Biology subjects

Daniels, S.

Publications and source records attributed to Daniels, S..

5 recordsLinked to original sources

bioRxiv2024

A Multi-Omics Approach to Defining Target Organ Injury in Youth with Primary Hypertension

BACKGROUNDPrimary hypertension in childhood tracks into adulthood and may be associated with increased cardiovascular risk. Studies conducted in children and adolescents provide an opportunity to explore the early cardiovascular target organ injury (CV-TOI) in a population free from many of the co-morbid cardiovascular disease risk factors that confound studies in adults. METHODSYouths (n=132, mean age 15.8 years) were stratified by blood pressure (BP) as low, elevated, and high-BP and by left ventricular mass index (LVMI) as low- and high-LVMI. Systemic circulating RNA, miRNA, and methylation profiles in peripheral blood mononuclear cells and deep proteome profiles in serum were determined using high-throughput sequencing techniques. RESULTSVASH1 gene expression was elevated in youths with high-BP with and without high-LVMI. VASH1 expression levels positively correlated with systolic BP (r=0.3143, p=0.0034). The expression of hsa-miR-335-5p, one of the VASH1-predicted miRNAs, was downregulated in high-BP with high-LVMI youths and was inversely correlated with systolic BP (r=-0.1891, p=0.0489). GSE1 hypermethylation, circulating PROZ upregulation (log2FC=0.61, p=0.0049 and log2FC=0.62, p=0.0064), and SOD3 downregulation (log2FC=-0.70, p=0.0042 and log2FC=-0.64, p=0.010) were observed in youths with elevated BP and high-BP with high-LVMI. Comparing the transcriptomic and proteomic profiles revealed elevated HYAL1 levels in youths displaying high-BP and high-LVMI. CONCLUSIONSThe findings are compatible with a novel blood pressure-associated mechanism that may occur through impaired angiogenesis and extracellular matrix degradation through dysregulation of Vasohibin-1 and Hyaluronidase1 was identified as a possible mediator of CV-TOI in youth with high-BP and suggests strategies for ameliorating TOI in adult-onset primary hypertension.

genomics↗

bioRxiv2024

Impaired Cortico-Amygdala Functional Connectivity Can Drive Social Behavior Deficits in Synucleinopathies

The small molecule protein -synuclein forms insoluble aggregates in a group of neurological disorders, including Parkinsons disease and dementia with Lewy bodies (DLB), which are collectively called synucleinopathies. In PD and DLB, the amygdala has been identified as a particularly susceptible region in the brain for the deposition of Lewy-like -synuclein aggregates. Though -synuclein aggregation is closely associated with neurodegeneration, there is a poor correlation between neurodegeneration in the amygdala and the clinical features of PD/DLB. We hypothesize that, prior to neurodegeneration, -synuclein aggregation disrupts functional cortical modulation of the amygdala circuits, leading to emotion dysregulation in synucleinopathies. In the present study, we combined electrophysiology, optogenetics, mouse model of synucleinopathies, and behavioral analysis to test this hypothesis. Using an -synuclein preformed fibrils (PFFs)-based mouse model of synucleinopathies, we reported dynamic changes in the levels of -synuclein pathology in the basolateral amygdala (BLA). Such dynamic changes of pathology associated with a decreased cortico-BLA connection strength prior to a significant loss of cortical axon terminals. In parallel to the reduced cortico-BLA connection, PFFs-injected mice manifested impaired social preference behavior. The impaired sociability of PFFs-injected mice could be rescued by chemogenetic stimulation of cortico-BLA inputs. Altogether, we presented a series of evidence to delineate key circuit events associated with -synuclein pathology development in the amygdala circuits. The present work highlights the necessity of a thorough investigation of functional consequences of -synuclein aggregation to advance our understand of pathophysiology of synucleinopathies and development of effective therapies.

neuroscience↗

bioRxiv2022

Reduced Thalamic Excitation to Motor Cortical Pyramidal Tract Neurons in a Mouse Model of Parkinsonism

Degeneration of midbrain dopaminergic (DA) neurons causes a reduced motor output from the primary motor cortex (M1), underlying the motor symptoms of Parkinsons disease (PD). However, cellular and circuitry mechanisms of M1 dysfunction in PD remain undefined. Using multidisciplinary approaches, we found that DA degeneration induces cell-subtype- and inputs-specific reduction of thalamic excitation to M1 pyramidal tract (PT) neurons. Physiological and anatomical analyses suggest that DA degeneration induces a loss of thalamocortical synapses to M1 PT neurons, resulting in an impaired thalamic driving of their activities. Moreover, we showed that the decreased thalamocortical connectivity are mediated by an excessive activation of NMDA receptors of M1 PT neurons. Further, the decreased thalamocortical transmission in parkinsonism can be rescued by chemogenetically suppressing basal ganglia outputs. Together, our data suggest that the reduced motor cortical outputs in parkinsonism are not only an immediate consequence of basal ganglia inhibition but also involves specific local circuitry adaptations within M1. This study reveals novel insight in the pathophysiology of parkinsonian motor deficits.

neuroscience↗

bioRxiv2022

Synaptic Location Is a Determinant of the Detrimental Effects of α-Synuclein Pathology to Glutamatergic Transmission in the Basolateral Amygdala

The presynaptic protein -synuclein (Syn) has been suggested to be involved in the pathogenesis of Parkinsons disease (PD). In PD, the amygdala is prone to develop insoluble Syn aggregates, and it has been suggested that circuit dysfunction involving the amygdala contributes to the psychiatric symptoms. Yet, how Syn aggregates affect amygdala function is unknown. In this study, we examined Syn in glutamatergic axon terminals and the impact of its aggregation on glutamatergic transmission in the basolateral amygdala (BLA). We found that Syn is primarily present in the vesicular glutamate transporter 1-expressing (vGluT1+) terminals in mouse BLA, which is consistent with higher levels of Syn expression in vGluT1+ glutamatergic neurons in the cerebral cortex relative to the vGluT2+ glutamatergic neurons in the thalamus. We found that Syn aggregation selectively decreased the cortico-BLA, but not the thalamo-BLA, transmission; and that cortico-BLA synapses displayed enhanced short-term depression upon repetitive stimulation. In addition, using confocal microscopy, we found that vGluT1+ axon terminals exhibited decreased levels of soluble Syn, which suggests that lower levels of soluble Syn might underlie the enhanced short-term depression of cortico-BLA synapses. In agreement with this idea, we found that cortico-BLA synaptic depression was also enhanced in Syn knockout mice. In conclusion, both basal and dynamic cortico-BLA transmission were disrupted by abnormal aggregation of Syn and these changes might be relevant to the perturbed cortical control of the amygdala that has been suggested to play a role in psychiatric symptoms in PD.

neuroscience↗

bioRxiv2017

Utilising a Cohort Study of Hepatitis B Virus (HBV) Vaccine-Mediated Immunity in South African Children to Model Infection Dynamics: Can We Meet Global Targets for Elimination by 2030?

BackgroundSustainable Development Goals set a challenge for the elimination of hepatitis B virus (HBV) infection as a public health concern by the year 2030. Deployment of a robust prophylactic vaccine and enhanced interventions for prevention of mother to child transmission (PMTCT) are cornerstones of elimination strategy. However, in light of the estimated global burden of 290 million cases, enhanced efforts are required to underpin optimisation of public health strategy. Robust analysis of population epidemiology is particularly crucial for populations in Africa made vulnerable by HIV co-infection, poverty, stigma and poor access to prevention, diagnosis and treatment.\n\nMethodsWe here set out to evaluate the current and future role of HBV vaccination and PMTCT as tools for elimination. We first investigated the current impact of paediatric vaccination in a cohort of children with and without HIV infection in Kimberley, South Africa. Second, we used these data to inform a new model to simulate the ongoing impact of preventive interventions. By applying these two approaches in parallel, we are able to determine both the current impact of interventions, and the future projected outcome of ongoing preventive strategies over time.\n\nResultsExisting efforts have been successful in reducing paediatric prevalence of HBV infection in this setting to <1%, demonstrating the success of the existing vaccine campaign. Our model predicts that, if consistently deployed, combination efforts of vaccination and PMTCT can significantly reduce population prevalence (HBsAg) by 2030, such that a major public health impact is possible even without achieving elimination. However, the prevalence of HBV e-antigen (HBeAg)-positive carriers will decline more slowly, representing a persistent population reservoir. We show that HIV co-infection significantly reduces titres of vaccine-mediated antibody, but has a relatively minor role in influencing the projected time to elimination. Our model can also be applied to other settings in order to predict time to elimination based on specific interventions.\n\nConclusionsThrough extensive deployment of preventive strategies for HBV, significant positive public health impact is possible, although time to HBV elimination as a public health concern is likely to be substantially longer than that proposed by current goals.

microbiology↗