Olfactory dysfunction, often the earliest symptom of Parkinson’s disease (PD), can precede clinical diagnosis by over 20 years, yet its mechanism and link to α-synuclein pathology remain unclear. To understand the impact of α-synuclein pathology on the topographic olfactory sensory map that supports the detection and discrimination of particular odors, we created two double transgenic mouse models (α-Syn/M72 and α-Syn/P2) expressing tagged-M72 or tagged-P2 odor receptors in a human wild-type α-synuclein over-expressing background. We demonstrated that the sensory map is disrupted in these mice. Histological analysis showed a significant reduction in M72 and P2 olfactory sensory neurons (OSNs), with altered glomerular topographies as axons converged into supernumerary glomeruli of varying size and location. These findings suggest that α-synuclein overexpression impairs the mechanism guiding the convergence of OSN axons and thus formation of a precise olfactory sensory map. As OSNs in the nasal epithelium are accessible via non-invasive biopsy, they are a potential source of prodromal PD biomarkers.

Unintentional weight loss is common among patients with Parkinson’s disease (PD) and is associated with poor quality of life and accelerated disease progression. To explore how early α-synuclein pathology contributes to metabolic dysregulation leading to weight loss in PD, transgenic mice overexpressing human wild-type α-synuclein (α-Syn) and controls were fed a high-fat diet (HFD) chow for 4 months. Compared with controls on HFD, α-Syn mice on HFD exhibited a dramatically leaner phenotype, improved glucose tolerance, a major decrease in fat mass, an increase in energy expenditure, a decrease in insulin signaling in the olfactory bulb, aggravated olfactory and motor dysfunctions, and an increase in mortality. Our results show that high-fat diet in α-Syn mice provides a sensitive tool for assessing the underlying mechanism of metabolic dysfunction and its impact on weight loss and disease progression in PD. Moreover, a role is proposed for olfactory dysfunction in PD-related unintentional weight loss.

Human aging presents an evolutionary paradox: while aging rates remain constant, healthspan and lifespan vary widely. We address this conundrum via salutogenesis-the active production of health-through immune resilience (IR), the capacity to resist disease despite aging and inflammation. Analyzing ~17,500 individuals across lifespan stages and inflammatory challenges, we identified a core salutogenic mechanism: IR centered on TCF7, a conserved transcription factor maintaining T-cell stemness and regenerative potential. IR integrates innate and adaptive immunity to counter three aging and mortality drivers: chronic inflammation (inflammaging), immune aging, and cellular senescence. By mitigating these aging mechanisms, IR confers survival advantages: At age 40, individuals with poor IR face a 9.7-fold higher mortality rate-a risk equivalent to that of 55.5-year-olds with optimal IR-resulting in a 15.5-year gap in survival. Optimal IR preserves youthful immune profiles at any age, enhances vaccine responses, and reduces burdens of cardiovascular disease, Alzheimer's, and serious infections. Two key salutogenic evolutionary themes emerge: first, female-predominant IR, including TCF7, likely reflects evolutionary pressures favoring reproductive success and caregiving; second, midlife (40-70 years) is a critical window where optimal IR reduces mortality by 69%. After age 70, mortality rates converge between resilient and non-resilient groups, reflecting biological limits on longevity extension. TNFα-blockers restore salutogenesis pathways, indicating IR delays aging-related processes rather than altering aging rates. By reframing aging as a salutogenic-pathogenic balance, we establish TCF7-centered IR as central to healthy longevity. Targeted midlife interventions to enhance IR offer actionable strategies to maximize healthspan before biological constraints limit benefits.

Unintentional weight loss, primarily due to the loss of fat mass rather than muscle mass, is common among patients with Parkinson’s disease (PD) and is associated with poor quality of life and accelerated disease progression. Since transgenic mice overexpressing human wild-type α-synuclein (α-Syn mice) are modestly leaner than control mice, and since diabetes, a metabolic disorder, is a major risk factor for PD, we reasoned that high-fat diet-induced diabetes/metabolic dysregulation in α-Syn mice may serve as a robust tool for exploring how early α-synuclein pathology contributes to metabolic dysregulation, leading to weight loss in PD. Thus, α-Syn and age-matched controls were fed a high-fat diet (HFD) chow (60% fat calories) ad libitum for four months. Compared with controls on HFD (control-HFD), α-Syn mice on HFD (α-Syn-HFD) were dramatically leaner. The resistance to gaining weight in α-Syn-HFD mice was accompanied by improved glucose tolerance, a dramatic decrease in fat mass, and an increase in energy expenditure. Despite this leaner phenotype and better glucose tolerance, the mortality was much higher in male α-Syn-HFD mice than in all controls, but was unaffected in females, suggesting protective effects of female sex hormones, as well as lower α-synuclein levels. Immunoblot analysis of insulin signaling in the olfactory bulb, the proposed initial seeding site of α-synuclein pathology, revealed a decrease of IGF-IRβ, p GSK, and p mTOR in α-Syn-HFD mice. Since GSK-3β and mTOR regulate synaptic plasticity, we assessed levels of PSD-95 and synaptophysin in the olfactory bulb. As anticipated, we observed a significant decrease in the levels of PSD-95, along with a potentially compensatory increase in synaptophysin levels. Our results show that α-Syn mice, when challenged with diet-induced diabetes/metabolic dysregulation, clearly reveal a profile of robust metabolic dysfunction, thus providing a sensitive tool for assessing the underlying mechanism of metabolic dysfunction and its impact on weight loss and disease progression in PD. We propose a role for olfactory dysfunction in PD-related unintentional weight loss and suggest that strategies aimed at increasing body weight/BMI will improve the quality of life and prognosis for people living with PD.

Glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic neurons in various models of Parkinson’s disease (PD). Cell-based GDNF gene delivery mitigates neurodegeneration and improves both motor and non-motor functions in PD mice. As PD is a chronic condition, this study aims to investigate the long-lasting benefits of hematopoietic stem cell (HSC)-based macrophage/microglia-mediated CNS GDNF (MMC-GDNF) delivery in an MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model. The results indicate that GDNF treatment effectively ameliorated MPTP-induced motor deficits for up to 12 months, which coincided with the protection of nigral dopaminergic neurons and their striatal terminals. Also, the HSC-derived macrophages/microglia were recruited selectively to the neurodegenerative areas of the substantia nigra. The therapeutic benefits appear to involve two mechanisms: (1) macrophage/microglia release of GDNF-containing exosomes, which are transferred to target neurons, and (2) direct release of GDNF by macrophage/microglia, which diffuses to target neurons. Furthermore, the study found that plasma GDNF levels were significantly increased from baseline and remained stable over time, potentially serving as a convenient biomarker for future clinical trials. Notably, no weight loss, altered food intake, cerebellar pathology, or other adverse effects were observed. Overall, this study provides compelling evidence for the long-term therapeutic efficacy and safety of HSC-based MMC-GDNF delivery in the treatment of PD.

Some people remain healthier throughout life than others but the underlying reasons are poorly understood. Here we hypothesize this advantage is attributable in part to optimal immune resilience (IR), defined as the capacity to preserve and/or rapidly restore immune functions that promote disease resistance (immunocompetence) and control inflammation in infectious diseases as well as other causes of inflammatory stress. We gauge IR levels with two distinct peripheral blood metrics that quantify the balance between (i) CD8 + and CD4 + T-cell levels and (ii) gene expression signatures tracking longevity-associated immunocompetence and mortality-associated inflammation. Profiles of IR metrics in ~48,500 individuals collectively indicate that some persons resist degradation of IR both during aging and when challenged with varied inflammatory stressors. With this resistance, preservation of optimal IR tracked (i) a lower risk of HIV acquisition, AIDS development, symptomatic influenza infection, and recurrent skin cancer; (ii) survival during COVID-19 and sepsis; and (iii) longevity. IR degradation is potentially reversible by decreasing inflammatory stress. Overall, we show that optimal IR is a trait observed across the age spectrum, more common in females, and aligned with a specific immunocompetence-inflammation balance linked to favorable immunity-dependent health outcomes. IR metrics and mechanisms have utility both as biomarkers for measuring immune health and for improving health outcomes.

BACKGROUND:Allergic asthma (AA) and allergic rhinoconjunctivitis (ARC) are common comorbid environmentally triggered diseases. We hypothesized that severe AA/ARC reflects a maladaptive or unrestrained response to ubiquitous aeroallergens. METHODS:We performed provocation studies wherein six separate cohorts of persons (total n = 217) with ARC, with or without AA, were challenged once or more with fixed concentrations of seasonal or perennial aeroallergens in an aeroallergen challenge chamber (ACC). RESULTS:Aeroallergen challenges elicited fully or partially restrained vs. unrestrained evoked symptom responsiveness, corresponding to the resilient and adaptive vs. maladaptive AA/ARC phenotypes, respectively. The maladaptive phenotype was evoked more commonly during challenge with a non-endemic versus endemic seasonal aeroallergen. In an AA cohort, symptom responses evoked after house dust mite (HDM) challenges vs. recorded in the natural environment were more accurate and precise predictors of asthma severity and control, lung function (FEV1), and mechanistic correlates of maladaptation. Correlates included elevated levels of peripheral blood CD4+ and CD8+ T-cells, eosinophils, and T-cell activation, as well as gene expression proxies for ineffectual epithelial injury/repair responses. Evoked symptom severity after HDM challenge appeared to be more closely related to levels of CD4+ and CD8+ T-cells than eosinophils, neutrophils, or HDM-specific IgE. CONCLUSIONS:Provocation studies support the concept that resilience, adaptation, and maladaptation to environmental disease triggers calibrate AA/ARC severity. Despite the ubiquity of aeroallergens, in response to these disease triggers in controlled settings (ie, ACC), most atopic persons manifest the resilient or adaptive phenotype. Thus, ARC/AA disease progression may reflect the failure to preserve the resilient or adaptive phenotype. The triangulation of CD8+ T-cell activation, airway epithelial injury/repair processes and maladaptation in mediating AA disease severity needs more investigation.

BACKGROUND:Signifying the 2-compartments/1-disease paradigm, allergic rhinoconjunctivitis (ARC) and asthma (AA) are prevalent, comorbid conditions triggered by environmental factors (eg, house dust mites [HDMs]). However, despite the ubiquity of triggers, progression to severe ARC/AA is infrequent, suggesting either resilience or adaptation.OBJECTIVE:We sought to determine whether ARC/AA severity relates to maladaptive responses to disease triggers.METHODS:Adults with HDM-associated ARC were challenged repetitively with HDMs in an aeroallergen challenge chamber. Mechanistic traits associated with disease severity were identified.RESULTS:HDM challenges evoked maladaptive (persistently higher ARC symptoms), adaptive (progressive symptom reduction), and resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Nasal airway traits, defined by low inflammation-effectual epithelial integrity, moderate inflammation-effectual epithelial integrity, and higher inflammation-ineffectual epithelial integrity, were hallmarks of the resilient, adaptive, and maladaptive evoked phenotypes, respectively. Highlighting a crosstalk mechanism, peripheral blood inflammatory tone calibrated these traits: ineffectual epithelial integrity associated with CD8+ T cells, whereas airway inflammation associated with both CD8+ T cells and eosinophils. Hallmark peripheral blood maladaptive traits were increased natural killer and CD8+ T cells, lower CD4+ mucosal-associated invariant T cells, and deficiencies along the TLR-IRF-IFN antiviral pathway. Maladaptive traits tracking HDM-associated ARC also contributed to AA risk and severity models.CONCLUSIONS:Repetitive challenges with HDMs revealed that maladaptation to disease triggers may underpin ARC/AA disease severity. A combinatorial therapeutic approach may involve reversal of loss-of-beneficial-function traits (ineffectual epithelial integrity, TLR-IRF-IFN deficiencies), mitigation of gain-of-adverse-function traits (inflammation), and blocking of a detrimental crosstalk between the peripheral blood and airway compartments.

BACKGROUND:The risk of severe coronavirus disease 2019 (COVID-19) varies significantly among persons of similar age and is higher in males. Age-independent, sex-biased differences in susceptibility to severe COVID-19 may be ascribable to deficits in a sexually dimorphic protective attribute that we termed immunologic resilience (IR). OBJECTIVE:We sought to examine whether deficits in IR that antedate or are induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection independently predict COVID-19 mortality. METHODS:IR levels were quantified with 2 novel metrics: immune health grades (IHG-I [best] to IHG-IV) to gauge CD8+ and CD4+ T-cell count equilibrium, and blood gene expression signatures. IR metrics were examined in a prospective COVID-19 cohort (n = 522); primary outcome was 30-day mortality. Associations of IR metrics with outcomes in non-COVID-19 cohorts (n = 13,461) provided the framework for linking pre-COVID-19 IR status to IR during COVID-19, as well as to COVID-19 outcomes. RESULTS:IHG-I, tracking high-grade equilibrium between CD8+ and CD4+ T-cell counts, was the most common grade (73%) among healthy adults, particularly in females. SARS-CoV-2 infection was associated with underrepresentation of IHG-I (21%) versus overrepresentation (77%) of IHG-II or IHG-IV, especially in males versus females (P < .01). Presentation with IHG-I was associated with 88% lower mortality, after controlling for age and sex; reduced risk of hospitalization and respiratory failure; lower plasma IL-6 levels; rapid clearance of nasopharyngeal SARS-CoV-2 burden; and gene expression signatures correlating with survival that signify immunocompetence and controlled inflammation. In non-COVID-19 cohorts, IR-preserving metrics were associated with resistance to progressive influenza or HIV infection, as well as lower 9-year mortality in the Framingham Heart Study, especially in females. CONCLUSIONS:Preservation of immunocompetence with controlled inflammation during antigenic challenges is a hallmark of IR and associates with longevity and AIDS resistance. Independent of age, a male-biased proclivity to degrade IR before and/or during SARS-CoV-2 infection predisposes to severe COVID-19.

Jane Austen’s Emma is famous for being among the earliest and most sophisticated expositions of free-indirect discourse which is used to represent ironically a match-making heroine of 21 years whose judgements are usually faulty. It is also famous as a brilliant courtship romance or love story, much imitated in recent years. Less often noticed is that it is a fiercely satiric comedy about the rise of the middle class and the penetration of genteel English society with the language and values of market capitalism. Drawing inspiration from John Bender’s Imagining the Penitentiary and Karl Polanyi’s The Great Transformation this essay proposes that the author’s use of free-indirect discourse constructs Emma as a subject who does not comprehend her own subjectivity, and whose need to be taught to see herself objectively, thanks to the tutelage of Mr. Knightley, opens a paradox in which the subject and its subjectivity need to comprehend themselves objectively as exchangeable objects within a capitalist market society. This paradox is identified as coming to prominence in Adam Smith’s Theory of Moral Sentiments, and, for those who refuse to learn regulation, in the Panopticon penitentiary advocated by Jeremy Bentham.

Mammalian aging is associated with reduced tissue regeneration and loss of physiological integrity. With age, stem cells diminish in their ability to regenerate adult tissues, likely contributing to age-related morbidity. Thus, we replaced aged hematopoietic stem cells (HSCs) with young-donor HSCs using a novel mobilization-enabled hematopoietic stem cell transplantation (HSCT) technology as an alternative to the highly toxic conditioning regimens used in conventional HSCT. Using this approach, we are the first to report an increase in median lifespan (12%) and a decrease in overall mortality hazard (HR: 0.42, CI: 0.273-0.638) in aged mice following transplantation of young-donor HSCs. The increase in longevity was accompanied by reductions of frailty measures and increases in food intake and body weight of aged recipients. Young-donor HSCs not only preserved youthful function within the aged bone marrow stroma, but also at least partially ameliorated dysfunctional hematopoietic phenotypes of aged recipients. This compelling evidence that mammalian health and lifespan can be extended through stem cell therapy adds a new category to the very limited list of successful anti-aging/life-extending interventions. Our findings have implications for further development of stem cell therapies for increasing health and lifespan.

Lentiviral vectors are increasingly used as efficient gene transfer tools in the experimental and clinical gene therapy treatment of acquired and inherited genetic diseases. Hematopoietic stem cells (HSCs) are characterized by the capacity for self-renewal, as well as multi-lineage differentiation and maintenance of the lymphohematopoietic system throughout life. As such, HSC transplantation (HSCT) has proven to be a powerful therapeutic modality for the treatment of both malignant and nonmalignant disorders. Transduction of lentiviral vectors into HSCs may offer long-term stable expression of a therapeutic gene in both preclinical and clinical settings. The purpose of this chapter is to describe an optimized procedure for lentiviral transduction of mouse HSCs followed by HSCT.

Neutrophils serve as the circulating cells that respond early and figure prominently in human host defense to infection and in inflammation in other settings. Optimal oxidant-dependent antimicrobial activity by neutrophils relies on the ability of stimulated phagocytes to utilize a multicomponent NADPH oxidase to generate oxidants. The frequent, severe, and often fatal infections experienced by individuals with chronic granulomatous disease (CGD), an inherited disorder in which one of the NADPH oxidase components is absent or dysfunctional, underscore the link between a functional phagocyte NADPH oxidase and robust host protection against microbial infection.The history of the discovery and characterization of the normal neutrophil NADPH oxidase and the saga of recognizing CGD and its underlying causes together illustrate how the observations of astute clinicians and imaginative basic scientists synergize to forge new understanding of both basic cell biology and pathogenesis of human disease.In this chapter, we review the events in the stepwise evolution of our understanding of the phagocyte NADPH oxidase, both in the context of normal human neutrophil function and in the setting of CGD. The phagocyte oxidase complex employs a heterodimeric transmembrane protein composed of gp91phox and p22phox to relay electrons from NADPH to molecular oxygen, while other cofactors contribute to localization and regulation of the activity of the assembled oxidase. The b-type cytochrome gp91phox, also known as NOX2, serves as the catalytic component of this multicomponent enzyme complex. Although many of the features of the composition and regulation of the phagocyte oxidase may apply as well to NOX2 expressed in non-phagocytes and to other members of the NOX protein family, exceptions exist and pose special challenges to investigators exploring the biology of NADPH oxidases.

Although olfactory dysfunction is an early warning sign of Alzheimer's and Parkinson's diseases, and is commonly present in a range of other neurodegenerative disorders, the mechanisms for its pathogenesis are not yet clear. Since fMRI allows the mapping of spatial and temporal patterns of activity in multiple brain regions simultaneously, it serves as a powerful tool to study olfactory dysfunction in animal models of neurodegenerative diseases. Nonetheless, there have been no reports to date of mapping odor-induced activation patterns beyond the olfactory bulb to the extended networks of olfactory and limbic archicortex, likely due to the small size of the mouse brain. Therefore, using an 11.7 T magnet and a blood volume-weighted fMRI technique, we mapped the functional neuroanatomy of the mouse olfactory system. Consistent with reports on imaging of the much larger human brain, we mapped activity in regions of the olfactory bulb, as well as olfactory and limbic archicortex. By using two distinct odorants, we further demonstrated odorant-specific activation patterns. Our work thus provides a methodological framework for fMRI studies of olfactory dysfunction in mouse models of neurodegeneration.

There is increasing evidence that widespread cortical cerebral blood flow deficits occur early in the course of Parkinson's disease. Although cerebral blood flow measurement has been suggested as a potential biomarker for early diagnosis of Parkinson's disease, as well as a means for tracking response to treatment, the relationship of cerebral blood flow to α-synucleinopathy, a major pathological hallmark of Parkinson's disease, remains unclear. Therefore, we performed arterial spin-labeling magnetic resonance imaging and diffusion tensor imaging on transgenic mice overexpressing human wild-type α-synuclein and age-matched controls to measure cerebral blood flow and degenerative changes. As reported for early-stage Parkinson's disease, α-synuclein mice exhibited a significant reduction in cortical cerebral blood flow, which was accompanied by motor coordination deficits and olfactory dysfunction. Although no overt degenerative changes were apparent in diffusion tensor imaging images, magnetic resonance imaging volumetric analysis revealed a significant reduction in olfactory bulb volume, similar to that seen in Parkinson's disease patients. Our data, representing the first report of cerebral blood flow deficit in an animal model of Parkinson's disease, suggest a causative role for α-synucleinopathy in cerebral blood flow deficits in Parkinson's disease. Thus, α-synuclein transgenic mice comprise a promising model to study Parkinson's disease-related mechanisms of cerebral blood flow deficits and to investigate further its utility as a potential biomarker for Parkinson's disease.

Daniel Defoe’s Captain Singleton has received modest critical attention, perhaps because it appears to modern readers as a relatively unexciting narrative which endorses piratical theft by unconvincing arguments, and because it passes over in silence the dreadful violence for which pirates were famous and abominated. The text is highly problematic. This essay establishes the historical context of the novel within the ambiguous attitude of the British state towards piracy at the time Defoe is writing. The State condoned piracy under the name privateering when it served British mercantilist interests, and condemned piracy when it threatened British colonial trade. A second layer of ambiguity is provided by Defoe’s personal fascination with the accumulation of great wealth by immoral or illicit means. This essay explores how both sets of contradictions are fundamental to mercantilist ideology of rising capitalism: the ideology of honest trade and fair-dealing masked the primitive accumulation of capital by atrocious violence, sometimes official and State-sponsored; sometimes individualistic and ad hoc. The essay also explores how Captain Singleton contributes to the imaginative appropriation of Africa and the Indian and Southern Pacific Oceans, preparing for their hegemonic subjection to the British Empire, and entry into British literature, across the next two hundred years.

Glial cell-line-derived neurotrophic factor (GDNF) is a potent neuroprotective agent in cellular and animal models of Parkinson's disease (PD). However, CNS delivery of GDNF in clinical trials has proven challenging due to blood-brain barrier (BBB) impermeability, poor diffusion within brain tissue, and large brain size. We report that using non-toxic mobilization-enabled preconditioning, hematopoietic stem cell (HSC) transplantation-based macrophage-mediated gene delivery may provide a solution to overcome these obstacles. Syngeneic bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into 14-week-old MitoPark mice exhibiting PD-like impairments. Transplant preconditioning with granulocyte colony-stimulating factor (G-CSF) and AMD3100 was used to vacate bone marrow stem cell niches. Chimerism reached ∼80% after seven transplantation cycles. Transgene-expressing macrophages infiltrated degenerating CNS regions of MitoPark mice (not wild-type littermate controls), resulting in increased GDNF levels in the midbrain. Macrophage GDNF delivery not only markedly improved motor and non-motor dysfunction, but also dramatically mitigated the loss of dopaminergic neurons in both substantia nigra and the ventral tegmental area and preserved axonal terminals in the striatum. Striatal dopamine levels were almost completely restored. Our data support further development of mobilization-enabled HSC transplantation (HSCT)-based macrophage-mediated GDNF gene delivery as a disease-modifying therapy for PD.

The primary role of the phagocytic leukocytes in host defenses is the ingestion and killing of invading microorganisms. The oxygen derivatives produced express toxicity either directly or by generation of additional reactive species on interaction with metal catalysts, phagocyte-derived enzymes, halide ions, or various nitrogenous compounds. The foregoing description of polymorphonuclear leukocyte (PMN) oxygen metabolism has many parallels in monocytes, macrophages, and eosinophils. PMN-derived oxidants are capable of injuring a variety of eukaryotic cells including tumor cells, erythrocytes, platelets, endothelial cells, fibroblasts, spermatozoa, lymphocytes, and phagocytes themselves. The products of oxygen reduction and of the Myeloperoxidase-hydrogen peroxide-halide system represent potent oxidizing agents by which PMN exert tumoricidal and microbicidal activity. Oxidant-dependent inactivation of soluble proteins by PMN has been shown to include granule enzymes and nonenzymatic proteins released by PMN during stimulation.