Biology subjects

Kelly, C.

Publications and source records attributed to Kelly, C..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

Modelling the Impact of Dominant Transport Pathways on Antarctic Krill Fishing Activity in the Southern Ocean

Antarctic krill (Euphasia superba) are a key component in the Southern Ocean ecosystem, especially in the Atlantic sector, where the majority of the population is concentrated. The Norwegian commercial krill fishery exclusively targets three subareas in the Antarctic: the western Antarctic Peninsula, and the northern shelves of both the South Orkney Islands and South Georgia. Given its reliance on oceanic transport from other regions and the potential impact of rising sea temperatures on the northern habitat, the South Georgian krill population is particularly sensitive to altering environmental conditions. The relative distance from the peninsular regions to South Georgia means that choosing to trawl in this region implies a higher risk, which is why it is exclusively targeted in winter when extensive sea-ice makes peninsular regions unsafe and inaccessible to commercial fishery operations. In this article, we show that relative to operations at South Orkney and the Antarctic Pensinsula, average catches at South Georgia have been lower with higher variability over the past 15 years. Using a Lagrangian modelling approach, we illustrate that variability in advection from source regions in the Antarctic Peninsula are correlated with proceeding catch values at South Georgia. This was not the case for source release sites at the South Orkney Islands. The dominant transport pathways for krill were strongly determined by position of regional fronts and the source sites of recruits to South Georgia were related to the position of fronts at both the Antarctic Peninsula and South Orkney Islands. This study highlights the importance of advective patterns on the variability in krill fishing activity and supports the hypothesis that South Georgia is a sink region for krill in the Southern Ocean while the western Antarctic Peninsula is a central source site.

ecology↗

bioRxiv2025

Immune cell mitochondrial phenotypes are largely preserved in mitochondrial diseases and do not reflect disease severity

ObjectiveTo profile immune cell mitochondrial phenotypes in mitochondrial diseases (MitoD) and evaluate how those phenotypes relate to disease manifestations or biomarkers. MethodsWe profiled mitochondrial content and OxPhos enzymatic activities in isolated monocytes, lymphocytes, neutrophils, platelets, and mixed peripheral blood mononuclear cells (PBMCs) from 37 individuals with MitoD (m.3243A>G, n=23; single, large-scale mitochondrial DNA (mtDNA) deletions, n=14) and 68 healthy women and men from the MiSBIE study. ResultsWe first confirm and quantify robust cell type differences in mitochondrial content, activities of OxPhos complexes I, II, and IV, and the mitochondrial respiratory capacity (MRC) index. In relation to MitoD, neither mitochondrial content nor OxPhos capacity were consistently affected, other than a mild monocyte-specific reduction in complex I (partially mtDNA encoded) relative to complex II (entirely nDNA encoded), consistent with the mtDNA defects examined. Relative to the large differences in cell type-specific mitochondrial phenotypes, differences in MitoD relative to controls were generally small (<25%) across mitochondrial measures. The MitoD biomarkers GDF15 and FGF21, as well as clinical disease severity measures, were most strongly related to mitochondrial abnormalities in platelets, and most weakly related to mitochondrial OxPhos capacity in lymphocytes, which are known to eliminate mtDNA defects. Finally, comparing PBMCs collected in the morning/fasted state to the afternoon/fed state following a stressful experience, we report significant time-dependent changes in mitochondrial biology over the time scale of hours. ConclusionsOverall, these results demonstrate that the dynamic and cell-type specific mitochondrial phenotypes are preserved in mitochondrial diseases and are generally unrelated to the severity of MitoD symptoms.

pathology↗

bioRxiv2024

Impact of commercial gut health interventions on caecal metagenome and broiler performance

BackgroundMaintaining gut health is a persistent and unresolved challenge in the poultry industry. Given the critical role of gut health in chicken performance and welfare, there is a pressing need to identify effective gut health intervention (GHI) strategies to ensure optimal outcomes in poultry farming. In this study, across three broiler production cycles, we compared the metagenomes and performance of broilers provided with ionophores as control against birds subjected to five different GHI combinations involving vaccination, probiotics, prebiotics, essential oils, and reduction of ionophore use. ResultsUsing a binning strategy, 84 ([≥]75% completeness, [≤] 5% contamination) metagenome-assembled genomes (MAGs) from 118 caecal samples were recovered and annotated for their metabolic potential. The majority of these (n = 52, 61%) had a differential response across all cohorts and are associated with the performance parameter - European Poultry Efficiency Factor (EPEF). The control group exhibited the highest EPEF, followed closely by the cohort where probiotics are used in conjunction with vaccination. The use of Probiotics B, a commercial Bacillus strain-based formulation, was determined to contribute to the superior performance of birds. GHI supplementation generally affected abundance of microbial enzymes relating to carbohydrate and protein digestion, and metabolic pathways relating to energy, nucleotide synthesis, short-chain fatty acid synthesis, and drug-transport systems. These shifts are hypothesised to differentiate performance among groups and cycles, highlighting the beneficial role of several bacteria including Rikenella microfusus and UBA7160 species. ConclusionsAll GHIs are shown to be effective methods for gut microbial modulation, with varying influences on MAG diversity, composition and microbial functions. These metagenomic insights greatly enhance our understanding of microbiota-related metabolic pathways, enabling us to devise strategies against enteric pathogens related to poultry products and presenting new opportunities to improve overall poultry performance and health.

microbiology↗

bioRxiv2024

Increasing the representation of minoritized youth for inclusive and reproducible brain-behavior associations

Population neuroscience datasets allow researchers to estimate reliable effect sizes for brain-behavior associations because of their large sample sizes. However, these datasets undergo strict quality control to mitigate sources of noise, such as head motion. This practice often excludes a disproportionate number of minoritized individuals. We employ motion-ordering and motion-ordering+resampling (bagging) to test if these methods preserve functional MRI (fMRI) data in the Adolescent Brain Cognitive Development Study (N=5,733). Black and Hispanic youth exhibited excess head motion relative to data collected from White youth, and were discarded disproportionately when using conventional approaches. Both methods retained more than 99% of Black and Hispanic youth. They produced reproducible brain-behavior associations across low-/high-motion racial/ethnic groups based on motion-limited fMRI data. The motion-ordering and bagging methods are two feasible approaches that can enhance sample representation for testing brain-behavior associations and fulfill the promise of consortia datasets to produce generalizable effect sizes across diverse populations.

neuroscience↗

bioRxiv2024

Using fingerprinting as a testbed for strategies to improve reproducibility of functional connectivity

Reproducible functional connectivity-based biomarkers have remained elusive despite the promise of deeply phenotyped consortia. An important component of reproducibility is reliability over repeated measures, often measured by the intraclass correlation coefficient (ICC). Here, we test the use of functional connectome fingerprinting as a way to select pre- and post-processing parameters. We hypothesized that whichever parameters yielded the best fingerprint accuracies would also improve the ICC across scans. Using five datasets from the Consortium for Replicability and Reproducibility, we found that higher identification accuracies were achieved when using: (I) global signal regression; (II) finer brain parcellations; (III) cortical regions compared to subcortical and cerebellar structures; (IV) medial frontal and frontoparietal networks relative to the whole-brain; (V) discriminative edges; (VI) longer scan duration; and (VII) lower sample size. We observed that the ICC was consistently "poor" across the five datasets even with the application of two optimal fingerprint-informed pipelines. The fingerprint-informed pipelines may enable comparison, benchmarking, and adjudication of functional connectivity-based analysis pipelines or novel analytic approaches, as a means to enhance their reproducibility in heterogeneous populations. Key PointsO_LIConnectome-based fingerprinting can provide a useful testbed for reproducible functional connectivity analysis pipelines. C_LIO_LIFingerprint-informed pipelines offer an intuitive and less resource intensive way to select data pre-/post-processing parameters for improving the reproducibility of the functional connectome. C_LIO_LIConnectome-based fingerprinting offers an alternative approach to test-retest reliability. C_LI

neuroscience↗

bioRxiv2024

Data rescue in high-motion youth cohorts for robust and reproducible brain-behavior relationships

Recognition of the detrimental impact of participant motion on functional connectivity measures has led to the adoption of increasingly stringent quality control standards to minimize potential motion artifacts. These stringent standards can lead to the exclusion of many participants, creating a tension with a countervailing requirement for large sample sizes that can provide adequate statistical power, particularly for brain-behavior association studies. Here, we test and validate two techniques aimed at mitigating the impact of head motion on functional connectivity estimates, and show that these techniques enable the retention of a substantial proportion of participants who would otherwise be excluded based on motion criteria, such as a minimum mean framewise displacement (FD) threshold. Specifically, we first show that functional connectomes computed using time series data that have been ordered according to motion (i.e., framewise displacement -- FD) and (1) subsetted to include the lowest-motion time points ("motion ordered") or (2) subsetted and resampled ("bagged") are reproducible, in that they enable the successful identification of an individual from a group using functional connectome fingerprinting. Second, we demonstrate that motion-ordered and bagged functional connectomes yield robust brain-behavior associations, which, when examined as a function of sample size, are comparable to those obtained using the standard full time series. Finally, we show that the utility of both approaches lies in maximizing participant inclusivity by allowing for the retention of high-motion participants that would otherwise be discarded. Given equivalent performance of the two approaches across these tests of reproducibility, validity, and utility, we conclude by recommending motion-ordering to enable data rescue, maximize inclusivity, and address the need for adequately powered samples in functional connectivity research, while maintaining stringent data quality standards. While our findings were reproducible across different head motion thresholds and edges in the functional connectome, we outline possibilities for further validation and assessment of generalization using other behavioral phenotypes and consortia datasets.

neuroscience↗

bioRxiv2024

Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases

Growth Differentiation Factor 15 (GDF15) is a protein that reflects mitochondrial energetic stress and is linked to physical and mental health symptoms, aging, and mortality. Here, we tested the hypothesis that GDF15 is a stress-responsive biomarker through a series of observational and experimental studies. We report four main findings. First, in the UK Biobank (n=53,026) and Framingham Heart Study (FHS) Offspring (n=3,460) cohorts, plasma GDF15 levels were elevated in individuals with symptoms of depression and anxiety. In the FHS cohort, GDF15 was also higher in participants exposed to chronic psychosocial stressors, including lower educational attainment, lower family income, and higher job strain. Second, plasma GDF15 levels in the FHS cohort correlated positively with epigenetic clocks measuring biological aging and effect sizes of GDF15 associations with psychosocial stressors were comparable to those observed for the clocks. Third, in a two-participant intensive-sampling study (n=112 days), saliva GDF15 showed a robust awakening response similar to established stress-related hormones. However, it exhibited a distinct negative pattern, peaking at waking and declining by 42-92% within 30-45 minutes. Finally, in two laboratory experiments (n=148), acute social-evaluative stress significant increased GDF15 levels in plasma and saliva within minutes. Together, these findings suggest that psychosocial stress may contribute to mitochondrial energetic stress indexed by GDF15, with implications for aging and health. This work opens new avenues for using GDF15 as a non-invasive biomarker to study the biological embedding of stress and its impact on aging trajectories. Significance statementGrowth Differentiation Factor 15 (GDF15) is a circulating protein elevated with mitochondrial energetic stress, aging, and diseases. Our findings show that GDF15 is elevated with depressive and anxiety symptoms and in those exposed to chronic psychosocial stress. Elevated plasma GDF15 also correlates with accelerated biological aging, as measured by epigenetic clocks. The effect sizes linking GDF15 to psychosocial stressors were comparable to those observed for the epigenetic clocks. Saliva GDF15 shows a robust negative awakening response characterized by elevated levels at awakening before declining within 30-45 minutes. Acute social-evaluative stress induced increase in plasma and saliva GDF15. Together, these findings suggest GDF15 can be used to study the energetic mechanisms for the biological embedding of stress across the lifespan.

physiology↗

bioRxiv2022

Zinc supplementation induced transcriptional changes in primary human retinal pigment epithelium: a single cell RNA sequencing study to understand age-related macular degeneration

Zinc supplementation had been shown to be beneficial to slow the progression of age-related macular degeneration (AMD). However, the molecular mechanism underpinning this benefit is not well understood. In this study, we used single-cell RNA sequencing to identify transcriptomic changes induced by zinc supplementation in human primary retinal pigment epithelial (RPE) cells in culture. The RPE cells were allowed to mature for up to 19 weeks. After one or 18 weeks in culture, we supplemented the culture medium with 125 M added zinc for one week. During maturation RPE cells developed high transepithelial electrical resistance, extensive, but variable, pigmentation and deposited sub-RPE material similar to the hallmark lesions of AMD. Unsupervised cluster analysis of the combined transcriptome of the cells isolated after two-, nine- and 19 weeks in culture, showed a significant degree of heterogeneity. Clustering based on 234 pre-selected RPE specific genes, identified from the literature, divided the cells into two distinct clusters we defined as more- and less-differentiated cells. The proportion of more differentiated cells increased with time in culture, but appreciable numbers of cells remained less differentiated even at 19 weeks. Pseudotemporal ordering identified 537 genes that could be implicated in the dynamics of RPE cell differentiation (FDR< 0.05). Zinc treatment resulted in the differential expression of 281 of these genes (FDR< 0.05). These genes were associated with several biological pathways including extracellular remodelling, retinoid metabolism and modulation of ID1/ID3 transcriptional regulation, to name a few. Overall, zinc had a multitude of effects on the RPE transcriptome including a number of genes that are involved in pigmentation, complement regulation, mineralisation and cholesterol metabolism processes associated with AMD.

cell biology↗

bioRxiv2022

Effects of netarsudil-family Rho kinase inhibitors on human trabecular meshwork cell contractility and actin remodeling using a bioengineered ECM hydrogel

Interactions between trabecular meshwork (TM) cells and their extracellular matrix (ECM) are critical for normal outflow function in the healthy eye. Multifactorial dysregulation of the TM is the principal cause of elevated intraocular pressure that is strongly associated with glaucomatous vision loss. Key characteristics of the diseased TM are pathologic contraction and actin stress fiber assembly, contributing to overall tissue stiffening. Among first-line glaucoma medications, the Rho-associated kinase inhibitor (ROCKi) netarsudil is known to directly target the stiffened TM to improve outflow function via tissue relaxation involving focal adhesion and actin stress fiber disassembly. Yet, no in vitro studies have explored the effect of netarsudil on human TM (HTM) cell contractility and actin remodeling in a 3D ECM environment. Here, we use our bioengineered HTM cell-encapsulated ECM hydrogel to investigate the efficacy of different netarsudil-family ROCKi compounds on reversing pathologic contraction and actin stress fibers. Netarsudil and all related experimental ROCKi compounds exhibited significant ROCK1/2 inhibitory and focal adhesion disruption activities. Furthermore, all ROCKi compounds displayed potent contraction-reversing effects on HTM hydrogels upon glaucomatous induction in a dose-dependent manner, relatively consistent with their biochemical/cellular inhibitory activities. At their tailored EC50 levels, netarsudil-family ROCKi compounds exhibited distinct effect signatures of reversing pathologic HTM hydrogel contraction and actin stress fibers, independent of the cell strain used. Netarsudil outperformed the experimental ROCKi compounds in support of its clinical status. In contrast, at uniform EC50-levels using netarsudil as reference, all ROCKi compounds performed similarly. Collectively, our data suggest that netarsudil exhibits high potency to rescue HTM cell pathobiology in a tissue-mimetic 3D ECM microenvironment, solidifying the utility of our bioengineered hydrogel model as a viable screening platform to further our understanding of TM pathophysiology in glaucoma.

cell biology↗

bioRxiv2022

Single cell RNA-seq identifies inflammation-induced loss of CFTR-expressing airway ionocytes in non-eosinophilic asthma

Asthma is the most common chronic airways disease worldwide and the severe treatment resistant subtype of asthma is responsible for the majority of disease burden. Asthma is heterogeneous in nature and can be classified according to airway infiltrates as eosinophilic or non-eosinophilic (sometimes referred to as Type 2 low), which is further divided into paucigranulocytic (low levels of granulocytes), or neutrophilic asthma characterized by elevated neutrophils, and mixed Type 1 and Type 17 cytokines in airway tissue, sputum, and bronchoalveolar lavage. Severe non-eosinophilic asthma currently has fewer effective treatment options and many of these patients fail to qualify for newer biologic monoclonal therapies. The cystic fibrosis transmembrane conductance regulator (CFTR) is a key protein whose function is dysregulated in multiple respiratory diseases including cystic fibrosis and chronic obstructive pulmonary disease (COPD) and has proven a valuable therapeutic target. Using human bronchial epithelial cells (hBECs) isolated differentiated at air-liquid interface we demonstrated a reduced function of the CFTR in non-eosinophilic asthma. Characterization of the cell and molecular differences in airway epithelial cells between severe asthma subtypes using single cell RNA-sequencing (scRNAseq) revealed that airway epithelial cells from non-eosinophilic asthma, and in particular neutrophilic asthma patients, fail to differentiate into CFTR-expressing ionocytes compared with eosinophilic asthma or healthy donors. We identified a novel ionocyte transcriptional signature, which was present in both bronchial and tracheal airway epithelial samples indicating conserved anatomical gene regulation. Using protein markers and immunofluorescent quantification loss of ionocytes was confirmed in non-eosinophilic asthma hBECs. Similarly, ioncytes were also diminished in the airways of a murine model of neutrophilic-dominant but not eosinophilic allergen asthma models. Furthermore, treatment of hBECs from healthy donors with a neutrophilic asthma-like inflammatory cytokine mixture, but not IL-13, led to loss of ionocytes primarily due to IFN-{gamma}. Inflammation-induced loss of CFTR-expressing ionocytes in airway cells from non-eosinophilic asthma may represent a key feature of disease pathogenesis and a novel drug target for this difficult-to-treat disease.

cell biology↗

bioRxiv2022

BrainQCNet: a Deep Learning attention-based model for multi-scale detection of artifacts in brain structural MRI scans

Analyses of structural MRI (sMRI) data depend on robust upstream data quality control (QC). It is also crucial that researchers seek to retain maximal amounts of data to ensure reproducible, generalizable models and to avoid wasted effort, including that of participants. The time-consuming and difficult task of manual QC evaluation has prompted the development of tools for the automatic assessment of brain sMRI scans. Existing tools have proved particularly valuable in this age of Big Data; as datasets continue to grow, reducing execution time for QC evaluation will be of considerable benefit. The development of Deep Learning (DL) models for artifact detection in structural MRI scans offers a promising avenue toward fast, accurate QC evaluation. In this study, we trained an interpretable Deep Learning model, ProtoPNet, to classify minimally preprocessed 2D slices of scans that had been manually annotated with a refined quality assessment (ABIDE 1; n = 980 scans). To evaluate the best model, we applied it to 2141 ABCD scans for which gold-standard manual QC annotations were available. We obtained excellent accuracy: 82.4% for good quality scans (Pass), 91.4% for medium to low quality scans (Fail). Further validation using 799 scans from ABIDE 2 and 750 scans from ADHD-200 confirmed the reliability of our model. Accuracy was comparable to or exceeded that of existing ML models, with fast processing and prediction time (1 min per scan, GPU machine, CUDA-compatible). Our attention model also performs better than traditional DL (i.e., convolutional neural network models) in detecting poor quality scans. To facilitate faster and more accurate QC prediction for the neuroimaging community, we have shared the model that returned the most reliable global quality scores as a BIDS-app (https://github.com/garciaml/BrainQCNet).

neuroscience↗

bioRxiv2021

Multimodal Gradient Mapping of Rodent Hippocampus

The hippocampus plays a central role in supporting our coherent and enduring sense of self and our place in the world. Understanding its functional organisation is central to understanding this complex role. Previous studies suggest function varies along a long hippocampal axis, but there is disagreement about the presence of sharp discontinuities or gradual change along that axis. Other open questions relate to the underlying drivers of this variation and the conservation of organisational principles across species. Here, we delineate the primary organisational principles underlying patterns of hippocampal functional connectivity (FC) in the mouse using gradient analysis on resting state fMRI data. We further applied gradient analysis to mouse gene co-expression data to examine the relationship between variation in genomic anatomy and functional organisation. Two principal FC gradients along a hippocampal axis were revealed. The principal gradient exhibited a sharp discontinuity that divided the hippocampus into dorsal and ventral compartments. The second, more continuous, gradient followed the long axis of the ventral compartment. Dorsal regions were more strongly connected to areas involved in spatial navigation while ventral regions were more strongly connected to areas involved in emotion, recapitulating patterns seen in humans. In contrast, gene co-expression gradients showed a more segregated and discrete organisation. Our findings suggest that hippocampal functional organisation exhibits both sharp and gradual transitions and that hippocampal genomic anatomy exerts a subtle influence on this organisation.

neuroscience↗

bioRxiv2021

Transcriptional integration of distinct microbial and nutritional signals by the small intestinal epithelium

To preserve its physiologic functions, the intestine must interpret and adapt to complex combinations of stimuli from dietary and microbial sources. However, the transcriptional strategies by which the intestinal epithelium integrates and adapts to dietary and microbial information remains unresolved. We compared adult mice reared germ free (GF) or conventionalized with a microbiota (CV) either fed normally or after a single high-fat meal (HFM). Jejunal epithelium preparations were queried using genomewide assays for RNA-seq, the activating histone mark H3K27ac ChIP-seq, and ChIP-seq of the microbially-responsive transcription factor HNF4A. We identified distinct nutritional and microbial responses at certain genes, but also apparent simultaneous influence of both stimuli at many other loci and regulatory regions. Increased expression levels and H3K27ac enrichment following HFM at a subset of these sites was dependent on microbial status. H3K27ac sites that were preferentially increased by HFM in the presence of microbes neighbor lipid anabolism and proliferation genes as well as intestinal stem cell (ISC) markers, were usually active only in ISCs, and were not HNF4A targets. In contrast, H3K27ac sites that were preferentially increased by HFM in the absence of microbes neighbored targets of the nuclear receptor and energy homeostasis regulator PPARA, were frequently accessible only in enterocytes, and were HNF4A bound. These results reveal that HNF4A supports a differentiated enterocyte and FAO program in GF, and that suppression of HNF4A by the combination of microbes and HFM may result in preferential activation of IEC proliferation programs. Microbial and nutritional responses are therefore integrated with some of the same transcriptional programs that regulate intestinal proliferation and differentiation.

genomics↗

bioRxiv2021

Iron Status Influences Mitochondrial Disease Progression in Complex I-Deficient Mice

Mitochondrial dysfunction caused by aberrant Complex I assembly and reduced activity of the electron transport chain is pathogenic in many genetic and age-related diseases. Mice missing the Complex I subunit NADH dehydrogenase [ubiquinone] iron-sulfur protein 4 (NDUFS4) are a leading mammalian model of severe mitochondrial disease that exhibit many characteristic symptoms of Leigh Syndrome including oxidative stress, neuroinflammation, brain lesions, and premature death. NDUFS4 knockout mice have decreased expression of nearly every Complex I subunit. As Complex I normally contains at least 8 iron-sulfur clusters and more than 25 iron atoms, we asked whether a deficiency of Complex I may lead to intracellular iron perturbations thereby accelerating disease progression. Consistent with this, iron supplementation accelerates symptoms of brain degeneration in these mice while iron restriction delays the onset of these symptoms and increases survival. NDUFS4 knockout mice display signs of iron overload in the liver including increased expression of hepcidin, and show changes in iron responsive element-regulated proteins consistent with increased intracellular iron that were prevented by iron restriction. These results suggest that perturbed iron homeostasis may contribute to pathology in Leigh Syndrome and possibly other mitochondrial disorders.

molecular biology↗

bioRxiv2020

Fxr signaling and microbial metabolism of bile salts in the zebrafish intestine

Bile salt synthesis, secretion into the intestinal lumen, and resorption in the ileum occurs in all vertebrate classes. In mammals, bile salt composition is determined by host and microbial enzymes, affecting signaling through the bile salt-binding transcription factor Farnesoid X receptor (Fxr). However, these processes in other vertebrate classes remain poorly understood. We show that key components of hepatic bile salt synthesis and ileal transport pathways are conserved and under control of Fxr in zebrafish. Zebrafish bile salts consist primarily of a C27 bile alcohol and a C24 bile acid which undergo multiple microbial modifications including bile acid deconjugation that augments Fxr activity. Using single-cell RNA sequencing, we provide a cellular atlas of the zebrafish intestinal epithelium and uncover roles for Fxr in transcriptional and differentiation programs in ileal and other cell types. These results establish zebrafish as a non-mammalian vertebrate model for studying bile salt metabolism and Fxr signaling.

physiology↗

bioRxiv2020

Chronic Psychosocial Stress and Experimental Pubertal Delay Affect Socioemotional Behavior and Amygdala Functional Connectivity in Adolescent Female Rhesus Macaques

In females, pubertal onset appears to signal the opening of a window of increased vulnerability to the effects of stress on neurobehavioral development. What is the impact of pubertal timing on this process? We assessed the effects of pubertal timing and stress on behavior and amygdala functional connectivity (FC) in adolescent female macaques, whose social hierarchy provides an ethologically valid model of chronic psychosocial stress. Monkeys experienced puberty spontaneously (n=34) or pubertal delay via Lupron treatment from age 16-33 months (n=36). We examined the effects of stress (continuous dimension spanning dominant/low-stress to subordinate/high-stress) and experimental pubertal delay (Lupron-treated vs. Control) on socioemotional behavior and FC at 43-46 months, after all animals had begun puberty. Regardless of treatment, subordinate monkeys were more submissive and less affiliative, and exhibited weaker FC between amygdala and dorsolateral prefrontal cortex and stronger FC between amygdala and temporal pole. Regardless of social rank, Lupron-treated monkeys were also more submissive, less affiliative, and explored less in a "Human Intruder" task but were less anxious than untreated monkeys; they exhibited stronger FC between amygdala and orbitofrontal cortex. No interactions between rank and Lupron treatment were observed. These data suggest that some of the effects of chronic subordination stress and delayed puberty overlap behaviorally, such that late-onset puberty-linked exposure to female hormones mimics chronic stress. In the brain, however, delayed puberty and subordination stress had separable effects, suggesting that the overlapping socioemotional outcomes may be mediated by distinct neuroplastic mechanisms. To gain further insights, additional longitudinal studies are required.

neuroscience↗

bioRxiv2020

Impact of industrial production system parameters on chicken microbiomes: mechanisms to improve performance and reduce Campylobacter

BackgroundThe factors affecting host-pathogen ecology in terms of the microbiome remain poorly studied. Chickens are a key source of protein with gut health heavily dependent on the complex microbiome which has key roles in nutrient assimilation and vitamin and amino acid biosynthesis. The chicken gut microbiome may be influenced by extrinsic production system parameters such as Placement Birds/m2 (stocking density), feed type and additives. Such parameters, in addition to on-farm biosecurity may influence performance and also pathogenic bacterial numbers such as Campylobacter. In this study, three different production systems Normal (N), Higher Welfare (HW) and Omega-3 Higher Welfare (O) were investigated "in a natural environment" at day 7 and day 30 with a range of extrinsic parameters assessing performance in correlation with microbial dynamics and Campylobacter presence. ResultsOur data identified production system N as significantly dissimilar from production systems HW and O when comparing the prevalence of genera. An increase in Placement Birds/m2 density led to a decrease in environmental pressure influencing the microbial community structure. Prevalence of genera such as Eisenbergiella within HW and O, and likewise Alistipes within N were representative. These genera have roles directly relating to energy metabolism, amino acid, nucleotide and short chain fatty acid (SCFA) utilisation. Thus, an association exists between consistent and differentiating parameters of the production systems, that affect feed utilisation, advance our knowledge of mechanistic underpinnings, leading to competitive exclusion of genera based on competition for nutrients and other factors. Campylobacter was identified within specific production system and presence was linked with the increased diversity and increased environmental pressure on microbial community structure. Addition of Omega-3 though did alter prevalence of specific genera, in our analysis did not differentiate itself from HW production system. However, Omega-3 was linked with a positive impact on weight gain. ConclusionsOverall, our results show that microbial communities in different industrial production systems are deterministic in elucidating the underlying biological confounders, and these recommendations are transferable to farm practices and diet manipulation leading to improved performance and better intervention strategies against Campylobacter within the food chain. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=125 SRC="FIGDIR/small/084251v2_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@c43951org.highwire.dtl.DTLVardef@8efa5corg.highwire.dtl.DTLVardef@d6db70org.highwire.dtl.DTLVardef@1e09fb9_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2019

Stability and similarity of the pediatric connectome as developmental outcomes

Patterns of functional connectivity are unique at the individual level, enabling test-retest matching algorithms to identify a subject from among a group using only their functional connectome. Recent findings show that accuracies of these algorithms in children increase with age. Relatedly, the persistence of functional connectivity (FC) patterns across tasks and rest also increases with age. This study investigated the hypothesis that within-subject stability and between-subject similarity of the whole-brain pediatric connectome are developmentally relevant outcomes. Using data from 210 help-seeking children and adolescents, ages 6-21 years (Healthy Brain Network Biobank), we computed whole-brain FC matrices for each participant during two different movies (MovieDM and MovieTP) and two runs of task-free rest (all from a single scan session) and fed these matrices to a test-retest matching algorithm. We replicated the finding that matching accuracies for children and youth (ages 6-21 years) are low (18-44%), and that cross-state and cross-movie accuracies were the lowest. Results also showed that parcellation resolution and the number of volumes used in each matrix affect fingerprinting accuracies. Next, we calculated three measures of whole-connectome stability for each subject: cross-rest (Rest1-Rest2), crossstate (MovieDM-Rest1), and cross-movie (MovieDM-MovieTP), and three measures of within-state between-subject connectome similarity for Rest1, MovieDM, and MovieTP. We show that stability and similarity were correlated, but that these measures were not related to age. A principal component analysis of these measures yielded two components that we used to test for brain-behavior correlations with IQ, general psychopathology, and social skills measures (n=119). The first component was significantly correlated with the social skills measure (r=-0.26, p=0.005). Post hoc correlations showed that the social skills measure correlated with both cross-rest stability (r=-0.29, p=0.001) and with connectome similarity during MovieDM (r=-0.28, p=0.002). These findings suggest that the stability and similarity of the whole-brain connectome relate to overall brain development, and in particular, to those regions that support social skills. We infer that the development of the functional connectome simultaneously achieves patterns of FC that are distinct at the individual subject level, that are shared across individuals, and that are persistent across states and across runs--features which presumably combine to optimize neural processing during development. Future longitudinal work could reveal the developmental trajectories of stability and similarity of the connectome. Highlights- Identification algorithms yielded low accuracies in this developmental sample. - Individual differences in FC were not as persistent across states or movies. - Connectome within-subject stability and between-subject similarity were interrelated. - Stability during rest and similarity during a movie correlate with social skills scores.

neuroscience↗