Sepsis is a prevalent health issue that can lead to central nervous system (CNS) inflammation with long-term behavioral and cognitive alterations. Using unbiased proteomic profiling of over 100 ...different cytokines, we found that Lipocalin-2 (LCN2) was the most substantially elevated protein in the CNS after peripheral administration of lipopolysaccharide (LPS). To determine whether the high level of LCN2 in the CNS is protective or deleterious, we challenged Lcn2
mice with peripheral LPS and determined effects on behavior and neuroinflammation. At a time corresponding to peak LCN2 induction in wild-type (WT) mice injected with LPS, Lcn2
mice challenged with LPS had exacerbated levels of pro-inflammatory cytokines and exhibited significantly worsened behavioral phenotypes. To determine the extent of global inflammatory changes dependent upon LCN2, we performed an RNAseq transcriptomic analysis. Compared with WT mice injected with LPS, Lcn2
mice injected with LPS had unique transcriptional profiles and significantly elevated levels of multiple pro-inflammatory molecules. Several LCN2-dependent pathways were revealed with this analysis including, cytokine and chemokine signaling, nucleotide-binding oligomerization domain-like receptor signaling and Janus kinase-signal transducer and activator of transcription signaling. These findings demonstrate that LCN2 serves as a potent protective factor in the CNS in response to systemic inflammation and may be a potential candidate for limiting sepsis-related CNS sequelae.
Autoantibody specific for the aquaporin-4 astrocytic water channel is restricted to serum and CSF of patients with neuromyelitis optica (NMO) and related CNS inflammatory demyelinating disorders ...(relapsing optic neuritis and longitudinally extensive transverse myelitis). NMO-typical lesions are distinct from MS-typical lesions. Aquaporin-4 is lost selectively at vasculocentric sites of edema/inflammation coinciding with focal deposits of immunoglobulins (Ig) G, M, and terminal complement products, with and without myelin loss. Evidence for antigen-specific autoantibody pathogenicity is lacking.
We used confocal microscopy and flow cytometry to evaluate the selectivity and immunopathological consequences of Ig binding to surface epitopes of living target cells expressing aquaporin-4 fused at its cytoplasmic N-terminus with GFP. We tested serum, IgG-enriched and IgG-depleted serum fractions, and CSF from patients with NMO, neurologic control patients, and healthy subjects. We also analyzed aquaporin-4 immunoreactivity in myelinated adult mouse optic nerves and spinal cord, and plasma cell Ig isotypes in archived brain tissue from an NMO patient.
Serum IgG from patients with NMO binds to the extracellular domain of aquaporin-4; it is predominantly IgG(1), and it initiates two potentially competing outcomes, aquaporin-4 endocytosis/degradation and complement activation. Serum and CSF lack aquaporin-4-specific IgM, and plasma cells in CNS lesions of NMO contain only IgG. Paranodal astrocytic endfeet highly express aquaporin-4.
NMO patients' serum IgG has a selective pathologic effect on cell membranes expressing aquaporin-4. IgG targeting astrocytic processes around nodes of Ranvier could initiate demyelination.
Abstract Mutations in the LRRK2 gene represent the most common genetic cause of late onset Parkinson's disease. The physiological and pathological roles of LRRK2 are yet to be fully determined but ...evidence points towards LRRK2 mutations causing a gain in kinase function, impacting on neuronal maintenance, vesicular dynamics and neurotransmitter release. To explore the role of physiological levels of mutant LRRK2, we created knock-in (KI) mice harboring the most common LRRK2 mutation G2019S in their own genome. We have performed comprehensive dopaminergic, behavioral and neuropathological analyses in this model up to 24 months of age. We find elevated kinase activity in the brain of both heterozygous and homozygous mice. Although normal at 6 months, by 12 months of age, basal and pharmacologically induced extracellular release of dopamine is impaired in both heterozygous and homozygous mice, corroborating previous findings in transgenic models over-expressing mutant LRRK2. Via in vivo microdialysis measurement of basal and drug-evoked extracellular release of dopamine and its metabolites, our findings indicate that exocytotic release from the vesicular pool is impaired. Furthermore, profound mitochondrial abnormalities are evident in the striatum of older homozygous G2019S KI mice, which are consistent with mitochondrial fission arrest. We anticipate that this G2019S mouse line will be a useful pre-clinical model for further evaluation of early mechanistic events in LRRK2 pathogenesis and for second-hit approaches to model disease progression.
The balance and distribution of epithelial cell types is required to maintain tissue homeostasis. A hallmark of airway diseases is epithelial remodeling, leading to increased goblet cell numbers and ...an overproduction of mucus. In the conducting airway, basal cells act as progenitors for both secretory and ciliated cells. To identify mechanisms regulating basal cell fate, we developed a screenable 3D culture system of airway epithelial morphogenesis. We performed a high-throughput screen using a collection of secreted proteins and identified inflammatory cytokines that specifically biased basal cell differentiation toward a goblet cell fate, culminating in enhanced mucus production. We also demonstrate a specific requirement for Notch2 in cytokine-induced goblet cell metaplasia in vitro and in vivo. We conclude that inhibition of Notch2 prevents goblet cell metaplasia induced by a broad range of stimuli and propose Notch2 neutralization as a therapeutic strategy for preventing goblet cell metaplasia in airway diseases.
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•Airway basal cells differentiate into goblet and ciliated cells in 3D cultures•Inflammatory cytokines bias airway basal cell fate to drive goblet cell metaplasia•Notch2 is a key node required for goblet cell metaplasia•Targeting Notch2 prevents goblet cell metaplasia, regardless of the stimulus
Goblet cell metaplasia, resulting in excessive mucus production, is a hallmark of airway diseases. Here, Danahay et al. demonstrate that inhibition of Notch2 prevents goblet cell metaplasia in response to diverse stimuli in vitro and in vivo, validating Notch2 blockade as a therapeutic strategy for airway diseases.
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•Real coffee bean motion in a pilot-scale drum roaster was mapped using PEPT.•Coffee bean density, drum rotation speed and batch size determine flow profiles.•Distinct regions of ...occupancy correspond to beans in-flight and the bean-bed.•Data can be coupled with heat transfer simulations for physics-driven models.
Physicochemical transformation of coffee during roasting depends on the applied time–temperature profile (i.e., rate of heat transfer), with heat transfer phenomena governed by particle dynamics. Positron Emission Particle Tracking (PEPT), a non-invasive imaging technique, was used here to characterise the granular flow of coffee in a real, pilot-scale rotating drum roaster. The experimental study established the impact of drum speed, batch size and bean density (i.e., roast degree) on the system’s particle dynamics. Particle motion data revealed two distinct regions: (i) a disperse (low occupancy, high velocity) region of in-flight particles and (ii) a dense (high occupancy, low velocity) bean bed. Implications of these results for heat transfer suggest that controlling drum speed for different density coffees will provide roaster operators with a tool to modulate conductive heat transfer from the heated drum to the bean bed. These comprehensive data thus inform roasting best practices and support the development of physics-driven models coupling heat and mass transfer to particle dynamics.
In adult patients, autoantibodies targeting the water channel aquaporin-4 (AQP4) are a biomarker for a spectrum of CNS inflammatory demyelinating disorders with predilection for optic nerves and ...spinal cord (neuromyelitis optica NMO). Here we describe the neurologic, serologic, and radiographic findings associated with CNS AQP4 autoimmunity in childhood.
A total of 88 consecutive seropositive children were identified through service evaluation for NMO-IgG. Sera of 75 were tested for coexisting autoantibodies. Clinical information was available for 58.
Forty-two patients (73%) were non-Caucasian, and 20 (34%) had African ethnicity. Median age at symptom onset was 12 years (range 4-18). Fifty-seven (98%) had attacks of either optic neuritis (n = 48; 83%) or transverse myelitis (n = 45; 78%), or both. Twenty-six (45%) had episodic cerebral symptoms (encephalopathy, ophthalmoparesis, ataxia, seizures, intractable vomiting, or hiccups). Thirty-eight (68%) had brain MRI abnormalities, predominantly involving periventricular areas (in descending order of frequency): the medulla, supratentorial and infratentorial white matter, midbrain, cerebellum, thalamus, and hypothalamus. Additional autoantibodies were detected in 57 of 75 patients (76%), and 16 of 38 (42%) had a coexisting autoimmune disorder recorded (systemic lupus erythematosus, Sjögren syndrome, juvenile rheumatoid arthritis, Graves disease). Attacks were recurrent in 54 patients (93%; median follow-up, 12 months). Forty-three of 48 patients (90%) had residual disability: 26 (54%) visual impairment and 21 (44%) motor deficits (median Expanded Disability Status Scale 4.0 at 12 months).
Aquaporin-4 autoimmunity is a distinctive recurrent and widespread inflammatory CNS disease in children.
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•COVID-19 pandemic is clearly challenging the entire food system.•A collective action is needed in order to build food systems that are resilient.•Food systems are multidisciplinary ...and highly interconnected.•Food security is important in times of shocks and crises.
Increasing the dietary fiber of staple foods such as bread is an attractive way to promote healthy eating in a large part of the population, where dietary fiber consumption is reportedly below the ...recommended values. However, many consumers prefer white breads, which are typically low in dietary fiber. In this work, white bread was made from two wheat cultivars with differing fiber contents. The resulting breads showed similar quality parameters (volume, specific volume, firmness, inner structure characteristics) with any differences maintained below 7%. Bread digestibility was evaluated using a novel dynamic in vitro digestion model. Reduced digestion rates of 30% were estimated for the high-fiber white bread compared to that in the control. Overall, this work demonstrates the potential to produce healthy, high-fiber white breads that are acceptable to consumers, with a reduced rate of starch digestion, by exploiting a genetic variation in the dietary fiber content of wheat cultivars.
Positron emission particle tracking (PEPT) has been used to investigate the motion of radioactively labeled tracer particles attached to fabrics and solid fabric enhancer (SFE) delivery articles, ...such as dryer sheets, in the domestic clothes dryer. This work examines the dynamics of motion within the dryer across a range of operating conditions. Six regions within the dryer drum are identified, demonstrating the range of movements experienced by items during tumbling. These show clear correlation with existing flow regimes describing behavior of granular media in rotating drums. Fabric motion is primarily cataracting to maximize the surface area of fabric available to interact with drying air in the falling region, with some conditions moving toward centrifuging or cascading flows. Movement in the axial direction was significantly slower than the primary radial flow. Dryer sheets were more prone to centrifuging than fabrics, with significant time spent in contact with the drum wall. Conversely, a wool dryer ball was more likely to cascade, spending time mixed into the top of a fabric bed which forms in the impact and lifting regions. Behavior in this bed is primarily determined by frictional interactions with the drum wall, which subsequently affects behavior in the 5 remaining regions. The most significant changes to this behavior were observed when changing fabric moisture content and volumetric fill ratio, with wet fabrics and smaller load sizes both exhibiting faster falling speeds and spending more time in the fabric bed. The changes were most significant in the lifting, falling and detachment regions, with varying acceleration and shearing likely to influence both fabric wear and SFE delivery.
Exercise reduces the risk of inflammatory disease by modulating a variety of tissue and cell types, including those within the gastrointestinal tract. Recent data indicates that exercise can also ...alter the gut microbiota, but little is known as to whether these changes affect host function. Here, we use a germ-free (GF) animal model to test whether exercise-induced modifications in the gut microbiota can directly affect host responses to microbiota colonization and chemically-induced colitis. Donor mice (n = 19) received access to a running wheel (n = 10) or remained without access (n = 9) for a period of six weeks. After euthanasia, cecal contents were pooled by activity treatment and transplanted into two separate cohorts of GF mice. Two experiments were then conducted. First, mice were euthanized five weeks after the microbiota transplant and tissues were collected for analysis. A second cohort of GF mice were colonized by donor microbiotas for four weeks before dextran-sodium-sulfate was administered to induce acute colitis, after which mice were euthanized for tissue analysis. We observed that microbial transplants from donor (exercised or control) mice led to differences in microbiota β-diversity, metabolite profiles, colon inflammation, and body mass in recipient mice five weeks after colonization. We also demonstrate that colonization of mice with a gut microbiota from exercise-trained mice led to an attenuated response to chemical colitis, evidenced by reduced colon shortening, attenuated mucus depletion and augmented expression of cytokines involved in tissue regeneration. Exercise-induced modifications in the gut microbiota can mediate host-microbial interactions with potentially beneficial outcomes for the host.
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