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The BK Channel Limits the Pro-Inflammatory Activity of Macrophages.
Get PDFMacrophages play a crucial role in the innate immune response, serving as key effector cells in the defense against pathogens. Although the role of the large-conductance voltage and calcium-activated potassium channel, also known as the KCa1.1 or BK channel, in regulating neurotransmitter release and smooth muscle contraction is well known, its potential involvement in immune regulation remains unclear. We employed BK-knockout macrophages and noted that the absence of a BK channel promotes the polarization of macrophages towards a pro-inflammatory phenotype known as M1 macrophages. Specifically, the absence of the BK channel resulted in a significant increase in the secretion of the pro-inflammatory cytokine IL-6 and enhanced the activity of extracellular signal-regulated kinases 1 and 2 (Erk1/2 kinases), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and the transcription factor ATF-1 within M1 macrophages. Additionally, the lack of the BK channel promoted the activation of the AIM2 inflammasome without affecting the activation of the NLRC4 and NLRP3 inflammasomes. To further investigate the role of the BK channel in regulating AIM2 inflammasome activation, we utilized BK channel inhibitors, such as paxilline and iberiotoxin, along with the BK channel activator NS-11021. Pharmacological inactivation of the BK channel increased, and its stimulation inhibited IL-1β production following AIM2 inflammasome activation in wild-type macrophages. Moreover, wild-type macrophages displayed increased calcium influx when activated with the AIM2 inflammasome, whereas BK-knockout macrophages did not due to the impaired extracellular calcium influx upon activation. Furthermore, under conditions of a calcium-free medium, IL-1β production following AIM2 inflammasome activation was increased in both wild-type and BK-knockout macrophages. This suggests that the BK channel is required for the influx of extracellular calcium in macrophages, thus limiting AIM2 inflammasome activation. In summary, our study reveals a regulatory role of the BK channel in macrophages under inflammatory conditions
The Hemorrhagic Side of Primary Angiitis of the Central Nervous System (PACNS).
Get PDFPrimary Angiitis of the Central Nervous System (PACNS) is a rare cerebrovascular disease involving the arteries of the leptomeninges, brain and spinal cord. Its diagnosis can be challenging, and the current diagnostic criteria show several limitations. Among the clinical and neuroimaging manifestations of PACNS, intracranial bleeding, particularly intracerebral hemorrhage (ICH), is poorly described in the available literature, and it is considered infrequent. This review aims to summarize the available data addressing this issue with a dedicated focus on the clinical, neuroradiological and neuropathological perspectives. Moreover, the limitations of the actual data and the unanswered questions about hemorrhagic PACNS are addressed from a double point of view (PACNS subtyping and ICH etiology). Fewer than 20% of patients diagnosed as PACNS had an ICH during the course of the disease, and in cases where ICH was reported, it usually did not occur at presentation. As trigger factors, both sympathomimetic drugs and illicit drugs have been proposed, under the hypothesis of an inflammatory response due to vasoconstriction in the distal cerebral arteries. Most neuroradiological descriptions documented a lobar location, and both the large-vessel PACNS (LV-PACNS) and small-vessel PACNS (SV-PACNS) subtypes might be the underlying associated phenotypes. Surprisingly, amyloid beta deposition was not associated with ICH when histopathology was available. Moreover, PACNS is not explicitly included in the etiological classification of spontaneous ICH. This issue has received little attention in the past, and it could be addressed in future prospective studies
High-resolution land use/cover forecasts for Switzerland in the 21st century.
Get PDFWe present forecasts of land-use/land-cover (LULC) change for Switzerland for three time-steps in the 21st century under the representative concentration pathways 4.5 and 8.5, and at 100-m spatial and 14-class thematic resolution. We modelled the spatial suitability for each LULC class with a neural network (NN) using > 200 predictors and accounting for climate and policy changes. We improved model performance by using a data augmentation algorithm that synthetically increased the number of cells of underrepresented classes, resulting in an overall quantity disagreement of 0.053 and allocation disagreement of 0.15, which indicate good prediction accuracy. These class-specific spatial suitability maps outputted by the NN were then merged in a single LULC map per time-step using the CLUE-S algorithm, accounting for LULC demand for the future and a set of LULC transition rules. As the first LULC forecast for Switzerland at a thematic resolution comparable to available LULC maps for the past, this product lends itself to applications in land-use planning, resource management, ecological and hydraulic modelling, habitat restoration and conservation
Behavioural responses related to increasing core body temperature of grazing dairy cows experiencing moderate heat stress.
Get PDFExposure to direct solar radiation, high ambient temperature, lack of wind movement, coupled with own metabolic heat production, makes grazing dairy cows vulnerable to heat stress. In pastures, it would be beneficial to monitor heat stress by observable changes in behaviour. We hypothesised that grazing dairy cows exhibit behavioural changes due to increasing heat load in temperate climate. Over two consecutive summers, 38 full-time grazing Holstein dairy cows were investigated in 12 experimental periods of up to 3 consecutive days where the cows were repeatedly exposed to various levels of moderate heat load determined by the comprehensive climate index (CCI). The CCI defines the ambient climate conditions, combining air temperature, relative humidity, solar radiation and wind speed. Vaginal temperature (VT) was automatically measured as an indicator of heat stress. In addition, as a less invasive method, we investigated if reticular temperature (RET) can be indicative of heat stress on pastures. Walking activity, lying-, feeding, and ruminating durations were recorded continuously with sensors. Respiration rate (RR), proximity to and competition at the water trough, social licking, self-licking, inter-individual distance, and fly intensity were directly observed. Data were analysed in the morning (0900-1100 h) and during the hottest time of day when cows were on pasture (1230-1430 h). The VT and RET showed similar patterns in relation to the CCI, suggesting that RET can be suitable for continuous monitoring of heat stress on pastures. In the morning, the cow's VT and RET did not relevantly react to the CCI. During the period 1230-1430 h, the cow's mean VT (mean vaginal temperature (VTMEAN); range: 37.7-40.3 °C) and mean RET (mean reticular temperature; range: 37.0-41.1 °C) were positively related to the mean CCI (mean comprehensive climate index) in this period (mean ± SD: 25.9 ± 5.71 °C). For cows with greater VTMEAN, an increased mean RR and decreased durations of walking, lying, feeding, and ruminating were found. These cows were also more likely to be in proximity to the water trough and to have small inter-individual distances. Changes in these traits seem to reflect behavioural adaptations to heat stress in a temperate climate and could be used to detect the heat stress in individual dairy cows on pastures
Pancreatic Neuroendocrine Microtumors (WHO 2022) Are Not Always Low-Grade Neoplasms: A Case with a Highly Increased Proliferation Rate.
Get PDFTraditionally considered non-functional low proliferative benign neuroendocrine proliferations measuring less than 5 mm, pancreatic (neuro)endocrine microadenomas are now classified as pancreatic neuroendocrine microtumors in the 2022 WHO classification of endocrine and neuroendocrine tumors. This case report discussed the features of an incidentally identified 4.7-mm glucagon-expressing pancreatic neuroendocrine microtumor with MEN1 mutation only, chromosomally stable and an epigenetic alpha-like phenotype. The tumor was associated with an unexplained increased proliferation rate in Ki-67 of 15%. There was no associated DAXX/ATRX deficiency. The presented case challenges the conventional thought of a low proliferative disease of the so-called "pancreatic neuroendocrine microadenomas" and provides additional support to the 2022 WHO classification that also requires grading of these neoplasms. Despite exhibiting molecular features of less aggressive behavior, the case also underscores the biological complexity of pancreatic neuroendocrine microtumors. By recognizing the heterogenous spectrum of neuroendocrine neoplasms, the current case also contributes to ongoing discussions on how to optimize the clinical management of such tumors
A Multicompartment Assessment of Microplastic Contamination in Semi-remote Boreal Lakes.
Get PDFMicroplastic contamination is ubiquitous across the globe, even in remote locations. Still, the sources and pathways of microplastics to such locations are largely unknown. To investigate microplastic contamination in a semi-remote location, we measured microplastic concentrations in nine oligotrophic lakes within and around the International Institute for Sustainable Development-Experimental Lakes Area in northwestern Ontario, Canada. Our first objective was to establish ambient concentrations of microplastics in bottom sediments, surface water, and atmospheric deposition in semi-remote boreal lakes. Across all lakes, mean shallow and deep sediment microplastic concentrations, near-surface water microplastic concentrations from in situ filtering, and dry atmospheric microplastic deposition rates were 551 ± 354 particles kg-1 , 177 ± 103 particles kg-1 , 0.2 ± 0.3 particles L-1 , and 0.4 ± 0.2 particles m-2 day-1 , respectively. Our second objective was to investigate whether microplastic contamination of these lakes is driven by point sources including local runoff and direct anthropogenic inputs or nonpoint sources such as atmospheric deposition. Lakes were selected based on three levels of anthropogenic activity-low, medium, and high-though activity levels were minimal across all study lakes compared with highly populated areas. Whereas a positive correlation would indicate that point sources were a likely pathway, we observed no relationship between the level of anthropogenic activity and microplastic contamination of surface water. Moreover, the composition of microplastics in surface water and atmospheric deposition were similar, comprising mostly polyester and acrylic fibers. Together, these results suggest that atmospheric deposition may be the main pathway of microplastics to these remote boreal lakes. Environ Toxicol Chem 2024;00:1-13. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC
not opaque flow – Workflows zur Aufbereitung und Auswertung historischer Dokumente
Get PDFDeep Learning hat bereits neue Erkenntnisse in den digitalen Geisteswissenschaften ermöglicht. Vormoderne Sprachen und Sprachen des globalen Südens bringen allerdings Herausforderungen mit sich, die aktuell diesen analytischen Zugriff in diesem Bereich noch nicht erlauben. Das Projekt "The Flow" entwickelt Lösungen für solche historische Korpora in den Bereichen Handschriftenerkennung, Entitätsidentifikation, Event-Extraktion, Topic Modeling und Clustering. Die Entwicklung der Webanwendung nopaque zielt darauf ab, diese bestehenden Methoden bzw. Werkzeuge in einem übergreifenden Workflow zu verbinden. Der Workshop stellt den aktuellen Stand von nopaque bzw. den Workflow vor. Ziel ist es, bei der Etablierung eines allgemein anwendbaren Workflows für Deep Learning die Vielfalt der Quellen und geisteswissenschaftlichen Forschung zu berücksichtigen. Wir laden Teilnehmer:innen ein, Ideen und Erfahrungen einzubringen und Implementierungen für nicht standardisierte Layouts, Schriften und Sprachen zu diskutieren. Der Workshop trägt dazu bei, unser Projektziel zu erreichen: maschinelles Lernen in allen Bereichen der Geschichtswissenschaft zugänglicher zu machen
The clinical frailty scale for risk stratification in patients with fibrotic interstitial lung disease.
Get PDFBACKGROUND
Previous studies have shown the importance of frailty in patients with fibrotic interstitial lung disease (ILD).
RESEARCH QUESTION
Is the Clinical Frailty Scale (CFS) a valid tool to improve risk stratification in patients with fibrotic ILD?
STUDY DESIGN AND METHODS
Patients with fibrotic ILD were included from the prospective multicenter Canadian Registry for Pulmonary Fibrosis. The CFS was assessed using available information from initial ILD clinic visits. Patients were stratified into fit (CFS 1-3), vulnerable (CFS 4), and frail (CFS 5-9) subgroups. Cox proportional hazards and logistic regression models with mixed effects were used to estimate time to death or lung transplantation. A derivation and validation cohort were used to establish prognostic performance. Trajectories of functional tests were compared using joint models.
RESULTS
Of the 1587 patients with fibrotic ILD, 858 (54%) were fit, 400 (25%) vulnerable and 329 (21%) frail. Frailty was a risk factor for early mortality (HR 5.58, 95%CI 3.64-5.76, p<0.001) in the entire cohort, in individual ILD diagnoses, and after adjustment for potential confounders. Adding frailty to established risk prediction parameters improved the prognostic performance in derivation and validation cohorts. Frail patients had larger annual declines in forced vital capacity (FVC) %-predicted compared to fit patients (-2.32 (95%CI -3.39 to -1.17) vs. -1.55 (95%CI -2.04 to -1.15); p=0.02, respectively).
INTERPRETATION
The simple and practical CFS is associated with pulmonary and physical function decline in patients with fibrotic ILD and provides additional prognostic accuracy in clinical practice
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