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Aging is a non-modifiable understudied risk factor for hypertension. We hypothesized that sympathetically mediated activation of renal sodium reabsorption drives age-dependent hypertension and the salt sensitivity of blood pressure (BP). Using 3-, 8-, and 16-month-old male and female Sprague-Dawley rats as a model of normal aging, we assessed BP, indices of sympathetic tone, and the physiological responses to acute and chronic sodium challenge including sodium chloride cotransporter (NCC) regulation. The effects of renal nerve ablation and NCC antagonism were assessed in hypertensive male rats. We observed sex-dependent impaired renal sodium handling (24 h sodium balance (meq), male 3-month 0.36 ± 0.1 vs. 16-month 0.84 ± 0.2; sodium load excreted during 5% bodyweight isotonic saline volume expansion (%) male 3-month 77 ± 5 vs. 16-month 22 ± 8), hypertension (MAP (mmHg) male 3-month 123 ± 4 vs. 16-month 148 ± 6), and the salt sensitivity of BP in aged male, but not female, rats. Attenuated sympathoinhibitory afferent renal nerve (ARN) responses contributed to increased sympathetic tone and hypertension in male rats. Increased sympathetic tone contributes to renal sodium retention, in part through increased NCC activity via a dysfunctional with-no-lysine kinase-(WNK) STE20/SPS1-related proline/alanine-rich kinase signaling pathway, to drive hypertension and the salt sensitivity of BP in aged male rats. NCC antagonism and renal nerve ablation, which reduced WNK dysfunction and decreased NCC activity, attenuated age-dependent hypertension in male Sprague-Dawley rats. The contribution of an impaired sympathoinhibitory ARN reflex to sex- and age-dependent hypertension in an NCC-dependent manner, via an impaired WNK1/WNK4 dynamic, suggests this pathway as a mechanism-based target for the treatment of age-dependent hypertension.
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Here, we describe a group of basal forebrain (BF) neurons expressing neuronal Per-Arnt-Sim (PAS) domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1+ neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1+ neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1+ neurons was high, five to six times that of neighboring cholinergic, parvalbumin, or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1+ neurons to brain regions involved in sleep-wake control, motivated behaviors, and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area, and olfactory bulb. Chemogenetic activation of BF Npas1+ neurons in the light period increased the amount of wakefulness and the latency to sleep for 2 to 3 h, due to an increase in long wake bouts and short NREM sleep bouts. NREM slow-wave and sigma power, as well as sleep spindle density, amplitude, and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1+ neurons in stress responsiveness, the anatomical projections of BF Npas1+ neurons and the effect of activating them suggest a possible role for BF Npas1+ neurons in motivationally driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia, and other neuropsychiatric conditions involving BF.
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Prosencéfalo Basal , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Neuronas GABAérgicas , Vigilia , Animales , Masculino , Prosencéfalo Basal/metabolismo , Prosencéfalo Basal/fisiología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/fisiología , Ratones Transgénicos , Sueño/fisiología , Vigilia/fisiologíaRESUMEN
Hypertension affects approximately one in two United States adults and sex plays an important role in the pathogenesis of hypertension. The Na+-Cl- cotransporter (NCC), regulated by a kinase network including with-no-lysine kinase (WNK)1 and WNK4, STE20/SPS1-related proline alanine-rich kinase (SPAK), and oxidative stress response 1 (OxSR1), is critical to Na+ reabsorption and blood pressure regulation. Dietary salt differentially modulates NCC in salt-sensitive and salt-resistant rats, in part by modulation of WNK/SPAK/OxSR1 signaling. In this study, we tested the hypothesis that sex-dependent differences in NCC regulation contribute to the development of the salt sensitivity of blood pressure using male and female Sprague-Dawley (SD), Dahl salt-resistant (DSR), and Dahl salt-sensitive (DSS) rats. In normotensive salt-resistant SD and DSR rats, a high-salt diet evoked significant decreases in NCC activity, expression, and phosphorylation. In males, these changes were associated with no change in WNK1 expression, a decrease in WNK4 levels, and suppression of SPAK/OxSR1 expression and phosphorylation. In contrast, in females, there was decreased NCC activity associated with suppression of SPAK/OxSR1 expression and phosphorylation. In hypertensive DSS rats, the ability of females to suppress NCC (in opposition to males) via a SPAK/OxSR1 mechanism likely contributes to their lower magnitude of salt-sensitive hypertension. Collectively, our findings support the existence of sex differences in male versus female rats with NCC regulation during dietary salt intake involving suppression of WNK4 expression in male rats only and the involvement of SPAK/OxSR1 signaling in both males and females.NEW & NOTEWORTHY NCC regulation is sex dependent. In normotensive male and female Sprague-Dawley and Dahl salt-resistant rats, which exhibit dietary Na+-evoked NCC suppression, male rats exhibit decreased WNK4 expression and decreased SPAK and OxSR1 levels, whereas female rats only suppress SPAK and OxSR1. In hypertensive Dahl salt-sensitive rats, the ability of females to suppress NCC (in opposition to males) via a SPAK/OxSR1 mechanism likely contributes to their lower magnitude of salt-sensitive hypertension.
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Presión Sanguínea , Hipertensión , Proteínas Serina-Treonina Quinasas , Ratas Endogámicas Dahl , Ratas Sprague-Dawley , Cloruro de Sodio Dietético , Miembro 3 de la Familia de Transportadores de Soluto 12 , Animales , Femenino , Masculino , Presión Sanguínea/efectos de los fármacos , Hipertensión/metabolismo , Hipertensión/fisiopatología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Miembro 3 de la Familia de Transportadores de Soluto 12/metabolismo , Miembro 3 de la Familia de Transportadores de Soluto 12/genética , Factores Sexuales , Fosforilación , Riñón/metabolismo , Riñón/efectos de los fármacos , Transducción de Señal , Ratas , Modelos Animales de EnfermedadRESUMEN
Analyzing scored sleep is a fundamental prerequisite to understanding how sleep changes between health and disease. Classically, this is accomplished by manually calculating various measures (e.g., percent of non-rapid eye movement sleep) from a collection of scored sleep files. This process can be tedious and error prone especially when studies include a large number of animals or involve long recording sessions. To address this issue, we present SleepInvestigatoR, a versatile tool that can quickly organize and analyze multiple scored sleep files into a single output. The function is written in the open-source statistical language R and has a total of 25 parameters that can be set to match a wide variety of experimenter needs. SleepInvestigatoR delivers a total of 22 unique measures of sleep, including all measures commonly reported in the rodent literature. A simple plotting function is also provided to quickly graph and visualize the scored data. All code is designed to be implemented with little formal coding knowledge and step-by-step instructions are provided on the corresponding GitHub page. Overall, SleepInvestigatoR provides the sleep researcher a critical tool to increase efficiency, interpretation, and reproducibility in analyzing scored rodent sleep.
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Respiratory syncytial virus (RSV) causes severe infections in infants, immunocompromised or elderly individuals resulting in annual epidemics of respiratory disease. Currently, limited clinical surveillance and the lack of predictable seasonal dynamics limits the public health response. Wastewater-based epidemiology (WBE) has recently been used globally as a key metric in determining prevalence of SARS-CoV-2 in the community but its application to other respiratory viruses is limited. In this study, we present an integrated genomic WBE approach, applying RT-qPCR and partial G-gene sequencing to track RSV levels and variants in the community. We report increasing detection of RSV in wastewater concomitant with increasing numbers of positive clinical cases. Analysis of wastewater-derived RSV sequences permitted identification of distinct circulating lineages within and between seasons. Altogether, our genomic WBE platform has the potential to complement ongoing global surveillance and aid the management of RSV by informing the timely deployment of pharmaceutical and non-pharmaceutical interventions.
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Plant defensins are a large family of small cationic proteins with diverse functions and mechanisms of action, most of which assert antifungal activity against a broad spectrum of fungi. The partial mechanism of action has been resolved for a small number of members of plant defensins, and studies have revealed that many act by more than one mechanism. The plant defensin Ppdef1 has a unique sequence and long loop 5 with fungicidal activity against a range of human fungal pathogens, but little is known about its mechanism of action. We screened the S. cerevisiae non-essential gene deletion library and identified the involvement of the mitochondria in the mechanism of action of Ppdef1. Further analysis revealed that the hyperpolarisation of the mitochondrial membrane potential (MMP) activates ROS production, vacuolar fusion and cell death and is an important step in the mechanism of action of Ppdef1, and it is likely that a similar mechanism acts in Trichophyton rubrum.
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Estimates of juvenile survival are critical for informing population dynamics and the ecology of fish, yet these demographic parameters are difficult to measure. Here, we demonstrate that advances in animal tracking technology provide opportunities to evaluate survival of juvenile tagged fish. We implemented a whole-lake telemetry array in conjunction with small acoustic tags (including tags < 1.0 g) to track the fate of stocked juvenile cisco (Coregonus artedi) as part of a native species restoration effort in the Finger Lakes region of New York, USA. We used time-to-event modeling to characterize the survival function of stocked fish, where we infer mortality as the cessation of tag detections. Survival estimates revealed distinct stages of juvenile cisco mortality including high immediate post-release mortality, followed by a period of elevated mortality during an acclimation period. By characterizing mortality over time, the whole-lake biotelemetry effort provided information useful for adapting stocking practices that may improve survival of stocked fish, and ultimately the success of the species reintroduction effort. The combination of acoustic technology and time-to-event modeling to inform fish survival may have wide applicability across waterbodies where receiver arrays can be deployed at scale and where basic assumptions about population closure can be satisfied.
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Lagos , Salmonidae , Animales , New York , Telemetría , AcústicaRESUMEN
Onychomycosis, or fungal nail infection, causes not only pain and discomfort but can also have psychological and social consequences for the patient. Treatment of onychomycosis is complicated by the location of the infection under the nail plate, meaning that antifungal molecules must either penetrate the nail or be applied systemically. Currently, available treatments are limited by their poor nail penetration for topical products or their potential toxicity for systemic products. Plant defensins with potent antifungal activity have the potential to be safe and effective treatments for fungal infections in humans. The cystine-stabilized structure of plant defensins makes them stable to the extremes of pH and temperature as well as digestion by proteases. Here, we describe a novel plant defensin, Ppdef1, as a peptide for the treatment of fungal nail infections. Ppdef1 has potent, fungicidal activity against a range of human fungal pathogens, including Candida spp., Cryptococcus spp., dermatophytes, and non-dermatophytic moulds. In particular, Ppdef1 has excellent activity against dermatophytes that infect skin and nails, including the major etiological agent of onychomycosis Trichophyton rubrum. Ppdef1 also penetrates human nails rapidly and efficiently, making it an excellent candidate for a novel topical treatment of onychomycosis.
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Here we describe a novel group of basal forebrain (BF) neurons expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. Immunohistochemical staining in Npas1-cre-2A-TdTomato mice revealed BF Npas1 + neurons are distinct from well-studied parvalbumin or cholinergic neurons. Npas1 staining in GAD67-GFP knock-in mice confirmed that the vast majority of Npas1 + neurons are GABAergic, with minimal colocalization with glutamatergic neurons in vGlut1-cre-tdTomato or vGlut2-cre-tdTomato mice. The density of Npas1 + neurons was high, 5-6 times that of neighboring cholinergic, parvalbumin or glutamatergic neurons. Anterograde tracing identified prominent projections of BF Npas1 + neurons to brain regions involved in sleep-wake control, motivated behaviors and olfaction such as the lateral hypothalamus, lateral habenula, nucleus accumbens shell, ventral tegmental area and olfactory bulb. Chemogenetic activation of BF Npas1 + neurons in the light (inactive) period increased the amount of wakefulness and the latency to sleep for 2-3 hr, due to an increase in long wake bouts and short NREM sleep bouts. Non-REM slow-wave (0-1.5 Hz) and sigma (9-15 Hz) power, as well as sleep spindle density, amplitude and duration, were reduced, reminiscent of findings in several neuropsychiatric disorders. Together with previous findings implicating BF Npas1 + neurons in stress responsiveness, the anatomical projections of BF Npas1 + neurons and the effect of activating them suggest a possible role for BF Npas1 + neurons in motivationally-driven wakefulness and stress-induced insomnia. Identification of this major subpopulation of BF GABAergic neurons will facilitate studies of their role in sleep disorders, dementia and other neuropsychiatric conditions involving BF. SIGNIFICANCE STATEMENT: We characterize a group of basal forebrain (BF) neurons in the mouse expressing neuronal PAS domain 1 (Npas1), a developmental transcription factor linked to neuropsychiatric disorders. BF Npas1 + neurons are a major subset of GABAergic neurons distinct and more numerous than cholinergic, parvalbumin or glutamate neurons. BF Npas1 + neurons target brain areas involved in arousal, motivation and olfaction. Activation of BF Npas1 + neurons in the light (inactive) period increased wakefulness and the latency to sleep due to increased long wake bouts. Non-REM sleep slow waves and spindles were reduced reminiscent of findings in several neuropsychiatric disorders. Identification of this major subpopulation of BF GABAergic wake-promoting neurons will allow studies of their role in insomnia, dementia and other conditions involving BF.
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The genomic landscape of Stone Age Europe was shaped by multiple migratory waves and population replacements, but different regions do not all show similar patterns. To refine our understanding of the population dynamics before and after the dawn of the Neolithic, we generated and analyzed genomic sequence data from human remains of 56 individuals from the Mesolithic, Neolithic, and Eneolithic across Central and Eastern Europe. We found that Mesolithic European populations formed a geographically widespread isolation-by-distance zone ranging from Central Europe to Siberia, which was already established 10,000 years ago. We found contrasting patterns of population continuity during the Neolithic transition: people around the lower Dnipro Valley region, Ukraine, showed continuity over 4000 years, from the Mesolithic to the end of the Neolithic, in contrast to almost all other parts of Europe where population turnover drove this cultural change, including vast areas of Central Europe and around the Danube River.
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Flujo Génico , Genoma , Humanos , Europa (Continente) , Europa Oriental , Dinámica PoblacionalRESUMEN
Fusarium graminearum (F. graminearum) is a filamentous fungus that infects cereals such as corn, wheat, and barley, with serious impact on yield as well as quality when the grain is contaminated with mycotoxins. Despite the huge impact of F. graminearum on food security and mammalian health, the mechanisms used by F. graminearum to export virulence factors during infection are not fully understood and may involve non-classical secretory pathways. Extracellular vesicles (EVs) are lipid-bound compartments produced by cells of all kingdoms that transport several classes of macromolecules and are implicated in cell-cell communication. EVs produced by human fungal pathogens carry cargo that facilitate infection, leading us to ask whether plant fungal pathogens also deliver molecules that increase virulence via EVs. We examined the metabolome of the EVs produced by F. graminearum to determine whether they carry small molecules that could modulate plant-pathogen interactions. We discovered that EVs from F. graminearum were produced in liquid medium-containing inducers of trichothecene production, but in lower quantities compared to other media. Nanoparticle tracking analysis and cryo-electron microscopy revealed that the EVs were morphologically similar to EVs from other organisms; hence, the EVs were metabolically profiled using LC-ESI-MS/MS. This analysis revealed that EVs carry 2,4-dihydroxybenzophenone (BP-1) and metabolites that have been suggested by others to have a role in host-pathogen interactions. BP-1 reduced the growth of F. graminearum in an in vitro assay, suggesting that F. graminearum might use EVs to limit metabolite self-toxicity.
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Attention is impaired in many neuropsychiatric disorders, as well as by sleep disruption, leading to decreased workplace productivity and increased risk of accidents. Thus, understanding the neural substrates is important. Here we test the hypothesis that basal forebrain neurons that contain the calcium-binding protein parvalbumin modulate vigilant attention in mice. Furthermore, we test whether increasing the activity of basal forebrain parvalbumin neurons can rescue the deleterious effects of sleep deprivation on vigilance. A lever release version of the rodent psychomotor vigilance test was used to assess vigilant attention. Brief and continuous low-power optogenetic excitation (1 s, 473 nm @ 5 mW) or inhibition (1 s, 530 nm @ 10 mW) of basal forebrain parvalbumin neurons was used to test the effect on attention, as measured by reaction time, under control conditions and following 8 hr of sleep deprivation by gentle handling. Optogenetic excitation of basal forebrain parvalbumin neurons that preceded the cue light signal by 0.5 s improved vigilant attention as indicated by quicker reaction times. By contrast, both sleep deprivation and optogenetic inhibition slowed reaction times. Importantly, basal forebrain parvalbumin excitation rescued the reaction time deficits in sleep-deprived mice. Control experiments using a progressive ratio operant task confirmed that optogenetic manipulation of basal forebrain parvalbumin neurons did not alter motivation. These findings reveal for the first time a role for basal forebrain parvalbumin neurons in attention, and show that increasing their activity can compensate for disruptive effects of sleep deprivation.
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Autotransporters (ATs) are a large family of bacterial secreted and outer membrane proteins that encompass a wide range of enzymatic activities frequently associated with pathogenic phenotypes. We present the structural and functional characterisation of a subtilase autotransporter, Ssp, from the opportunistic pathogen Serratia marcescens. Although the structures of subtilases have been well documented, this subtilisin-like protein is associated with a 248 residue ß-helix and itself includes three finger-like protrusions around its active site involved in substrate interactions. We further reveal that the activity of the subtilase AT is required for entry into epithelial cells as well as causing cellular toxicity. The Ssp structure not only provides details about the subtilase ATs, but also reveals a common framework and function to more distantly related ATs. As such these findings also represent a significant step forward toward understanding the molecular mechanisms underlying the functional divergence in the large AT superfamily.
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Antineoplásicos , Subtilisina , Sistemas de Secreción Tipo V , Transporte BiológicoRESUMEN
BACKGROUND: NHS England commissioned four independent service providers to pilot low-calorie diet programmes to drive weight loss, improve glycaemia and potentially achieve remission of Type 2 Diabetes across 10 localities. Intervention fidelity might contribute to programme success. Previous research has illustrated a drift in fidelity in the design and delivery of other national diabetes programmes. AIMS: (1) To describe and compare the programme designs across the four service providers; (2) To assess the fidelity of programme designs to the NHS England service specification. METHODS: The NHS England service specification documents and each provider's programme design documents were double-coded for key intervention content using the Template for Intervention Description and Replication Framework and the Behaviour Change Technique (BCT) Taxonomy. RESULTS: The four providers demonstrated fidelity to most but not all of the service parameters stipulated in the NHS England service specification. Providers included between 74% and 87% of the 23 BCTs identified in the NHS specification. Twelve of these BCTs were included by all four providers; two BCTs were consistently absent. An additional seven to 24 BCTs were included across providers. CONCLUSIONS: A loss of fidelity for some service parameters and BCTs was identified across the provider's designs; this may have important consequences for programme delivery and thus programme outcomes. Furthermore, there was a large degree of variation between providers in the presence and dosage of additional BCTs. How these findings relate to the fidelity of programme delivery and variation in programme outcomes and experiences across providers will be examined.
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Diabetes Mellitus Tipo 2 , Humanos , Terapia Conductista/métodos , Restricción Calórica , Inglaterra , Medicina EstatalRESUMEN
Extracellular vesicles (EVs) from human fungal pathogens have been implicated in fungal virulence, yet little is known about their role in the host-pathogen interaction. Progress has been hampered by the lack of a specific marker for fungal EVs that can be used to monitor EV isolation and tracking in biological systems. Here we report the effect of a SUR7 gene knockout on the production, properties, and role of EVs in the virulence of Candida albicans. Sur7 is a component of the membrane compartment of Can1 (MCC) complex and is enriched in the EVs from C. albicans and other fungal species. MCC is a plasma membrane complex which together with the eisosome, a cytoplasmic protein complex, is a key regulator in plasma membrane organisation and plasma membrane associated processes. The SUR7 knockout strain produces smaller EVs than the wild-type (WT) with different protein and carbohydrate cargos. Furthermore, proteins with known roles in Candida pathogenesis were present in WT EVs and absent or diminished in the sur7Δ EVs. We demonstrate that the reduced virulence of the sur7Δ cells can be partially restored with EVs from a WT strain. These findings demonstrate the importance of Sur7-like proteins in the biogenesis of EVs in fungi and enhance our understanding of the role of fungal EVs in human pathogenesis.
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Disturbances to aquatic habitats are not uniformly distributed within the Great Lakes and acute effects can be strongest in nearshore areas where both landscape and within lake effects can have strong influence. Furthermore, different fish species respond to disturbances in different ways. A means to identify and evaluate locations and extent of disturbances that affect fish is needed throughout the Great Lakes. We used partial Canonical Correspondence Analysis to separate "natural" effects on nearshore assemblages from disturbance effects. Species-specific quadratic models of fish abundance as functions of in-lake disturbance or watershed-derived disturbance were developed separately for each of 35 species and lakewide predictions mapped for Lake Erie. Most responses were unimodal and more species decreased in abundance with increasing watershed disturbance than increased. However, eight species increased in abundance with current in-lake disturbance conditions. Optimum Yellow Perch (Perca flavescens) abundance occurred at in-lake disturbance values less than the gradient mean, but decreased continuously from minimum watershed disturbance to higher values. Bands of optimum in-lake conditions occurred throughout the eastern and western portions of the Lake Erie nearshore zone; some areas were less disturbed than desirable. However, watershed-derived disturbance conditions were generally poor for Yellow Perch throughout the lake. In contrast, optimum Smallmouth Bass (Micropterus dolomieu) abundance occurred at in-lake disturbance values greater than the gradient mean and continuously increased with increasing watershed disturbance. Smallmouth Bass responses to disturbance indicated that most of the nearshore zone was less disturbed than is desirable and were most abundant in areas that the Yellow Perch response indicated were highly disturbed. Mapping counts of species response models that agreed on the disturbance level in each spatial unit of the nearshore zone showed a fine-scale mosaic of areas in which habitat restoration may benefit many or few species. This tool may assist managers in prioritizing conservation and restoration efforts and evaluating environmental conditions that may be improved.
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The emergence of SARS-CoV-2 variants has exacerbated the COVID-19 global health crisis. Thus far, all variants carry mutations in the spike glycoprotein, which is a critical determinant of viral transmission being responsible for attachment, receptor engagement and membrane fusion, and an important target of immunity. Variants frequently bear truncations of flexible loops in the N-terminal domain (NTD) of spike; the functional importance of these modifications has remained poorly characterised. We demonstrate that NTD deletions are important for efficient entry by the Alpha and Omicron variants and that this correlates with spike stability. Phylogenetic analysis reveals extensive NTD loop length polymorphisms across the sarbecoviruses, setting an evolutionary precedent for loop remodelling. Guided by these analyses, we demonstrate that variations in NTD loop length, alone, are sufficient to modulate virus entry. We propose that variations in NTD loop length act to fine-tune spike; this may provide a mechanism for SARS-CoV-2 to navigate a complex selection landscape encompassing optimisation of essential functionality, immune-driven antigenic variation and ongoing adaptation to a new host.
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COVID-19 , SARS-CoV-2 , COVID-19/genética , Humanos , Filogenia , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genéticaRESUMEN
Experimental evidence has implicated multiple neurotransmitter systems in either the direct or indirect modulation of cortical arousal and attention circuitry. In this review, we selectively focus on three such systems: 1) norepinephrine (NE)-containing neurons of the locus coeruleus (LC), 2) acetylcholine (ACh)-containing neurons of the basal forebrain (BF), and 3) parvalbumin (PV)-containing gamma-aminobutyric acid neurons of the BF. Whereas BF-PV neurons serve as a rapid and transient arousal system, LC-NE and BF-ACh neuromodulation are typically activated on slower but longer-lasting timescales. Recent findings suggest that the BF-PV system serves to rapidly respond to even subtle sensory stimuli with a microarousal. We posit that salient sensory stimuli, such as those that are threatening or predict the need for a response, will quickly activate the BF-PV system and subsequently activate both the BF-ACh and LC-NE systems if the circumstances require longer periods of arousal and vigilance. We suggest that NE and ACh have overlapping psychological functions with the main difference being the precise internal/environmental sensory situations/contexts that recruit each neurotransmitter system - a goal for future research to determine. Implications of dysfunction of each of these three attentional systems for our understanding of neuropsychiatric conditions are considered. Finally, the contemporary availability of research tools to selectively manipulate and measure the activity of these distinctive neuronal populations promises to answer longstanding questions, such as how various arousal systems influence downstream decision-making and motor responding.
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Prosencéfalo Basal , Locus Coeruleus , Acetilcolina , Nivel de Alerta/fisiología , Atención/fisiología , Prosencéfalo Basal/metabolismo , Locus Coeruleus/metabolismo , Norepinefrina , Parvalbúminas/metabolismo , Vigilia/fisiologíaRESUMEN
BACKGROUND: Invasive bacterial infections (IBI) in children present a difficult clinical challenge. They are often life-threatening, however in the early stages they can be hard to differentiate from benign viral infections. This leaves clinicians with the risk of missing a serious IBI diagnosis or inappropriately using antimicrobials in a child with a viral infection- contributing to the ongoing development of increased antimicrobial resistance. Hence, biomarkers which could aid in early detection of IBI and differentiation from viral infections are desirable. Mid-Regional pro-Adrenomedullin (MR-proADM) is a biomarker which has been associated with IBI. The aim of this systematic review was to determine its diagnostic accuracy in identifying children with IBI. METHODS: A strategy was devised to search online databases MEDLINE, Embase, Web of Science and Scopus for human clinical trials reporting the accuracy of MR-proADM in children. Against predesigned inclusion and exclusion criteria full texts were selected for inclusion and data extraction. True positives, false positives, true negatives and false negatives were extracted from each included study to fill 2 × 2 tables. Using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool methodological quality of each study was assessed. RESULTS: A total of 501 articles were initially identified. After the removal of duplicates and abstract screening 11 texts were fully reviewed and four texts (totaling 1404 patients) were included in the systematic analysis. Only one study was of a high quality and that study accounted for the vast majority of patients. A single study reported the diagnostic accuracy of MR-proADM for invasive bacterial infection reporting an Area under the Curve of 0.69. The paucity of available studies made meta-analysis and studies of heterogeneity impossible. CONCLUSION: There is a paucity of research regarding the diagnostic accuracy of MR-proADM in the diagnosis of invasive bacterial infections in children. Initial results would suggest that MR-proADM testing alone is poor at identifying IBI in young children. It remains unclear if MR-proADM performs differently in older children or in children with signs and symptoms of IBI. TRIAL REGISTRATION: PROSPERO CRD42018096295 .