Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for ...the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG neurons from eight organ donors. We identified 12 clusters of human sensory neurons, 5 of which are C nociceptors, as well as 1 C low-threshold mechanoreceptors (LTMRs), 1 Aβ nociceptor, 2 Aδ, 2 Aβ, and 1 proprioceptor subtypes. By focusing on expression profiles for ion channels, G protein-coupled receptors (GPCRs), and other pharmacological targets, we provided a rich map of potential drug targets in the human DRG with direct comparison to mouse sensory neuron transcriptomes. We also compared human DRG neuronal subtypes to nonhuman primates showing conserved patterns of gene expression among many cell types but divergence among specific nociceptor subsets. Last, we identified sex differences in human DRG subpopulation transcriptomes, including a marked increase in calcitonin-related polypeptide alpha (
) expression in female pruritogen receptor-enriched nociceptors. This comprehensive spatial characterization of human nociceptors might open the door to development of better treatments for acute and chronic pain disorders.
Migraine is the second leading cause for disability worldwide and the most common neurological disorder. It is also three times more common in women; reasons for this sex difference are not known. ...Using preclinical behavioral models of migraine, we show that application of calcitonin gene-related peptide (CGRP) to the rat dura mater produces cutaneous periorbital hypersensitivity. Surprisingly, this response was observed only in females; dural CGRP at doses from 1 pg to 3.8 μg produce no responses in males. In females, dural CGRP causes priming to a pH 7.0 solution after animals recover from the initial CGRP-induced allodynia. Dural application of interleukin-6 causes acute responses in males and females but only causes priming to subthreshold dural CGRP (0.1 pg) in females. Intracisternal application of BDNF also causes similar acute hypersensitivity responses in males and females but only priming to subthreshold dural CGRP (0.1 pg) in females. Females were additionally primed to a subthreshold dose of the NO-donor sodium nitroprusside (0.1 mg/kg) following dural CGRP. Finally, the sexually dimorphic responses to dural CGRP were not specific to rats as similar female-specific hypersensitivity responses were seen in mice, where increased grimace responses were also observed. These data are the first to demonstrate that CGRP-induced headache-like behavioral responses at doses up to 3.8 μg are female-specific both acutely and following central and peripheral priming. These data further implicate dural CGRP signaling in the pathophysiology of migraine and propose a model where dural CGRP-based mechanisms contribute to the sexual disparity of this female-biased disorder.
Calcitonin gene-related peptide (CGRP) has long been implicated in the pathophysiology of migraine, and CGRP-based therapeutics are efficacious for the treatment of migraine in humans. However, the location of action for CGRP in migraine remains unclear. We show here that application of CGRP to the cranial meninges causes behavioral responses consistent with headache in preclinical rodent models. Surprisingly, however, these responses are only observed in females. Acute responses to meningeal CGRP are female-specific and sensitization to CGRP after two distinct stimuli are also female-specific. These data implicate the dura mater as a primary location of action for CGRP in migraine and suggest that female-specific mechanisms downstream of CGRP receptor activation contribute to the higher prevalence of migraine in women.
Abstract
The inclusion of women in preclinical pain studies has become more commonplace in the last decade as the National Institutes of Health (NIH) released its “Sex as a Biological Variable” ...mandate. Presumably, basic researchers have not had a comprehensive understanding about neuroimmune interactions in half of the population and how hormones play a role in this. To date, we have learned that sex hormones contribute to sexual differentiation of the nervous system and sex differences in behavior throughout the lifespan; however, the cycling of sex hormones does not always explain these differences. Here, we highlight recent advances in our understanding of sex differences and how hormones and immune interactions influence sensory neuron activity to contribute to physiology and pain. Neuroimmune mechanisms may be mediated by different cell types in each sex, as the actions of immune cells are sexually dimorphic. Unfortunately, the majority of studies assessing neuronal contributions to immune function have been limited to males, so it is unclear if the mechanisms are similar in females. Finally, pathways that control cellular metabolism, like nuclear receptors, have been shown to play a regulatory role both in pain and inflammation. Overall, communication between the neuroimmune and endocrine systems modulate pain signaling in a sex-dependent manner, but more research is needed to reveal nuances of these mechanisms.
Abstract
The linewidth-size (σ-R) relationship of the interstellar medium (ISM) has been extensively measured and analysed, in both the local ISM and in nearby normal galaxies. Generally, a power law ...describes the relationship well with an index ranging from 0.2 to 0.6, and is now referred to as one of the 'Larson's Relationships'. The nature of turbulence and star formation is considered to be intimately related to these relationships, so evaluating the σ-R correlations in various environments is important for developing a comprehensive understanding of the ISM. We measure the linewidth-size relationship in the Central Molecular Zone (CMZ) of the Galactic Centre using spectral line observations of the high-density tracers N2H+, HCN, H13CN and HCO+. We construct dendrograms, which map the hierarchical nature of the position-position-velocity (PPV) data, and compute the linewidths and sizes of the dendrogram-defined structures. The dispersions range from ∼2 to 30 km s−1 in structures spanning sizes 2-40 pc. By performing Bayesian inference, we show that a power law with exponent 0.3-1.1 can reasonably describe the σ-R trend. We demonstrate that the derived σ-R relationship is independent of the locations in the PPV data set where σ and R are measured. The uniformity in the σ-R relationship indicates that turbulence in the CMZ is driven on the large scales beyond ≳30 pc. We compare the CMZ σ-R relationship to that measured in the Galactic molecular cloud Perseus. The exponents between the two systems are similar, suggestive of a connection between the turbulent properties within a cloud to its ambient medium. Yet, the velocity dispersion in the CMZ is systematically higher, resulting in a scaling coefficient that is approximately five times larger. The systematic enhancement of turbulent velocities may be due to the combined effects of increased star formation activity, larger densities and higher pressures relative to the local ISM.
Pulmonary tuberculosis, a disease caused by Mycobacterium tuberculosis (Mtb), manifests with a persistent cough as both a primary symptom and mechanism of transmission. The cough reflex can be ...triggered by nociceptive neurons innervating the lungs, and some bacteria produce neuron-targeting molecules. However, how pulmonary Mtb infection causes cough remains undefined, and whether Mtb produces a neuron-activating, cough-inducing molecule is unknown. Here, we show that an Mtb organic extract activates nociceptive neurons in vitro and identify the Mtb glycolipid sulfolipid-1 (SL-1) as the nociceptive molecule. Mtb organic extracts from mutants lacking SL-1 synthesis cannot activate neurons in vitro or induce cough in a guinea pig model. Finally, Mtb-infected guinea pigs cough in a manner dependent on SL-1 synthesis. Thus, we demonstrate a heretofore unknown molecular mechanism for cough induction by a virulent human pathogen via its production of a complex lipid.
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•An Mtb organic extract activates nociceptive neurons and induces cough in guinea pigs•Mtb sulfolipid-1 is necessary and sufficient to trigger neuronal activation and cough•Guinea pigs infected with an SL-1-deficient Mtb mutant do not cough
Mycobacterium tuberculosis produces a glycolipid called sulfolipid-1 (SL-1) that triggers cough by activating nociceptive neurons.
Green electricity products are increasingly made available to consumers in many countries in order to address a number of environmental and social concerns. Most of the literature on this green ...electricity market focuses on consumers’ characteristics and product attributes that could affect participation. However, the contribution of this environmental consumerism to the overall environmental good does not depend on participation alone. The real impact relies on market participation for green consumers (the proportion of green consumers) combined with the level of green consumption intensity – the commitment levels, or proportion of consumption that is green. We design an online interface that closely mimics the real market decision environment for electricity consumers in Western Australia and use an error component model to analyze consumers’ choice of green electricity products and their commitment levels. We show that product attributes have limited impact on the choice of green products; however, there is still great potential for better participation by improving the design of green electricity programs. When green products are selected, most respondents select the minimum commitment possible, and this is insensitive to the premium being charged on green power, suggesting that we are largely observing a buy-in ‘warm glow’ for carbon mitigation.
The increasing rate of resistance of bacterial infection against antibiotics requires next generation approaches to fight potential pandemic spread. The development of vaccines against pathogenic ...bacteria has been difficult owing, in part, to the genetic diversity of bacteria. Hence, there are many potential target antigens and little a priori knowledge of which antigen/s will elicit protective immunity. The painstaking process of selecting appropriate antigens could be avoided with whole-cell bacteria; however, whole-cell formulations typically fail to produce long-term and durable immune responses. These complications are one reason why no vaccine against any type of pathogenic E. coli has been successfully clinically translated. As a proof of principle, we demonstrate a method to enhance the immunogenicity of a model pathogenic E. coli strain by forming a slow releasing depot. The E. coli strain CFT073 was biomimetically mineralized within a metal–organic framework (MOF). This process encapsulates the bacteria within 30 min in water and at ambient temperatures. Vaccination with this formulation substantially enhances antibody production and results in significantly enhanced survival in a mouse model of bacteremia compared to standard inactivated formulations.
Strategic bias in discrete choice experiments Meginnis, Keila; Burton, Michael; Chan, Ron ...
Journal of environmental economics and management,
September 2021, 2021-09-00, Letnik:
109
Journal Article
Recenzirano
Odprti dostop
An induced value laboratory experiment is conducted to explore the vulnerability of discrete choice experiments to strategic misrepresentation of preferences. We consider strategic behaviour to arise ...when an agent: (i) believes the choice experiment will be used to determine a provision decision over a discrete set of alternatives; and (ii) has expectations about the relative likelihood of those alternatives being selected and delivered. In the experiment, agents receive induced values for the discrete set of provisioning alternatives. In treatments where agents receive information that their first best outcome is unlikely to win, we investigate the extent to which their choices change, in a manner consistent with them seeking to deliver their second best outcome in the provisioning decision. We find that 27% of respondents misrepresent their preferences and reveal evidence of strategic bias. We find that this behaviour is sufficient to change inferences about preferred provision at the aggregate level.
Climate change is forcing cities to reassess their water management practices, particularly for water-intensive applications like park irrigation. If water scarcity requires governments to deviate ...from current park management norms and allocate less water towards parks, it is essential that park managers design spaces that maintain community wellbeing. We apply the hedonic pricing method and use detailed park management information to assess the value of parks in a region where local climatic conditions require extensive irrigation to keep turf green, and where climate change is further constraining water supplies. Here we show that the impacts of irrigation on the value of parks differ depending on the dwelling types of the nearby housing populations that they serve. In most cases, the convention that parks have to be irrigated to deliver ecosystem services to the public is supported. However, we find that non-irrigated park areas are also valued positively by nearby apartment dwellers. Accelerating rates of urbanization and shifts towards high-density living may support the development of more diverse park options that are less water-intensive. Increased visibility of these alternative park forms, which could include more areas of native vegetation that do not require irrigation, may subsequently influence public expectations for landscape design.
•Climate change means that maintaining irrigation levels in urban parks may be challenging.•We provide novel estimates of park values and the extent to which they are affected by irrigation.•Prices for all property types are influenced by the presence of watered park areas.•Only apartment prices are influenced by the presence of non-watered park areas.•Having less watered grass in parks may save water without sacrificing public benefits.
We sought to investigate the effect of preoperative polypharmacy (PP) on the 90-day all-cause readmission rate in older adults undergoing corrective surgery for adult spinal deformity.
Older adults ...with a diagnosis of adult spinal deformity undergoing spinal surgery at a quaternary medical center from January 2016 to March 2019 were enrolled in this study. Patients were dichotomized into 2 groups stratified by the number of preoperative prescription medications, with PP defined as 5 or more prescription medications. The primary outcome measure was 90-day all-cause readmission rate. Secondary outcomes included postoperative changes in health-related quality of life measures.
Among 161 patients (mean standard deviation, 69.59 8.79 years), 97 patients were included in the PP cohort and 64 in the nonpolypharmacy (non-PP) cohort. Both groups were balanced at baseline. Duration of hospital stay (5.82 1.93 vs. 6.50 4.00 days), mean number of fusion levels, and duration of surgery were statistically similar between both groups (P > 0.05). There was no difference in the proportion of patients discharged directly home (31.25% vs. 40.42%, P = 0.36). The 90-day all-cause readmission rate was 3-fold higher in the PP cohort compared with the non-PP cohort. After adjusting for preoperative patient optimization, American Society of Anesthesiologists grade, surgical invasiveness, smoking, depression, and baseline functional disability, older adults with PP had a 9.79 increased odds of 90-day all-cause hospital readmission (P = 0.04). Changes in health-related quality of life measures were similar between both groups.
This study’s findings indicate that despite preoperative optimization, older adults exposed to polypharmacy are at a significantly increased risk of hospital readmission within 90 days of surgery.
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