Deficiency of Nucleotide-binding oligomerization domain-containing proteins (NOD) 1 and 2 reduces atherosclerosis.

Atherosclerosis is crucially fueled by inflammatory pathways including pattern recognition receptor (PRR)-related signaling of the innate immune system. Currently, the impact of the cytoplasmic PRRs nucleotide-binding oligomerization domain-containing protein (NOD) 1 and 2 is incompletely characterized. We, therefore, generated Nod1/Nod2 double knockout mice on a low-density lipoprotein receptor (Ldlr)-deficient background (= Ldlr-/-Nod1/2-/-) which were subsequently analyzed regarding experimental atherosclerosis, lipid metabolism, insulin resistance and gut microbiota composition. Compared to Ldlr-/- mice, Ldlr-/-Nod1/2-/- mice showed reduced plasma lipids and increased hepatic expression of the scavenger receptor LDL receptor-related protein 1 after feeding a high-fat diet for 12 weeks. Furthermore, intestinal cholesterol and its bacterial degradation product coprostanol were elevated in Ldlr-/-Nod1/2-/- mice, correlating with the increased abundance of Eubacterium coprostanoligenes as assessed by 3rd generation sequencing of the gut microbiota. Atherosclerotic plaques of Ldlr-/-Nod1/2-/- mice exhibited less lipid deposition and macrophage accumulation. Moreover, macrophages from Ldlr-/-Nod1/2-/- mice showed higher expression of the cholesterol efflux transporters Abca1 and Abcg1 and accordingly reduced foam cell formation. Deficiency of Nod1 and Nod2 led to reduced plaque lipid deposition and inflammatory cell infiltration in atherosclerotic plaques. This might be explained by diminished plasma lipid levels and foam cell formation due to altered expression of key regulators of the hepatic cholesterol pathway as well as differential intestinal cholesterol metabolism and microbiota composition.

Loss of cerebellar neurons in the progression of lentiviral disease: effects of CNS-permeant antiretroviral therapy.

BACKGROUND: The majority of investigations on HIV-associated neurocognitive disorders (HAND) neglect the cerebellum in spite of emerging evidence for its role in higher cognitive functions and dysfunctions in common neurodegenerative diseases. METHODS: We systematically investigated the molecular and cellular responses of the cerebellum as contributors to lentiviral infection-induced neurodegeneration, in the simian immunodeficiency virus (SIV)-infected rhesus macaque model for HIV infection and HAND. Four cohorts of animals were studied: non-infected controls, SIV-infected asymptomatic animals, and SIV-infected AIDS-diseased animals with and without brain-permeant antiretroviral treatment. The antiretroviral utilized was 6-chloro-2',3'-dideoxyguanosine (6-Cl-ddG), a CNS-permeable nucleoside reverse transcriptase inhibitor. Quantitation of granule cells and Purkinje cells, of an established biomarker of SIV infection (gp41), of microglial/monocyte/macrophage markers (IBA-1, CD68, CD163), and of the astroglial marker (GFAP) were used to reveal cell-specific cerebellar responses to lentiviral infection and antiretroviral therapy (ART). The macromolecular integrity of the blood brain barrier was tested by albumin immunohistochemistry. RESULTS: Productive CNS infection was observed in the symptomatic stage of disease, and correlated with extensive microglial/macrophage and astrocyte activation, and widespread macromolecular blood brain barrier defects. Signs of productive infection, and inflammation, were reversed upon treatment with 6-Cl-ddG, except for a residual low-grade activation of microglial cells and astrocytes. There was an extensive loss of granule cells in the SIV-infected asymptomatic cohort, which was further increased in the symptomatic stage of the disease and persisted after 6-Cl-ddG (administered after the onset of symptoms of AIDS). In the symptomatic stage, Purkinje cell density was reduced. Purkinje cell loss was likewise unaffected by 6-Cl-ddG treatment at this time. CONCLUSIONS: Our findings suggest that neurodegenerative mechanisms are triggered by SIV infection early in the disease process, i. e., preceding large-scale cerebellar productive infection and marked neuroinflammation. These affect primarily granule cells early in disease, with later involvement of Purkinje cells, indicating differential vulnerability of the two neuronal populations. The results presented here indicate a role for the cerebellum in neuro-AIDS. They also support the conclusion that, in order to attenuate the development of motor and cognitive dysfunctions in HIV-positive individuals, CNS-permeant antiretroviral therapy combined with anti-inflammatory and neuroprotective treatment is indicated even before overt signs of CNS inflammation occur.

Visualization as irritation: producing knowledge about medieval courts through uncertainty.

Visualizations are ubiquitous in data-driven research, serving as both tools for knowledge production and genuine means of knowledge communication. Despite criticisms targeting the alleged objectivity of visualizations in the digital humanities (DH) and reflections on how they may serve as representations of both scholarly perspective and uncertainty within the data analysis pipeline, there remains a notable scarcity of in-depth theoretical grounding for these assumptions in DH discussions. It is our understanding that only through theoretical foundations such as basic semiotic principles and perspectives on media modality one can fully assess the use and potential of visualizations for innovation in scholarly interpretation. We argue that visualizations have the capacity to "productively irritate" existing scholarly knowledge in a given research field. This does not just mean that visualizations depict patterns in datasets that seem not in line with prior research and thus stimulate deeper examination. Complementarily, "irritation" here consists of visualizations producing uncertainty about their own meaning-yet it is precisely this uncertainty in which the potential for greater insight lies. It stimulates questions about what is depicted and what is not. This turns out to be a valuable resource for scholarly interpretation, and one could argue that visualizing big data is particularly prolific in this sense, because due to their complexity researchers cannot interpret the data without visual representations. However, we argue that "productive irritation" can also happen below the level of big data. We see this potential rooted in the genuinely semiotic and semantic properties of visual media, which studies in multimodality and specifically in the field of Bildlinguistik have carved out: a visualization's holistic overview of data patterns is juxtaposed to its semantic vagueness, which gives way to deep interpretations and multiple perspectives on that data. We elucidate this potential using examples from medieval English legal history. Visualizations of data relating to legal functions and social constellations of various people in court offer surprising insights that can lead to new knowledge through "productive irritation."

A screening for cerebral deoxygenation during VT ablations in patients with structural heart disease.

BACKGROUND: Patients undergoing ventricular tachycardia (VT) ablation often present with structural heart disease (SHD) and reduced ejection fraction. Inducing VT by programmed electrical stimulation (PES) puts these patients at risk for hemodynamic instability and cerebral hypoperfusion. OBJECTIVE: The present study screens for cerebral oxygen desaturation phases (ODPs) in patients undergoing VT ablation. METHODS: Forty-seven patients (age 61 ± 14 years, 72% males) underwent ablation of sustained VT with simultaneous neuromonitoring using near-infrared spectroscopy (NIRS). RESULTS: Analysis of NIRS signal identified ODPs in 29 patients (62%). ODPs were associated with a higher prevalence of ischemic heart disease (IHD) (45% vs. 11%, p = 0.024), previous VT episodes (n = 16 vs. 4, p = 0.018), and VTs inducible by PES (n = 2.4 vs. 1.2, p = 0.004). Patients with ODPs were more likely to be admitted to intensive care unit (ICU) (78% vs. 33%, p = 0.005) and had more in-hospital VT recurrences (24% vs. 0%, p = 0.034). No differences were observed in VT recurrence rates after hospital discharge (41.4% vs. 44.4%, p = 0.60) and left ventricular ejection fraction (34% vs. 38%, p = 0.567). IHD (OR: 32.837, p = 0.006), ICU admission (OR: 14.112, p = 0.013), and the number of VTs inducible at PES (OR: 2.705, p = 0.015) were independently associated with ODPs. CONCLUSIONS: This study registers episodes of cerebral hypoperfusion in 62% of patients undergoing VT ablation and identifies IHD and the number of VTs inducible at PES as possible risk factors for these episodes.

Prognostic value of non-invasive programmed ventricular stimulation after VT ablation to predict VT recurrences.

BACKGROUND: The prognostic value of (non)-invasive programmed ventricular stimulation (NIPS) to predict recurrences of ventricular tachycardia (VT) is under discussion. Optimal endpoints of VT ablation are not well defined, and optimal timepoint of NIPS is unknown. The goal of this study was to evaluate the ability of programmed ventricular stimulation at the end of the VT ablation procedure (PVS) and NIPS after VT ablation to identify patients at high risk for VT recurrence. METHODS: Between January 2016 and February 2022, consecutive patients with VT and structural heart disease undergoing first VT ablation and consecutive NIPS were included. In total, 138 patients were included. All patients underwent NIPS through their implanted ICDs after a median of 3 (1-5) days after ablation (at least 2 drive cycle lengths (500 and 400 ms) and up to four right ventricular extrastimuli until refractoriness). Clinical VT was defined by comparison with 12-lead electrocardiograms and stored ICD electrograms from spontaneous VT episodes. Patients were followed for a median of 37 (13-61) months. RESULTS: Of the 138 patients, 104 were non-inducible (75%), 27 were inducible for non-clinical VTs (20%), and 7 for clinical VT (5%). In 107 patients (78%), concordant results of PVS and NIPS were observed. After 37 ± 20 months, the recurrence rate for any ventricular arrhythmia was 40% (normal NIPS 29% vs. inducible VT during NIPS 66%; log-rank p = 0.001) and for clinical VT was 3% (normal NIPS 1% vs. inducible VT during NIPS 9%; log-rank p = 0.045). Positive predictive value (PPV) and negative predictive value (NPV) of NIPS were higher compared to PVS (PPV: 65% vs. 46% and NPV: 68% vs. 61%). NIPS revealed the highest NPV among patients with ICM and LVEF > 35%. Patients with inducible VT during NIPS had the highest VT recurrences and overall mortality. Patients with both negative PVS and NIPS had the lowest any VT recurrence rates with 32%. Early re-ablation of patients with recurrent VTs during index hospitalization was feasible but did not reveal better long-term VT-free survival. CONCLUSIONS: In patients after VT ablation and structural heart disease, NIPS is superior to post-ablation PVS to stratify the risk of VT recurrences. The PPV and NPV of NIPS at day 3 were superior compared to PVS at the end of the procedure to predict recurrent VT, especially in patients with ICM.

Adaptability and elasticity of the mixed lipid bilayer vesicles containing non-ionic surfactant designed for targeted drug delivery across the skin.

Novel potential carriers for non-invasive drug delivery were prepared from polyoxyethylene(20) oleyl ether (C(18:1)EO(20)) and soybean phosphatidylcholine (SPC) in different relative molar ratios, R(e); this produced stiff SPC liposomes (2r(ves) approximately 120 nm) at one end and much smaller (2r(mic) or= R(e)(sat) = 0.25 in the bilayer. The surfactant-saturated bilayers exhibit bending rigidity of kappa(c) approximately 2.1 k(B)T, as determined with an improved vesicle adaptability assay involving analysis of normalised flux density through a nano-porous barrier as an activated transport process. Pore penetrability vs. driving pressure data measured with the mixed amphiphat vesicles resemble results of computer simulation of deformable vesicles penetrating a constriction [Gompper G, Kroll DM. 1995. Driven transport of fluid vesicles through narrow pores. Phys Rev E Stat Phys Plasmas Fluids Relat Interdiscip Topics. 52:4198-4208], confirming basic similarity of both processes. The improved assay can reveal partial lipid solubilisation at R(e)>R(e)(sat), which is linearly proportional to R(e) - R(e)(sat). C(18:1)EO(20)-SPC mixed vesicles that can cross narrow pores are arguably suitable for targeted drug delivery across intact skin.