Biology subjects

Fisher, P.

Publications and source records attributed to Fisher, P..

7 recordsLinked to original sources

bioRxiv2024

Beta Waves in Action: Context-Dependent Modulations of Subthalamo-Cortical Synchronization during Rapid Reversals of Movement Direction

The role of beta band activity in cortico-basal ganglia interactions during motor control has been studied extensively in resting-state and for simple movements, such as button pressing. However, little is known about how beta oscillations change and interact in more complex situations involving rapid changes of movement in various contexts. To close this knowledge gap, we combined magnetoencephalography (MEG) and local field potential recordings from the subthalamic nucleus (STN) in Parkinsons disease patients to study beta dynamics during initiation, stopping, and rapid reversal of rotational movements. The action prompts were manipulated to be predictable vs. unpredictable. We observed movement-related beta suppression at motor sequence start, and a beta rebound after motor sequence stop in STN power, motor cortical power, and STN-cortex coherence. Despite involving a brief stop of movement, no clear rebound was observed during reversals of turning direction. On the cortical level, beta power decreased bilaterally following reversals, but more so in the hemisphere ipsilateral to movement, due to a floor effect on the contralateral side. In the STN, power modulations varied across patients, with patients revealing brief increases or decreases of high-beta power. Importantly, cue predictability affected these modulations. Event-related increases of STN-cortex beta coherence were generally stronger in the unpredictable than in the predictable condition. In summary, this study reveals the influence of movement context on beta oscillations in basal ganglia-cortex loops when humans change ongoing movements according to external cues. We find that movement scenarios requiring higher levels of caution involve enhanced modulations of subthalamo-cortical beta synchronization. Further, our results confirm that beta oscillations reflect the start and end of motor sequences better than movement changes within a sequence. Significance StatementBeta synchrony between motor cortex and the subthalamic nucleus is intensified when instructional cues within a continuous motor sequence become less predictable, calling for more cautious behavior.

neuroscience↗

bioRxiv2024

Connecting the Dots: Approaching a Standardized Nomenclature for Molecular Connectivity Combining Data and Literature

PET-based connectivity computation is a molecular approach that complements fMRI-derived functional connectivity. However, the diversity of methodologies and terms employed in PET connectivity analysis has resulted in ambiguities and confounded interpretations, highlighting the need for a standardized nomenclature. Drawing parallels from other imaging modalities, we propose "molecular connectivity" as an umbrella term to characterize statistical dependencies between PET signals across brain regions at the individual level (within-subject). Like fMRI resting-state functional connectivity, "molecular connectivity" leverages temporal associations in the PET signal to derive brain network associations. Another within-subject approach evaluates regional similarities of tracer kinetics, which are unique in PET imaging, thus referred to as "kinetic connectivity". On the other hand, "molecular covariance" denotes group-level computations of covariance matrices across-subject. Further specification of the terminology can be achieved by including the employed radioligand, such as "metabolic connectivity/covariance" for [18F]FDG as well as "tau/amyloid covariance" for [18F]flutemetamol / [18F]flortaucipir. To augment these distinctions, high-temporal resolution functional [18F]FDG PET scans from 17 healthy participants were analysed with common techniques of molecular connectivity and covariance, allowing for a data-driven support of the above terminology. Our findings demonstrate that temporal band-pass filtering yields structured network organization, whereas other techniques like 3rd order polynomial fitting, spatio-temporal filtering and baseline normalization require further methodological refinement for high-temporal resolution data. Conversely, molecular covariance from across-subject data provided a simple means to estimate brain region interactions through regularized or sparse inverse covariance estimation. A standardized nomenclature in PET-based connectivity research can reduce ambiguity, enhance reproducibility, and facilitate interpretability across radiotracers and imaging modalities. Via a data-driven approach, this work provides a transparent framework for categorizing and comparing PET-derived connectivity and covariance metrics, laying the foundation for future investigations in the field.

neuroscience↗

bioRxiv2024

Associations between common genetic variants and income provide insights about the socioeconomic health gradient

We conducted a genome-wide association study (GWAS) on income among individuals of European descent and leveraged the results to investigate the socio-economic health gradient (N=668,288). We found 162 genomic loci associated with a common genetic factor underlying various income measures, all with small effect sizes. Our GWAS-derived polygenic index captures 1 - 4% of income variance, with only one-fourth attributed to direct genetic effects. A phenome-wide association study using this polygenic index showed reduced risks for a broad spectrum of diseases, including hypertension, obesity, type 2 diabetes, coronary atherosclerosis, depression, asthma, and back pain. The income factor showed a substantial genetic correlation (0.92, s.e. = .006) with educational attainment (EA). Accounting for EAs genetic overlap with income revealed that the remaining genetic signal for higher income related to better mental health but reduced physical health benefits and increased participation in risky behaviours such as drinking and smoking.

genetics↗

bioRxiv2021

Sulfite preservatives effects on the mouth microbiome: changes in viability, diversity and composition of microbiota

Processed foods make up about 70 percent of the American diet. Sulfites and other food preservatives are added to these foods largely to limit bacterial contamination. The mouth microbiota and its associated enzymes are the first to encounter food and therefore likely to be the most affected. Eight saliva samples from ten individuals were exposed to two sulfite preservatives, sodium sulfite and sodium bisulfite. One sample set was evaluated for bacteria composition utilizing 16s rRNA sequencing, and the number of viable cells in all sample sets was determined utilizing ATP assays at 10 and 40-minute exposure times. All untreated samples were analyzed for baseline lysozyme activity, and possible correlations between the number of viable cells and lysozyme activity. Sequencing results indicated significant increases in alpha diversity with sodium bisulfite exposure and changes in relative abundance of 3 amplicon sequence variants (ASV). Sodium sulfite treated samples showed a significant decrease in the Firmicutes/Bacteroidetes ratio, a marginally significant change in alpha diversity, and a significant change in the relative abundance for Proteobacteria, Firmicutes, Bacteroidetes, and for 6 ASVs. Beta diversity didnt show any separation between groups, however, all but one sample set was observed to be moving in the same direction under sodium sulfite treatment in a principal component analysis. ATP assays indicated a significant and consistent average decrease in activity ranging from 24 - 46% at both exposure times with both sulfites. Average initial rates of lysozyme activity between all individuals ranged from +/- 76% compared to individual variations of +/- 10 - 34%. No consistent, significant correlation was found between ATP and lysozyme activity in any sample sets. ConclusionsSulfite preservatives, at concentrations regarded as safe by the FDA, alter the relative abundance and richness of the microbiota found in saliva, and decrease the number of viable cells, within 10 minutes of exposure.

microbiology↗

bioRxiv2020

Establishment of a pig influenza challenge model for evaluation of monoclonal antibody delivery platforms

Monoclonal antibodies are a possible adjunct to vaccination and drugs in treatment of influenza virus infection. However questions remain whether small animal models accurately predict efficacy in humans. We have established the pig, a large natural host animal for influenza, with many physiological similarities to humans, as a robust model for testing monoclonal antibodies. We show that a strongly neutralizing monoclonal antibody (2-12C) against the hemagglutinin head administered prophylactically at 15 mg/kg reduced viral load and lung pathology after pandemic H1N1 influenza challenge. A lower dose of 1 mg/kg of 2-12C or a DNA plasmid encoded version of 2-12C, reduced pathology and viral load in the lungs, but not viral shedding in nasal swabs. We propose that the pig influenza model will be useful for testing candidate monoclonal antibodies and emerging delivery platforms prior to human trials.

immunology↗

bioRxiv2019

Misfolded α-synuclein causes hyperactive respiration without functional deficit in live neuronal cells

The misfolding and aggregation of the largely disordered protein, -synuclein, is a central pathogenic event that occurs in the synucleinopathies; a group of neurodegenerative disorders that includes Parkinsons disease. While there is a clear link between protein misfolding and neuronal vulnerability, the precise pathogenic mechanisms employed by disease-associated -synuclein are unresolved. Here, we studied the pathogenicity of misfolded -synuclein produced using the Protein Misfolding Cyclic Amplification (PMCA) assay. To do this, previous published methods were adapted to allow PMCA-induced protein fibrillization to occur under non-toxic conditions. Insight into potential intracellular targets of misfolded -synuclein was obtained using an unbiased lipid screen of 15 biologically relevant lipids that identified cardiolipin (CA) as a potential binding partner for PMCA-generated misfolded -synuclein. To investigate if such an interaction can impact the properties of -synuclein misfolding, protein fibrillization was carried out in the presence of the lipid. We show CA both accelerates the rate of -synuclein fibrillization and produces species that harbour enhanced resistance to proteolysis. Because CA is virtually exclusively expressed in the inner mitochondrial membrane, we then assessed the ability of these misfolded species to alter mitochondrial respiration in live non-transgenic SH-SY5Y neuroblastoma cells. Extensive analysis revealed misfolded -synuclein causes hyperactive mitochondrial respiration without causing any functional deficit. These data give strong support for the mitochondrion as a target for misfolded -synuclein and reveals persistent, hyperactive respiration as a potential up-stream pathogenic event associated with the synucleinopathies. Summary statementMisfolded -synuclein that was produced using the Protein Misfolding Cyclic Amplification (PMCA) assay was found to associate with cardiolipin and cause hyperactive respiration in neuronal cells.

neuroscience↗

bioRxiv2019

Gut feelings begin in childhood: how the gut metagenome links to early environment, caregiving, and behavior

Psychosocial environments impact normative behavioral development in children, increasing the risk of problem behaviors and psychiatric disorders across the lifespan. Converging evidence demonstrates early normative development is affected by the gut microbiome, which itself can be altered by early psychosocial environments. Nevertheless, these relationships are poorly understood in childhood, particularly beyond peri- and postnatal microbial colonization. To determine the gut microbiomes role in the associations between childhood adversity and behavioral development, we conducted a metagenomic investigation among cross-sectional sample of early school-aged children with a range of adverse experiences and caregiver stressors and relationships. Our results indicate that the taxonomic and functional composition of the gut microbiome links to behavioral dysregulation during a critical period of child development. Furthermore, our analysis reveals that both socioeconomic risk exposure and child behaviors associate with the relative abundances of specific taxa (e.g., Bacteroides and Bifidobacterium species) as well as functional modules encoded in their genomes (e.g., monoamine metabolism) that have been linked to cognition and health. We also identified heretofore novel linkages between gut microbiota, their functions, and behavior. These findings hold important translational implications for developmental psychology and microbiome sciences alike, as they suggest that caregiver behavior might mitigate the impact of socioeconomic risk on the microbiome and modify the relationship between subclinical symptoms of behavioral dysregulation and the gut microbiome in early school-aged children.

microbiology↗