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White, P. J.

Publications and source records attributed to White, P. J..

14 recordsLinked to original sources

A mechanistic model of threat-driven respiration and its homeostatic recovery in anxiety and depression

Anxiety and depression change how people breathe, often early in the illness, and wearable sensors now allow breathing to be monitored continuously. This work presents, to our knowledge, the first mechanistic model of how the brain's threat response sets breathing rate and depth and how fast breathing recovers after stress. A threat signal from the amygdala, shaped by stimulus magnitude and by cognitive appraisal (coping capacity and perceived stress), drives the breathing-control center that receives lung feedback: stretch receptors slow breathing and airway receptors speed it up. A simple electrical circuit stores the threat signal and expresses recovery as one time constant. We prove the model's key properties, test them under noise and parameter variation, and compare it with chest-belt recordings from 15 adults in the Wearable Stress and Affect Detection (WESAD) study. Breathing rate rose from 18 to 28 and 31 breaths per minute from normal to moderate to severe, an order that held in every test. Recovery took about 3, 10, and 50 seconds, paced by how long the airway-receptor signal lingers in the brainstem, and the circuit followed breathing closely (correlation 0.96-0.98). In WESAD, a spoken stress task raised anxiety and breath depth (p<0.001); speech set the breathing rhythm during the task, and breathing then returned to rest, as the model predicts for healthy people. A compact, provable model links clinical stress measures to the breathing signals that wearables record. It offers measurable targets for monitoring anxiety and depression: how strongly threat drives respiration and how quickly homeostatic regulation restores it.

physiology↗

BCKDK Inhibitors Directly Antagonize Angiotensin II Type 1 Receptor and Induce Vasodilation Independently of BCAA Catabolism or BCKDK

Branched-chain amino acids (BCAA) have been implicated in diabetes and heart failure, leading to ongoing clinical trials with inhibitors of BCKDK, a key regulator of BCAA catabolism. We have previously shown that these inhibitors promote vasodilation and lower blood pressure, well-known cardioprotective effects, but how this occurs remained unclear. We show here, using explanted vessels, in vivo hemodynamics and telemetry, and genetically modified mice, that the vasodilatory effect of BCKDK inhibitors is direct, rapid, independent of nitric oxide, independent of BCAA catabolism, and most strikingly, independent of BCKDK itself. Instead, we demonstrate, using structural and biochemical studies, that BCKDK inhibitors directly antagonize the angiotensin II type I receptor (AT1R) and consequent angiotensin-mediated vasoconstriction. These data demonstrate a strong off-target effect of BCKDK inhibitors, independent of BCAA or BCKDK, which may explain their cardioprotective effects but also questions if this protection would be additive to existing AT1R blockers.

physiology↗

Dietary protein source dictates the impact of obesogenic diets on hepatic steatosis and insulin resistance via carnitine-dependent regulation of acetyl-CoA carboxylase

Nutritional strategies to mitigate obesity and type 2 diabetes (T2D) have largely focused on dietary fat and carbohydrate composition, with less attention given to protein sources. While total dietary protein intake is recognized as an important modulator of energy balance and glucose metabolism, it remains unclear how the composition of dietary proteins can influence energy metabolism and body weight gain. Here, we investigated the metabolic effects of three distinct protein sources from meat (pork), dairy (casein) and plant (soy) on either a low-fat low sucrose (LFLS) or a high-fat high sucrose (HFHS) diet. While protein sources failed to influence metabolic homeostasis on LFLS, mice kept on the HFHS diet were distinctly impacted by the dietary protein sources. Pork and to a lesser extent soy protein feeding exacerbated obesity, glucose intolerance, and hepatic insulin resistance. Remarkably, livers of mice fed pork or soy protein on the HFHS diet were characterized by extensive microvesicular steatosis compared to the predominant macrovesicular steatosis in HFHS fed mice fed casein protein. Liver transcriptomic and metabolomic signatures in pork and soy protein fed mice were consistent with increased mitochondrial beta-oxidation. Intake of pork and soy proteins in HFHS fed mice lead to a striking reduction in hepatic acetyl CoA carboxylase 2 (ACC2) protein levels relative to casein fed HFHS mice. Pork and soy feeding raised carnitine exposure in the post-prandial period and we determined that exposure of hepatocytes to carnitine provokes downregulation of ACC2 and hepatic insulin resistance in the presence of palmitate:oleate and fructose. Collectively, these findings identify a novel mechanism by which dietary proteins modulate obesity and associated metabolic disturbances through a carnitine-mediated regulation of ACC2 protein and mitochondrial lipid handling in liver. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/732886v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@1cc5b9corg.highwire.dtl.DTLVardef@1929e43org.highwire.dtl.DTLVardef@d453faorg.highwire.dtl.DTLVardef@1d56149_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

Element partitioning, element localisation and transcriptome responses of date palms exposed to NaCl

Date palm (Phoenix dactylifera L.) is an economically important fruit crop in many (semi)arid regions. Large intra-species variation in susceptibility to NaCl has been reported. Controlled experiments were conducted to evaluate sodium (Na) and chlorine (Cl) partitioning in two-year old plants of six date palm varieties and to determine tissue location of Na and Cl and transcriptome responses to NaCl of two varieties. The largest Na concentrations were found in secondary roots, especially under NaCl treatment. By contrast, only small differences in within-plant partitioning of Cl were observed with less differences between varieties than for Na. Variety Sultana had the largest Na translocation factor. The variety Khalas exhibited better restriction of Na mobility, which may be a consequence of Na hotspots in roots, presumably immobilising Na in roots, which were absent in Sultana. In the root, shoot base and lower part of leaves, Cl accumulated in fibre bands and sclerenchyma sheaths of vascular bundles. RNAseq analysis revealed that Sultana and Khalas respond very differently to NaCl: Khalas modified expression of NaCl-specific genes in both roots and leaves, while Sultana responded manly in leaves. Gene ontology analysis showed that the expression changes for genes linked with photosynthesis and carbohydrate metabolism predominated as a response to NaCl. In Khalas, differentially expressed genes encoding for metal transporters and those reported to be involved in heat, salt and osmotic stress response were found. Large variability in Na and Cl accumulation in different date palm varieties may have practical agronomical consequences.

plant biology↗

Date palm acclimates to aridity by diverting organic osmolytes for root osmotic adjustment in parallel with leaf membrane remodeling and ROS scavenging

Highlight statementOsmotic strength of date palm roots increases with soil desiccation, for which the accumulation of organic osmolytes, such as sugars, is essential in complement to energetically cheap mineral osmotics. Date palm (Phoenix dactylifera L.) is an important crop in arid regions that is well-adapted to desert ecosystems. To understand the remarkable ability to grow and yield in water-limited environments, experiments were conducted in a simulated desert environment with water-withholding for up to four weeks. In response to drought, root, rather than leaf, osmotic strength increased, with sugars contributing more to the osmolyte increase than minerals. Consistently, carbon and amino acid metabolism was acclimated toward biosynthesis at both the transcriptional and translational levels. In leaves, a remodeling of membrane systems was observed, suggesting changes in thylakoid lipid composition, which together with the restructuring of the photosynthetic apparatus, indicated an acclimation preventing oxidative damage. Thus, xerophilic date palm avoids oxidative damage under drought by combined prevention and rapid detoxification of oxygen radicals. Although minerals were expected to serve as cheap key osmotics, date palm also relies on organic osmolytes for osmotic adjustment of the roots during desiccation. The diversion of these resources away from growth is consistent with date palms strategy of generally slow growth in harsh environments and clearly indicates a trade-off between growth and stress-related physiological responses.

plant biology↗

Nervous system reduction in branched-chain amino acid metabolism disrupts hippocampal neurogenesis and memory

A role for macronutrient metabolism in learning and memory is supported by numerous epidemiological studies. The Ppm1k gene encodes the branched-chain keto acid dehydrogenase (BCKDH) phosphatase that promotes the metabolism of branched-chain amino acids (BCAA). Here we show that nervous system deletion of Ppm1k in mice increases BCAA levels in brain tissue but not in plasma. These mice have significant impairments in working memory accompanied by a robust accumulation of DCX+/NeuroD1+ immature neurons within the dentate gyrus granule cell layer. Through single cell RNA sequencing and pathway analysis we identified substantial increases in transit-amplifying cells and immature neurons along with activated hedgehog signaling in Ppm1k deficient primary neural stem cells (NSCs). Inhibition of mTOR signaling reversed the effects of Ppm1k deletion on neuronal progenitor gene activation in primary NSCs. Together our findings uncover a new molecular link between BCAA metabolism, hippocampal neurogenesis, and cognitive performance.

neuroscience↗

HGFAC is a ChREBP Regulated Hepatokine that Enhances Glucose and Lipid Homeostasis

Carbohydrate Responsive Element-Binding Protein (ChREBP) is a carbohydrate sensing transcription factor that regulates both adaptive and maladaptive genomic responses in coordination of systemic fuel homeostasis. Genetic variants in the ChREBP locus associate with diverse metabolic traits in humans, including circulating lipids. To identify novel ChREBP-regulated hepatokines that contribute to its systemic metabolic effects, we integrated ChREBP ChIP-seq analysis in mouse liver with human genetic and genomic data for lipid traits and identified Hepatocyte Growth Factor Activator (HGFAC) as a promising ChREBP-regulated candidate in mice and humans. HGFAC is a protease that activates the pleiotropic hormone Hepatocyte Growth Factor (HGF). We demonstrate that HGFAC KO mice have phenotypes concordant with putative loss-of-function variants in human HGFAC. Moreover, in gain- and loss-of-function genetic mouse models, we demonstrate that HGFAC enhances lipid and glucose homeostasis, in part, through actions to activate hepatic PPAR{gamma} activity. Together, our studies show that ChREBP mediates an adaptive response to overnutrition via activation of an HGFAC-HGF-PPAR{gamma} signaling axis in the liver to preserve glucose and lipid homeostasis.

physiology↗

Retention of Lumpy Skin Disease Virus in Stomoxys Spp (Stomoxys Calsitrans, Stomoxys Sitiens, Stomoxys Indica) following intrathoracic inoculation, Diptera: Muscidae.

Lumpy skin disease (LSD) is an emerging disease in cattle in Kazakhstan and the means of transmission remains uncertain. In the current study, acquisition of Lumpy Skin Disease Virus (LSDV) by Stomoxys species following intrathoracic inoculation was demonstrated under laboratory conditions. Flies were injected with a virulent LSDV strain into the thorax region to bypass the midgut barrier. The fate of pathogen in the hemolymph of the flies was further examined using PCR and Virus isolation tests. LSDV was isolated from all three Stomoxys species immediately and up to 24h post intrathoracic inoculation while virus DNA was detectable up to 7d post intrathoracic inoculation.

ecology↗

Pharmacological Insights into Safety and Efficacy Determinants for the Development of Adenosine Receptor Biased Agonists in the Treatment of Heart Failure

Adenosine A1 receptors (A1R) are a potential target for cardiac injury treatment due to their cardioprotective/antihypertrophic actions, but drug development has been hampered by on-target side effects such as bradycardia and altered renal haemodynamics. Biased agonism has emerged as an attractive mechanism for A1R-mediated cardioprotection that is haemodynamically safe. Here we investigate the pre-clinical pharmacology, efficacy and side-effect profile of the A1R agonist neladenoson, shown to be safe but ineffective in phase IIb trials for the treatment of heart failure. We compare this agent with the well-characterised, pan-adenosine receptor (AR) agonist NECA, capadenoson, and the A1R biased agonist VCP746, previously shown to be safe and cardioprotective in pre-clinical models of heart failure. We show that like VCP746, neladenoson is biased away from Ca2+ influx relative to NECA and the cAMP pathway at the A1R, a profile predictive of a lack of adenosine-like side effects. Additionally, neladenoson was also biased away from the MAPK pathway at the A1R. In contrast to VCP746, which displays more adenosine-like signalling at the A2BR, neladenoson was a highly selective A1R agonist, with biased, weak agonism at the A2BR. Together these results show that unwanted haemodynamic effects of A1R agonists can be avoided by compounds biased away from Ca2+ influx relative to cAMP, relative to NECA. The failure of neladenoson to reach primary endpoints in clinical trials suggests that A1R-mediated cAMP inhibition may be a poor indicator of effectiveness in chronic heart failure. This study provides additional information that can aid future screening and/or design of improved AR agonists that are safe and efficacious in treating heart failure in patients. ONE-SENTENCE SUMMARYBiased agonists that preference against calcium influx relative to the cyclic AMP pathway, when compared to a conventional agonist, confer clinical safety to A1 adenosine receptor ligands.

pharmacology and toxicology↗

Transcriptional regulation of genes involved in Zn transport after foliar Zn application to Medicago sativa

Zinc (Zn) is an essential micronutrient for both plants and animals, and Zn deficiency is one of the most widespread problems for agricultural production. Although many studies have been performed on the biofortification of staple crops with Zn, few studies have focused on forage crops. In this study the molecular mechanisms of Zn transport-related in Medicago sativa L. were investigated following foliar Zn applications aimed at increasing the accumulation of Zn in edible tissues. Zinc uptake and redistribution between shoot and root were determined following the application of six Zn doses to leaves (0, 0.01, 0.1, 0.5, 1, 10 mg Zn plant-1). Twelve putative genes encoding proteins involved in Zn transport (MsZIP1-7, MsZIF1, MsMTP1, MsYSL1, MsHMA4 and MsNAS1) were identified and the changes in their expression following foliar Zn application were quantified using newly designed RT-qPCR assays. Shoot and root Zn concentration was increased following foliar Zn applications [&ge;] 0.1 mg plant-1. Increased expression of MsZIP2, MsHMA4 and MsNAS1 in shoots, and of MsZIP2 and MsHMA4 in roots, was observed with the largest Zn dose. By contrast, MsZIP3 was downregulated in shoots at Zn doses [&ge;] 0.1 mg plant-1. Three functional modules were identified in the M. sativa response to foliar Zn application: genes involved in Zn uptake by cells, genes involved in vacuolar Zn sequestration and genes involved in Zn redistribution within the plant. These results will inform genetic engineering strategies aimed at increasing the efficiency of crop Zn biofortification. One-sentence summaryUpregulation of ZIP2, NASI and HMA4 and downregulation of ZIP3 are associated with Zn sequestration and shoot-to-root translocation in Medicago sativa following foliar Zn biofortification

plant biology↗

Vaccination against antibiotic resistant gonorrhoea for men who have sex with men in England: a modelling study

BackgroundGonorrhoea incidence is increasing rapidly: diagnoses in men who have sex with men (MSM) in England increased eight-fold 2008-2017. Concurrently, antibiotic resistance is making treatment more difficult, leading to renewed interest in a gonococcal vaccine. The MeNZB meningococcal B vaccine is partially protective, and several other candidates are in development. We modelled realistic vaccination strategies under various scenarios of antibiotic resistance and vaccine protection level and duration, to assess the impact of vaccination and examine the feasibility of the WHOs target of reducing gonorrhoea incidence by 90% between 2016 and 2030.\n\nMethodsWe fitted a stochastic transmission-dynamic model, incorporating asymptomatic and symptomatic infection and heterogeneous sexual behaviour, to gonorrhoea incidence in MSM in England, 2008-17, using particle Markov Chain Monte Carlo methods. Bayesian forecasting was used to examine future scenarios, including emergence of extensively antibiotic-resistant (ABR) gonorrhoea.\n\nFindingsEven in the worst-case scenario of untreatable infection emerging, the WHO target could be met by vaccinating all MSM attending sexual health clinics with a 53%-protective vaccine lasting for >6 years, or a 70%-protective vaccine lasting >3 years. A vaccine like MeNZB, conferring 30% protection for 2-4 years, could reduce incidence in 2030 by 45% in the worst-case scenario, and by 75% if >70% of ABR gonorrhoea is treatable.\n\nInterpretationOur statistically-rigorous assessment shows that even a partially-protective vaccine, delivered through a practical targeting strategy, could have substantial benefit in reducing gonorrhoea incidence in the context of an epidemic with rising antibiotic resistance.

microbiology↗

A dynamic power-law sexual network model of gonorrhoea outbreaks

Human networks of sexual contacts are dynamic by nature, with partnerships forming and breaking continuously over time. Sexual behaviours are also highly heterogeneous, so that the number of partners reported by individuals over a given period of time is typically distributed as a power-law. Both the dynamism and heterogeneity of sexual partnerships are likely to have an effect in the patterns of spread of sexually transmitted diseases. To represent these two fundamental properties of sexual networks, we developed a stochastic process of dynamic partnership formation and dissolution, which results in power-law numbers of partners over time. Model parameters can be set to produce realistic conditions in terms of the exponent of the power-law distribution, of the number of individuals without relationships and of the average duration of relationships. Using an outbreak of antibiotic resistant gonorrhoea amongst men have sex with men as a case study, we show that our realistic dynamic network exhibits different properties compared to the frequently used static networks or homogeneous mixing models. We also consider an approximation to our dynamic network model in terms of a much simpler branching process. We estimate the parameters of the generation time distribution and offspring distribution which can be used for example in the context of outbreak reconstruction based on genomic data. Finally, we investigate the impact of a range of interventions against gonorrhoea, including increased condom use, more frequent screening and immunisation, concluding that the latter shows great promise to reduce the burden of gonorrhoea, even if the vaccine was only partially effective or applied to only a random subset of the population.

epidemiology↗

Diel predator activity drives a dynamic landscape of fear

AO_SCPLOWBSTRACTC_SCPLOWA landscape of fear (LOF) is a map that describes continuous spatial variation in an animals perception of predation risk. The relief on this map reflects, for example, places that an animal avoids to minimize risk. Although the LOF concept is a potential unifying theme in ecology that is often invoked to explain the ecological and conservation significance of fear, quantified examples of a LOF over large spatial scales are lacking as is knowledge about the daily dynamics of a LOF. Despite theory and data to the contrary, investigators often assume, implicitly or explicitly, that a LOF is a static consequence of a predators mere presence. We tested the prediction that a LOF in a large-scale, free-living system is a highly-dynamic map with peaks and valleys that alternate across the diel (24-hour) cycle in response to daily lulls in predator activity. We did so with extensive data from the case study of Yellowstone elk (Cervus elaphus) and wolves (Canis lupus) that was the original basis for the LOF concept. We quantified the elk LOF, defined here as spatial allocation of time away from risky places and times, across nearly 1000-km2 of northern Yellowstone National Park and found that it fluctuated with the crepuscular activity pattern of wolves, enabling elk to use risky places during wolf downtimes. This may help explain evidence that wolf predation risk has no effect on elk stress levels, body condition, pregnancy, or herbivory. The ability of free-living animals to adaptively allocate habitat use across periods of high and low predator activity within the diel cycle is an underappreciated aspect of animal behavior that helps explain why strong antipredator responses may trigger weak ecological effects, and why a LOF may have less conceptual and practical importance than direct killing.

ecology↗

Quantifying The Fitness Benefit And Cost Of Cefixime Resistance In Neisseria gonorrhoeae To Inform Prescription Policy

Gonorrhea is one of the most common bacterial sexually transmitted infections in England. Over 41,000 cases were recorded in 2015, more than half of which occurred in men who have sex with men (MSM). As the bacterium has developed resistance to each first-line antibiotic in turn, we need an improved understanding of fitness benefits and costs of antibiotic resistance to inform control policy and planning. Cefixime was recommended as a single dose treatment for gonorrhea from 2005 to 2010, during which time resistance increased and subsequently declined. We developed a stochastic compartmental model representing the natural history and transmission of cefixime sensitive and resistant strains of Neisseria gonorrhoeae in MSM in England, which was applied to data on diagnoses and prescriptions between 2008 and 2015. We estimated that asymptomatic carriers play a crucial role in overall transmission dynamics, with about 40% of infections remaining asymptomatic and untreated, accounting for 96% of onward transmission. The fitness cost of cefixime resistance in the absence of cefixime usage was estimated to be such that the number of secondary infections caused by resistant strains is only about half as much as for the susceptible strains, which is insufficient to maintain persistence. However, we estimated that treatment of cefixime-resistant strains with cefixime was unsuccessful in 84% of cases, representing a fitness benefit of resistance. This benefit was large enough to counterbalance the fitness cost when 31% of cases are treated with cefixime, and when more than 51% of cases were treated with cefixime the resistant strain had a net fitness advantage over the susceptible strain. Our findings have important implications for antibiotic stewardship and public health policies, and in particular suggest that cefixime could be used to treat a minority of gonorrhea cases without raising resistance levels.

microbiology↗