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Abstract Background Mutations in either of two genes comprising the STSL locus, ATP-binding cassette (ABC)-transporters ABCG5 (encoding sterolin-1) and ABCG8 (encoding sterolin-2), result in sitosterolemia, a rare autosomal recessive disorder of sterol trafficking characterized by increased plasma plant sterol levels. Based upon the genetics of sitosterolemia, ABCG5/sterolin-1 and ABCG8/sterolin-2 are hypothesized to function as obligate heterodimers. No phenotypic difference has yet been described in humans with complete defects in either ABCG5 or ABCG8. These proteins, based upon the defects in humans, are responsible for regulating dietary sterol entry and biliary sterol secretion. Methods In order to mimic the human disease, we created, by a targeted disruption, a mouse model of sitosterolemia resulting in Abcg8/sterolin-2 deficiency alone. Homozygous knockout mice are viable and exhibit sitosterolemia. Results Mice deficient in Abcg8 have significantly increased plasma and tissue plant sterol levels (sitosterol and campesterol) consistent with sitosterolemia. Interestingly, Abcg5/sterolin-1 was expressed in both liver and intestine in Abcg8/sterolin-2 deficient mice and continued to show an apical expression. Remarkably, Abcg8 deficient mice had an impaired ability to secrete cholesterol into bile, but still maintained the ability to secrete sitosterol. We also report an intermediate phenotype in the heterozygous Abcg8+/- mice that are not sitosterolemic, but have a decreased level of biliary sterol secretion relative to wild-type mice. Conclusion These data indicate that Abcg8/sterolin-2 is necessary for biliary sterol secretion and that loss of Abcg8/sterolin-2 has a more profound effect upon biliary cholesterol secretion than sitosterol. Since biliary sitosterol secretion is preserved, although not elevated in the sitosterolemic mice, this observation suggests that mechanisms other than by Abcg8/sterolin-2 may be responsible for its secretion into bile. more...

Abstract Micromagnetic Tomography (MMT) is a new technique that allows the determination of magnetic moments of individual grains in volcanic rocks. Current MMT studies either showed that it is possible to obtain magnetic moments of relatively small numbers of grains in ideal sample material or provided important theoretical advances in MMT inversion theory and/or its statistical framework. Here, we present a large‐scale application of MMT on a sample from the 1907‐flow from Hawaii's Kilauea volcano producing magnetic moments of 1,646 grains. We produced 261,305 magnetic moments in total for these 1,646 grains, an increase of three orders of magnitude compared to earlier studies to assess the robustness of the MMT results, and a major step toward the number of grains that is necessary for paleomagnetic applications of MMT. Furthermore, we show that the recently proposed signal strength ratio is a powerful tool to scrutinize and select MMT results. Despite this progress, still only relatively large iron‐oxide grains with diameters >1.5–2 μm can be reliably resolved, impeding a reliable paleomagnetic interpretation. To determine the magnetic moments of smaller ( more...

Preexisting anti–interferon-α (anti–IFN-α) autoantibodies in blood are associated with susceptibility to life-threatening COVID-19. However, it is unclear whether anti–IFN-α autoantibodies in the airways, the initial site of infection, can also determine disease outcomes. In this study, we developed a multiparameter technology, FlowBEAT, to quantify and profile the isotypes of anti–severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and anti–IFN-α antibodies in longitudinal samples collected over 20 months from the airways and blood of 129 donors spanning mild to severe COVID-19. We found that nasal IgA1 anti–IFN-α autoantibodies were induced after infection onset in more than 70% of mild and moderate COVID-19 cases and were associated with robust anti–SARS-CoV-2 immunity, fewer symptoms, and efficient recovery. Nasal anti–IFN-α autoantibodies followed the peak of host IFN-α production and waned with disease recovery, revealing a regulated balance between IFN-α and anti–IFN-α response. In contrast, systemic IgG1 anti–IFN-α autoantibodies appeared later and were detected only in a subset of patients with elevated systemic inflammation and worsening symptoms. These data reveal a protective role for nasal anti–IFN-α in the immunopathology of COVID-19 and suggest that anti–IFN-α autoantibodies may serve a homeostatic function to regulate host IFN-α after viral infection in the respiratory mucosa. Editor's summary: Autoantibodies targeting interferon-α (IFN-α) have been found in the circulation of those with severe COVID-19 and are considered a bad sign for disease progression. However, less is known about IFN-α–specific autoantibodies in other tissues, such as the mucosa. Here, Babcock et al. used a multiparameter flow cytometry technique called FlowBEAT to show that IgA1 autoantibodies targeting IFN-α could be found in the nasal mucosa and were associated with improved responses to SARS-CoV-2. The induction of these anti–IFN-α autoantibodies was temporally linked to a decline in IFN-α itself, suggesting that elicitation of these autoantibodies may be a mechanism to temper inflammation in the respiratory mucosa. These data suggest that there is a complex, location-dependent, role for antibodies against IFN-α and that these antibodies may tip the balance between protection and pathology. —Courtney Malo [ABSTRACT FROM AUTHOR] more...

Recent advances in developmental immunology have revealed a hematopoietic stem cell (HSC)-independent origin for various innate immune lineages, including mast cells (MCs). It is now established that adult bone marrow (BM) long-term HSCs do not regenerate MCs but, instead, the physiological production of MCs starts before the emergence of HSCs in the aorta-gonad-mesonephros (AGM) region and is mostly completed before birth. However, while the AGM region represents a major site of MC generation during ontogeny, whether the first emerging HSCs in the AGM or fetal liver (FL) possess the potential to regenerate MCs is unknown. Here, we combined three fate-mapping mouse models with detailed HSC transplantation assays to determine the potential of AGM and FL HSCs to produce MCs. We show that HSCs from E11.5 AGM and E12.5 FL efficiently repopulated MCs in recipients. In stark contrast, HSCs from ≥E14.5 FL failed to reconstitute MCs. An Endothelial (EC) fate-mapping study confirmed the EC origin of the majority of MCs. Additionally, our HSC-labeling showed that HSCs do not produce MCs in a physiological setting. Hence, although most MCs are generated and maintained via an HSC-independent pathway, the earliest HSCs to emerge in the AGM and seed the early FL can produce MCs, but only during a minimal time window. Our results challenge the stem cell theory in hematology and EC-derived mast cells may contribute to the pathogenesis of postnatal mast cell disorders. more...

We initiate the study of a new class of polynomials which we call quasi-subfield polynomials. First, we show that this class of polynomials could lead to more efficient attacks for the elliptic curve discrete logarithm problem via the index calculus approach. Specifically, we use these polynomials to construct factor bases for the index calculus approach and we provide explicit complexity bounds. Next, we investigate the existence of quasi-subfield polynomials. more...

IntroductionSoundscapes in nursing homes are often suboptimal for residents. This can cause them feeling anxious and unsafe, or develop behavioral and psychological problems. Residents with dementia cannot adapt nursing home environments to their needs due to cognitive and physical limitations. It is up to the staff of psycho-geriatric wards to improve the soundscape. We evaluated the effect of the sound awareness intervention Mobile Soundscape Appraisal and Recording Technology (MoSART+) on soundscapes in nursing homes.MethodsThe MoSART+ intervention was carried out in four nursing homes and took three months in each home. The MoSART+ intervention involved training ambassadors, assessing the soundscape with the MoSART application by the nursing staff to raise their sound awareness on random time points, discussing the measurements, and implementing micro-interventions. Soundscapes were assessed from 0 to 100 on four attributes: pleasantness, eventfulness, complexity, and range of affordances. Based on these scores, soundscapes were classified in four dimensions: calm, lively, boring, and chaotic. Nursing staff graded the environment on a scale of 0 to 10. T-test and Z-tests were used to analyze data.ResultsStaff recorded 1882 measurements with the MoSART app. “People,” “music, TV, and radio,” and “machines and appliances” were the most prevalent sound sources before and after the implementation of micro-interventions. Post-implementation of micro-interventions, soundscapes were pleasant (median 69.0; IQR 54.0–81.0), of low complexity (33.0; 18.0–47.0), uneventful (27.0; 14.0–46.5), and gave moderate affordances (50.0; 35.0–67.0). Changes in attributes were statistically significant (p < 0.01). The proportion of the dimension calm increased (z = 12.7, p < 0.01), the proportion of chaotic decreased (z = 15.0, p < 0.01), and the proportion of lively decreased not statically significant (z = 0.68, p = 0.79). The proportion of boring was unchanged. The proportion of grades ≥6 increased after implementation of the micro-interventions (z = 15.3, p < 0.01). The micro-interventions focused on removing or reducing disturbing sounds and were unique for each nursing home.DiscussionThe MoSART+ intervention resulted in a statistically significantly improvement of soundscapes, and more favorable evaluations of the nursing staff. The intervention empowered staff to adapt soundscapes. Nursing homes can improve soundscapes by raising sound awareness among staff.Trial RegistrationNetherlands National Trial Register (NL6831). more...

Signal transducer and activator of transcription 5 (STAT5a and STAT5b) are intrinsically critical for normal hematopoiesis but are also expressed in stromal cells. Here, STAT5ab knockout (KO) was generated with a variety of bone marrow hematopoietic and stromal Cre transgenic mouse strains. Vav1-Cre/+STAT5abfl/fl, the positive control for loss of multipotent hematopoietic function, surprisingly dysregulated niche factor mRNA expression, and deleted STAT5ab in CD45neg cells. Single-cell transcriptome analysis of bone marrow from Vav1-Cre/+ wild-type or Vav1-Cre/+STAT5abfl/fl mice showed hematopoietic stem cell (HSC) myeloid commitment priming. Nes+ cells were detected in both CD45neg and CD45+ clusters and deletion of STAT5ab with Nes-Cre caused hematopoietic repopulating defects. To follow up on these promiscuous Cre promoter deletions in CD45neg and CD45+ bone marrow cell populations, more stroma-specific Cre strains were generated and demonstrated a reduction in multipotent hematopoietic progenitors. Functional support for niche-supporting activity was assessed using STAT5-deficient mesenchymal stem cells (MSCs). With Lepr-Cre/+STAT5abfl/fl, niche factor mRNAs were downregulated with validation of reduced IGF-1 and CXCL12 proteins. Furthermore, advanced computational analyses revealed a key role for STAT5ab/Cish balance with Cish strongly co-expressed in MSCs and HSCs primed for differentiation. Therefore, STAT5ab-associated gene regulation supports the bone marrow microenvironment. [ABSTRACT FROM AUTHOR] more...

As the "codifier" of Le Spiritisme, the French writer, translator, and educator Allan Kardec (1804-1868) was a prominent figure among the promotors of the occult. The five books he wrote on the spirit world became best-sellers, both in France and abroad. Joyce, whose largely skeptical interest in the occult has been widely researched, owned one of Kardec's works and flagged passages in it. This article considers the varied ways in which Joyce may have used Kardec's teachings and vocabulary (for instance, "metempsychosis," "reincarnation," and "noctambules") in Ulysses. The cabman's shelter of "Eumaeus," in particular, functions as a spirit cabinet fit for a s@ance to be witnessed by Stephen and Bloom, "our two noctambules" (U 16.326). [ABSTRACT FROM AUTHOR] more...

Structural variant (SV) detection is essential for genomic studies, and long-read sequencing technologies have advanced our capacity to detect SVs directly from read or de novo assembly, also known as read-based and assembly-based strategy. However, to date, no independent studies have compared and benchmarked the two strategies. Here, on the basis of SVs detected by 20 read-based and eight assembly-based detection pipelines from six datasets of HG002 genome, we investigated the factors that influence the two strategies and assessed their performance with well-curated SVs. We found that up to 80% of the SVs could be detected by both strategies among different long-read datasets, whereas variant type, size, and breakpoint detected by read-based strategy were greatly affected by aligners. For the high-confident insertions and deletions at non-tandem repeat regions, a remarkable subset of them (82% in assembly-based calls and 93% in read-based calls), accounting for around 4000 SVs, could be captured by both reads and assemblies. However, discordance between two strategies was largely caused by complex SVs and inversions, which resulted from inconsistent alignment of reads and assemblies at these loci. Finally, benchmarking with SVs at medically relevant genes, the recall of read-based strategy reached 77% on 5X coverage data, whereas assembly-based strategy required 20X coverage data to achieve similar performance. Therefore, integrating SVs from read and assembly is suggested for general-purpose detection because of inconsistently detected complex SVs and inversions, whereas assembly-based strategy is optional for applications with limited resources. [ABSTRACT FROM AUTHOR] more...

Micromagnetic Tomography (MMT) is a new technique that allows the determination of magnetic moments of individual grains in volcanic rocks. Current MMT studies either showed that it is possible to obtain magnetic moments of relatively small numbers of grains in ideal sample material or provided important theoretical advances in MMT inversion theory and/or its statistical framework. Here, we present a large‐scale application of MMT on a sample from the 1907‐flow from Hawaii's Kilauea volcano producing magnetic moments of 1,646 grains. We produced 261,305 magnetic moments in total for these 1,646 grains, an increase of three orders of magnitude compared to earlier studies to assess the robustness of the MMT results, and a major step toward the number of grains that is necessary for paleomagnetic applications of MMT. Furthermore, we show that the recently proposed signal strength ratio is a powerful tool to scrutinize and select MMT results. Despite this progress, still only relatively large iron‐oxide grains with diameters >1.5–2 μm can be reliably resolved, impeding a reliable paleomagnetic interpretation. To determine the magnetic moments of smaller (<1 μm) grains that may exhibit pseudo‐single domain behavior and are therefore better paleomagnetic recorders, the resolution of the microcomputed tomography and magnetic scans necessary for MMT must be improved. Therefore, it is necessary to reduce the sample size in future MMT studies. Nevertheless, our study is an important step toward making MMT a useful paleomagnetic and rock‐magnetic technique. Plain Language Summary: The magnetic information of volcanic rocks is an invaluable archive of the behavior of the Earth's magnetic field through time. Recently, a new technique, Micromagnetic Tomography, was proposed that promises to determine the magnetic signals of individual iron‐bearing grains in these rocks. This would greatly improve our ability to obtain and interpret the magnetic information stored in them. Here, we go beyond the proof‐of‐concept of this exciting new technique and show that it is indeed possible to obtain statistically robust results for a set of rather large grains, with diameters >1.5–2 μm, in a sample from the 1907‐flow from Hawaii's Kilauea volcano. Key Points: We studied a sample from the 1907‐flow of Kilauea (Hawaii) with well‐known rock‐magnetic properties using Micromagnetic Tomography (MMT)We performed 16,874 MMT inversions to characterize the magnetic moments of 1,646 grains, resulting in 261,305 magnetic momentsMagnetic moments were found only for grains >1.5–2 μm that exhibit multidomain behavior, but these MMT results are statistically robust [ABSTRACT FROM AUTHOR] more...

The main player in biliary cholesterol secretion is the heterodimeric transporter complex, ABCG5/ABCG8, the function of which is necessary for the majority of sterols secreted into bile. It is not clear whether the primary step in this process is flopping of cholesterol from the inner to the outer leaflet of the canalicular membrane, with desorption by mixed micelles, or decreasing of the activation energy required for cholesterol desorption from the outer membrane leaflet. In this study, we investigated these mechanisms by infusing Abcg8+/+, Abcg8+/−, and Abcg8−/− mice with hydrophilic and hydrophobic bile salts. In Abcg8−/− mice, this failed to substantially stimulate biliary cholesterol secretion. Infusion of the hydrophobic bile salt taurodeoxycholate also resulted in cholestasis, which was induced in Abcg8−/− mice at a much lower infusion rate compared with Abc8−/− and Abcg8+/− mice, suggesting a reduced cholesterol content in the outer leaflet of the canalicular membrane. Indeed, isolation of canalicular membranes revealed a reduction of 45% in cholesterol content under these conditions in Abcg8−/− mice. Our data support the model that ABCG5/ABCG8 primarily play a role in flopping cholesterol (and sterols) from the inner leaflet to the outer leaflet of the canalicular membrane. more...