6J mice received mAb 5A3 -1, 0, or -1/+1 days post-infection (dpi). Subsets were challenged with CCHFV strain Turkey04 or IbAr10200 subcutaneously or intraperitoneally, and serially euthanized 3- and 7-dpi, when meeting euthanasia criteria or at study completion (14 dpi). CCHFV-IbAr10200-infected mice almost uniformly succumbed to infection, whereas CCHFV-Turkey04-infected...

Early deficits in dentate circuit and behavioral pattern separation after concussive brain injury

Thu, 5 Dec 2024 00:00:00 +0000

Traumatic brain injury leads to cellular and circuit changes in the dentate gyrus, a gateway to hippocampal information processing. Intrinsic granule cell firing properties and strong feedback inhibition in the dentate are proposed as critical to its ability to generate unique representation of similar inputs by a process known as pattern separation. Here we evaluate the impact of brain injury on cellular decorrelation of temporally patterned inputs in slices and behavioral discrimination of spatial locations in vivo one week after concussive lateral fluid percussion injury (FPI) in mice. Despite posttraumatic increases in perforant path evoked excitatory drive to granule cells and enhanced ΔFosB labeling, indicating sustained increase in excitability, the reliability of granule cell spiking was not compromised after FPI. Although granule cells continued to effectively decorrelate output spike trains recorded in response to similar temporally patterned input sets after FPI, their...

Editorial: Neuroinflammation in acquired epilepsy

Thu, 5 Dec 2024 00:00:00 +0000

Editorial: Neuroinflammation in acquired epilepsy

N 2-Alkyl-dG lesions elicit R-loop accumulation in the genome

Mon, 25 Nov 2024 00:00:00 +0000

Humans are exposed to DNA alkylating agents through endogenous metabolism, environmental exposure and cancer chemotherapy. The resulting alkylated DNA adducts may elicit genome instability by perturbing DNA replication and transcription. R-loops regulate various cellular processes, including transcription, DNA repair, and telomere maintenance. However, unscheduled R-loops are also recognized as potential sources of DNA damage and genome instability. In this study, by employing fluorescence microscopy and R-loop sequencing approaches, we uncovered, for the first time, that minor-groove N2-alkyl-dG lesions elicit elevated R-loop accumulation in chromatin and in plasmid DNA in cells. We also demonstrated that the N2-alkyl-dG-induced R-loops impede transcription elongation and compromise genome integrity. Moreover, genetic depletion of DDX23, a R-loop helicase, renders cells more sensitive toward benzo[a]pyrene diolepoxide, a carcinogen that induces mainly the minor-groove N2-dG adduct....

Development and validation of an LC-MS/MS methodology for the quantification of thyroid hormones in dko MCT8/OATP1C1 mouse brain

Fri, 22 Nov 2024 00:00:00 +0000

The Allan-Herndon Dudley Syndrome (AHDS) is a rare disease caused by the progressive loss of monocarboxylate transporter 8 (MCT8). In patients with AHDS, the absence of MCT8 impairs transport of thyroid hormones (TH) through the blood brain barrier, leading to a central state of TH deficiency. In mice, the AHDS is mimicked by simultaneous deletion of the TH transporters MCT8 and the solute carrier organic anion transporter family member 1c1 (OATP1C1). To support preclinical mouse studies, an analytical methodology was developed and successfully applied for quantifying selected thyroid hormones in mouse whole brain and in specific regions using liquid chromatography tandem mass-spectrometry (LC-MS/MS). An important requirement for the methodology was its high sensitivity since a very low concentration of THs was expected in MCT8/OATP1C1 double-knockout (dko) mouse brain. Seven THs were targeted: L-thyroxine (T4), 3,3´,5-triiodo-L-thyronine-thyronine (T3), 3,3´,5´-triiodo-L-thyronine-thyronine...

Glucoregulatory disruption in male mice offspring induced by maternal transfer of endocrine disrupting brominated flame retardants in DE-71

Fri, 22 Nov 2024 00:00:00 +0000

Introduction: Polybrominated diphenyl ethers (PBDEs) are commercially used flame retardants that bioaccumulate in human tissues, including breast milk. PBDEs produce endocrine and metabolic disruption in experimental animals and have been associated with diabetes and metabolic syndrome (MetS) in humans, however, their sex-specific diabetogenic effects are not completely understood. Our past works show glucolipid dysregulation resulting from perinatal exposure to the commercial penta-mixture of PBDEs, DE-71, in C57BL/6 female mice. Methods: As a comparison, in the current study, the effects of DE-71 on glucose homeostasis in male offspring was examined. C57BL/6N dams were exposed to DE-71 at 0.1 mg/kg/d (L-DE-71), 0.4 mg/kg/d (H-DE-71), or received corn oil vehicle (VEH/CON) for a total of 10 wks, including gestation and lactation and their male offspring were examined in adulthood. Results: Compared to VEH/CON, DE-71 exposure produced hypoglycemia after a 11 h fast (H-DE-71)....

Nanocarrier mediated delivery of insecticides into tarsi enhances stink bug mortality

Tue, 19 Nov 2024 00:00:00 +0000

Current delivery practices for insecticide active ingredients are inefficient with only a fraction reaching their intended target. Herein, we developed carbon dot based nanocarriers with molecular baskets (γ-cyclodextrin) that enhance the delivery of active ingredients into insects (southern green stink bugs, Nezara viridula L.) via their tarsal pores. Nezara viridula feeds on leguminous plants worldwide and is a primary pest of soybeans. After two days of exposure, most of the nanocarriers and their active ingredient cargo (>85%) remained on the soybean leaf surface, rendering them available to the insects. The nanocarriers enter stink bugs through their tarsi, enhancing the delivery of a fluorescent chemical cargo by 2.6 times. The insecticide active ingredient nanoformulation (10 ppm) was 25% more effective in controlling the stink bugs than the active ingredient alone. Styletectomy experiments indicated that the improved active ingredient efficacy was due to the nanoformulation...

The normal distribution of the hypoxic ventilatory response and methodological impacts: a meta‐analysis and computational investigation

Mon, 11 Nov 2024 00:00:00 +0000

The hypoxic ventilatory response (HVR) is the increase in breathing in response to reduced arterial oxygen pressure. Over several decades, studies have revealed substantial population-level differences in the magnitude of the HVR as well as significant inter-individual variation. In particular, low HVRs occur frequently in Andean high-altitude native populations. However, our group conducted hundreds of HVR measures over several years and commonly observed low responses in sea-level populations as well. As a result, we aimed to determine the normal HVR distribution, whether low responses were common, and to what extent variation in study protocols influence these findings. We conducted a comprehensive search of the literature and examined the distributions of HVR values across 78 studies that utilized step-down/steady-state or progressive hypoxia methods in untreated, healthy human subjects. Several studies included multiple datasets across different populations or experimental...

Protocol for the longitudinal study of neuroinflammation and reactive astrocytes in Lcn2CreERT2 mice

Mon, 11 Nov 2024 00:00:00 +0000

During brain disease, astrocytes can reprogram into a reactive state that alters many of their functions. Here, we present a protocol for studying neuroinflammation and reactive astrogliosis in mice using lipopolysaccharide (LPS) from E. coli. We describe steps for employing the Lcn2CreERT2 mouse crossed into a fluorescent Cre reporter line to label a subset of reactive astrocytes during and after inflammation. We then detail procedures for the longitudinal study of reactive astrocytes during the induction, progression, and/or resolution of astrogliosis. For complete details on the use and execution of this protocol, please refer to Agnew-Svoboda et al.¹.

Polyunsaturated fatty acids stimulate immunity and eicosanoid production in Drosophila melanogaster

Sat, 9 Nov 2024 00:00:00 +0000

Eicosanoids are a class of molecules derived from C20 polyunsaturated fatty acids (PUFAs) that play a vital role in mammalian and insect biological systems, including development, reproduction, and immunity. Recent research has shown that insects have significant but lower levels of C20 PUFAs in circulation in comparison to C18 PUFAs. It has been previously hypothesized in insects that eicosanoids are synthesized from C18 precursors, such as linoleic acid (LA), to produce downstream eicosanoids. In this study, we show that introduction of arachidonic acid (AA) stimulates production of cyclooxygenase, lipoxygenase, and cytochrome P450-derived eicosanoids. Downstream immune readouts showed that LA stimulates phagocytosis by hemocytes, while both LA and AA stimulate increased antimicrobial peptide production when D. melanogaster is exposed to a heat-killed bacterial pathogen. In totality, this work identifies PUFAs that are involved in insect immunity and adds evidence to the...

Early-life obesogenic environment integrates immunometabolic and epigenetic signatures governing neuroinflammation

Fri, 8 Nov 2024 00:00:00 +0000

Childhood overweight/obesity is associated with stress-related psychopathology, yet the pathways connecting childhood obesity to stress susceptibility are poorly understood. We employed a systems biology approach with 62 adolescent Lewis rats fed a Western-like high-saturated fat diet (WD, 41% kcal from fat) or a control diet (CD, 13% kcal from fat). A subset of rats underwent a 31-day model of predator exposures and social instability (PSS). Effects were assessed using behavioral tests, DTI (diffusion tensor imaging), NODDI (neurite orientation dispersion and density imaging), 16S rRNA gene sequencing for gut microbiome profiling, hippocampal microglia analysis, and targeted gene methylation. Parallel experiments on human microglia cells (HMC3) examined how palmitic acid influences cortisol-related inflammatory responses. Rats exposed to WD and PSS exhibited deficits in sociability, increased fear/anxiety-like behaviors, food consumption, and body weight. WD/PSS altered hippocampal...

Rapid Loss of Nutritional Symbionts in an Endemic Hawaiian Herbivore Radiation Is Associated with Plant Galling Habit

Fri, 8 Nov 2024 00:00:00 +0000

Insect herbivores frequently cospeciate with symbionts that enable them to survive on nutritionally unbalanced diets. While ancient symbiont gain and loss events have been pivotal for insect diversification and feeding niche specialization, evidence of recent events is scarce. We examine the recent loss of nutritional symbionts (in as little as 1 MY) in sap-feeding Pariaconus, an endemic Hawaiian insect genus that has undergone adaptive radiation, evolving various galling and free-living ecologies on a single host-plant species, Metrosideros polymorpha within the last ∼5 MY. Using 16S rRNA sequencing, we investigated the bacterial microbiomes of 19 Pariaconus species and identified distinct symbiont profiles associated with specific host-plant ecologies. Phylogenetic analyses and metagenomic reconstructions revealed significant differences in microbial diversity and functions among psyllids with different host-plant ecologies. Within a few millions of years, Pariaconus species...

A Divergent Synthesis of Numerous Pyrroloiminoquinone Alkaloids Identifies Promising Antiprotozoal Agents

Fri, 8 Nov 2024 00:00:00 +0000

On the basis of a streamlined route to the pyrroloiminoquinone (PIQ) core, we made 16 natural products spread across four classes of biosynthetically related alkaloid natural products, and multiple structural analogs, all in ≤8 steps longest linear sequence (LLS). The strategy features a Larock indole synthesis as the key operation in a five-step synthesis of a key methoxy-PIQ intermediate. Critically, this compound was readily diverged via selective methylation of either (or both) of the imine-like or pyrrole nitrogens, which then permitted further divergence by either O-demethylation to o-quinone natural products or displacement of the methoxy group with a range of amine nucleophiles. Based on a single, early report of their potential utility against the malaria parasite, we assayed these compounds against several strains of Plasmodium falciparum, as well as two species of the related protozoan parasite Babesia. In combination with evaluations of...

EphB2 Signaling Is Implicated in Astrocyte-Mediated Parvalbumin Inhibitory Synapse Development

Thu, 7 Nov 2024 00:00:00 +0000

Impaired inhibitory synapse development is suggested to drive neuronal hyperactivity in autism spectrum disorders (ASD) and epilepsy. We propose a novel mechanism by which astrocytes control the development of parvalbumin (PV)-specific inhibitory synapses in the hippocampus, implicating ephrin-B/EphB signaling. Here, we utilize genetic approaches to assess functional and structural connectivity between PV and pyramidal cells (PCs) through whole-cell patch-clamp electrophysiology, optogenetics, immunohistochemical analysis, and behaviors in male and female mice. While inhibitory synapse development is adversely affected by PV-specific expression of EphB2, a strong candidate ASD risk gene, astrocytic ephrin-B1 facilitates PV→PC connectivity through a mechanism involving EphB signaling in PV boutons. In contrast, the loss of astrocytic ephrin-B1 reduces PV→PC connectivity and inhibition, resulting in increased seizure susceptibility and an ASD-like phenotype. Our findings underscore...

Functional consequences of postnatal interventions in a mouse model of Fragile X syndrome

Thu, 7 Nov 2024 00:00:00 +0000

BACKGROUND: Fragile X syndrome (FXS) is a leading genetic cause of autism and intellectual disability with cortical hyperexcitability and sensory hypersensitivity attributed to loss and hypofunction of inhibitory parvalbumin-expressing (PV) cells. Our studies provide novel insights into the role of excitatory neurons in abnormal development of PV cells during a postnatal period of inhibitory circuit refinement. METHODS: To achieve Fragile X mental retardation gene (Fmr1) deletion and re-expression in excitatory neurons during the postnatal day (P)14-P21 period, we generated Cre^CaMKIIa/Fmr1^Flox/y (cOFF) and Cre^CaMKIIa/Fmr1^FloxNeo/y (cON) mice, respectively. Cortical phenotypes were evaluated in adult mice using biochemical, cellular, clinically relevant electroencephalogram (EEG) and behavioral tests. RESULTS: We found that similar to global Fmr1 KO mice, the density of PV-expressing cells, their activation, and sound-evoked gamma synchronization...

Aligning consciousness science and U.S. funding agency priorities

Thu, 7 Nov 2024 00:00:00 +0000

We recently completed the Fund Consciousness Science! Project: a workshop and subawards program aimed to align United States federal funding mechanisms and consciousness research. Here we describe the project’s motivation, execution, and outcomes to motivate similar efforts both locally and globally.

Urokinase plasminogen activator mediates changes in human astrocytes modeling fragile X syndrome

Thu, 7 Nov 2024 00:00:00 +0000

The function of astrocytes intertwines with the extracellular matrix, whose neuron and glial cell-derived components shape neuronal plasticity. Astrocyte abnormalities have been reported in the brain of the mouse model for fragile X syndrome (FXS), the most common cause of inherited intellectual disability, and a monogenic cause of autism spectrum disorder. We compared human FXS and control astrocytes generated from human induced pluripotent stem cells and we found increased expression of urokinase plasminogen activator (uPA), which modulates degradation of extracellular matrix. Several pathways associated with uPA and its receptor function were activated in FXS astrocytes. Levels of uPA were also increased in conditioned medium collected from FXS hiPSC-derived astrocyte cultures and correlated inversely with intracellular Ca²⁺ responses to activation of L-type voltage-gated calcium channels in human astrocytes. Increased uPA augmented neuronal phosphorylation of TrkB...

Editorial: Neural markers of sensory processing in development

Thu, 7 Nov 2024 00:00:00 +0000

Editorial: Neural markers of sensory processing in development

Astrocytic Ephrin-B1 Regulates Oligodendrocyte Development and Myelination

Thu, 7 Nov 2024 00:00:00 +0000

Astrocytes have been implicated in oligodendrocyte development and myelination, however, the mechanisms by which astrocytes regulate oligodendrocytes remain unclear. Our findings suggest a new mechanism that regulates astrocyte-mediated oligodendrocyte development through ephrin-B1 signaling in astrocytes. Using a mouse model, we examined the role of astrocytic ephrin-B1 signaling in oligodendrocyte development by deleting ephrin-B1 specifically in astrocytes during the postnatal days (P)14-P28 period and used mRNA analysis, immunohistochemistry, and mouse behaviors to study its effects on oligodendrocytes and myelination. We found that deletion of astrocytic ephrin-B1 downregulated many genes associated with oligodendrocyte development, myelination, and lipid metabolism in the hippocampus and the corpus callosum. Additionally, we observed a reduced number of oligodendrocytes and impaired myelination in the corpus callosum of astrocyte-specific ephrin-B1 KO mice. Finally, our...

Proximity Proteomics Revealed Aberrant mRNA Splicing Elicited by ALS-Linked Profilin‑1 Mutants

Tue, 5 Nov 2024 00:00:00 +0000

Profilin 1 (PFN1) is a cytoskeleton protein that modulates actin dynamics through binding to monomeric actin and polyproline-containing proteins. Mutations in PFN1 have been linked to the pathogenesis of familial amyotrophic lateral sclerosis (ALS). Here, we employed an unbiased proximity labeling strategy in combination with proteomic analysis for proteome-wide profiling of proteins that differentially interact with mutant and wild-type (WT) PFN1 proteins in human cells. We uncovered 11 mRNA splicing proteins that are preferentially enriched in the proximity proteomes of the two ALS-linked PFN1 variants, C71G and M114T, over that of wild-type PFN1. We validated the preferential interactions of the ALS-linked PFN1 variants with two mRNA splicing factors, hnRNPC and U2AF2, by immunoprecipitation, followed with immunoblotting. We also found that the two ALS-linked PFN1 variants promoted the exonization of Alu elements in the mRNAs of MTO1, TCFL5, WRN...