Multiple sclerosis is a leading cause of neurological disability in adults. Heterogeneity in multiple sclerosis clinical presentation has posed a major challenge for identifying genetic variants ...associated with disease outcomes. To overcome this challenge, we used prospectively ascertained clinical outcomes data from the largest international multiple sclerosis registry, MSBase. We assembled a cohort of deeply phenotyped individuals of European ancestry with relapse-onset multiple sclerosis. We used unbiased genome-wide association study and machine learning approaches to assess the genetic contribution to longitudinally defined multiple sclerosis severity phenotypes in 1813 individuals. Our primary analyses did not identify any genetic variants of moderate to large effect sizes that met genome-wide significance thresholds. The strongest signal was associated with rs7289446 (β = -0.4882, P = 2.73 × 10-7), intronic to SEZ6L on chromosome 22. However, we demonstrate that clinical outcomes in relapse-onset multiple sclerosis are associated with multiple genetic loci of small effect sizes. Using a machine learning approach incorporating over 62 000 variants together with clinical and demographic variables available at multiple sclerosis disease onset, we could predict severity with an area under the receiver operator curve of 0.84 (95% CI 0.79-0.88). Our machine learning algorithm achieved positive predictive value for outcome assignation of 80% and negative predictive value of 88%. This outperformed our machine learning algorithm that contained clinical and demographic variables alone (area under the receiver operator curve 0.54, 95% CI 0.48-0.60). Secondary, sex-stratified analyses identified two genetic loci that met genome-wide significance thresholds. One in females (rs10967273; βfemale = 0.8289, P = 3.52 × 10-8), the other in males (rs698805; βmale = -1.5395, P = 4.35 × 10-8), providing some evidence for sex dimorphism in multiple sclerosis severity. Tissue enrichment and pathway analyses identified an overrepresentation of genes expressed in CNS compartments generally, and specifically in the cerebellum (P = 0.023). These involved mitochondrial function, synaptic plasticity, oligodendroglial biology, cellular senescence, calcium and G-protein receptor signalling pathways. We further identified six variants with strong evidence for regulating clinical outcomes, the strongest signal again intronic to SEZ6L (adjusted hazard ratio 0.72, P = 4.85 × 10-4). Here we report a milestone in our progress towards understanding the clinical heterogeneity of multiple sclerosis outcomes, implicating functionally distinct mechanisms to multiple sclerosis risk. Importantly, we demonstrate that machine learning using common single nucleotide variant clusters, together with clinical variables readily available at diagnosis can improve prognostic capabilities at diagnosis, and with further validation has the potential to translate to meaningful clinical practice change.
Microscopy based on the interferometric detection of light scattered from nanoparticles (iSCAT) was introduced in our laboratory more than a decade ago. In this work, we present various capabilities ...of iSCAT for biological studies by discussing a selection of our recent results. In particular, we show tracking of lipid molecules in supported lipid bilayers (SLBs), tracking of gold nanoparticles with diameters as small as 5 nm and at frame rates close to 1 MHz, 3D tracking of Tat peptide-coated nanoparticles on giant unilamellar vesicles (GUVs), imaging the formation of lipid bilayers, sensing single unlabelled proteins and tracking their motion under electric fields, as well as challenges of studying live cell membranes. These studies set the ground for future quantitative research on dynamic biophysical processes at the nanometer scale.
•User experience is impacted by interaction style and conversation types in customer service chatbots.•Conversations that explore a topic of interest may strengthen perceived anthropomorphism and ...hedonic user experience compared to conversations aimed towards a narrow goal.•Button interaction may strengthen pragmatic and hedonic user experience compared to free text interaction, but not impact perceived anthropomorphism.•Conversation type may impact the perceived anthropomorphism in chatbots without impacting social presence.
Understanding the user experience of chatbots for customer service is essential to realize the potential of this technology. Such chatbots are typically designed for efficient and effective interactions, accentuating pragmatic quality, and there is a need to understand how to make these more pleasant and engaging, strengthening hedonic quality. One promising approach is to design for more humanlike chatbot interactions, that is, interactions resembling those of skilled customer service personnel. In a randomized experiment (n = 35) we investigated two chatbot interaction design features that may strengthen the impression of a humanlike character: (a) topic-led conversations, encouraging customer reflection, in contrast to task-led conversations, aiming for efficient goal completion, and (b) free text interaction, where users interact mainly using their own words, rather than button interaction, where users mainly interact through predefined answer alternatives. dependent variables were participant perceptions of anthropomorphism and social presence, two key concepts related to chatbot human likeness, in addition to pragmatic quality and hedonic quality. To further explore user perceptions of the interaction designs, the study also included semi-structured interviews. Topic-led conversations were found to strengthen anthropomorphism and hedonic quality. A similar effect was not found for free text interaction, reportedly due to lack in chatbot flexibility and adaptivity. Implications for theory and practice are suggested.
Determining the material properties and existing capacity of concrete infrastructure using nondestructive techniques is challenging due to evolving design requirements, unknown as-built conditions, ...and ongoing maintenance and deterioration. Concrete’s material properties, including density, porosity, and compressive strength, are usually determined by mechanical testing, but being able to measure these properties noninvasively could aid engineers in maintaining and designing concrete infrastructure. Research into nondestructive methods for determining material properties of concrete has shown relationships between mechanical properties and ground penetrating radar (GPR) properties such as dielectric constant, attenuation, and instantaneous amplitude. We investigated direct relationships between dielectric constant and the density, porosity, and compressive strength of 23 mature concrete samples with varying mix designs using a commercial 1 GHz GPR. In normal-weight concrete, weak trends were seen between a dielectric for compressive strength (R2=0.76) and one for density (R2=0.64), whereas no significant trend was found with porosity (R2=0.52). The GPR unit used provides acceptable data but has limited resolution for analyses and utility. The dielectrics showed distinct clustering by mix type—particularly the inclusion of materials such as blast furnace slag. While demonstrating that the dielectric constant is a candidate for rapid concrete comparisons, there is also a demonstrated need for further investigation of the complex relationships between mechanical and electromagnetic properties in concrete.
The International Multiple Sclerosis Genetics Consortium and MultipleMS Consortium recently reported a genetic variant associated with multiple sclerosis (MS) severity. However, it remains unclear if ...these variants remain associated with more robust, longitudinal measures of disease severity.
We examined the top variant, rs10191329, from Harroud et al.'s study in 1813 relapse-onset MS patients from the MSBase Registry to assess association with longitudinal disease severity.
Our analysis revealed no significant association between rs10191329 genotype and longitudinal binary disease severity (
> 0.05).
These findings highlight the complexity of genetic factors mediating long-term MS outcomes and the need for further research.
Main conclusion
Natural selection influenced adaptive divergence between
Cereus fernambucensis
and
Cereus insularis
, revealing key genes governing abiotic stress responses and supporting neoteny in
...C. insularis
.
Uncovering the molecular mechanisms driving adaptive divergence in traits related to habitat adaptation remains a central challenge. In this study, we focused on the cactus clade, which includes
Cereus sericifer
F.Ritter,
Cereus fernambucensis
Lem., and
Cereus insularis
Hemsley. These allopatric species inhabit distinct relatively drier regions within the Brazilian Atlantic Forest, each facing unique abiotic conditions. We leveraged whole transcriptome data and abiotic variables datasets to explore lineage-specific and environment-specific adaptations in these species. Employing comparative phylogenetic methods, we identified genes under positive selection (PSG) and examined their association with non-synonymous genetic variants and abiotic attributes through a PhyloGWAS approach. Our analysis unveiled signatures of selection in all studied lineages, with
C. fernambucensis
northern populations and
C. insularis
showing the most PSGs. These PSGs predominantly govern abiotic stress regulation, encompassing heat tolerance, UV stress response, and soil salinity adaptation. Our exclusive observation of gene expression tied to early developmental stages in
C. insularis
supports the hypothesis of neoteny in this species. We also identified genes associated with abiotic variables in independent lineages, suggesting their role as environmental filters on genetic diversity. Overall, our findings suggest that natural selection played a pivotal role in the geographic range of these species in response to environmental and biogeographic transitions.
Abstract Cereus jamacaru is a cactus distributed in Northeastern Brazil, with high symbolic value to this region. However, the interaction, behavior and the role of pollinators remains poorly ...understood. Here, we investigate the reproductive biology, addressing the ecological significance of floral attributes, including details about floral signaling. The study was carried at three areas of the Caatinga, in 2015, 2017 and 2021. We analyzed the floral morphometry, volume and concentration of the nectar, and characterized the colour and scent of flowers. Additionally, we described the pollinator behavior and performed controlled pollination experiments. The ‘Mandacaru’ is self-incompatible, has nocturnal anthesis and the nectar is accumulated as droplets in a long hypanthial tube. The flowers have a reflective pattern with a dark outer surface and a white inner surface. (E)-nerolidol is the major component (87.4%) of its floral perfume. We registered the sphingid moth Cocytius antaeus visiting the flowers. The floral attributes, attractants and rewards drives to a sphingophily, and the pollination treatments showed the dependence to fruit set by C. antaeus, the pollinator registered. In this case, if the apparent lack of pollinator diversity encompasses its entire range, the loss of the hawkmoth could severely impact the reproductive success of the cactus.
Acute Lymphoblastic Leukemia (ALL) is the most common pediatric cancer, and patients with relapsed ALL have a poor prognosis. Detection of ALL blasts remaining at the end of treatment, or minimal ...residual disease (MRD), and spread of ALL into the central nervous system (CNS) have prognostic importance in ALL. Current methods to detect MRD and CNS disease in ALL rely on the presence of ALL blasts in patient samples. Cell-free DNA, or small fragments of DNA released by cancer cells into patient biofluids, has emerged as a robust and sensitive biomarker to assess cancer burden, although cfDNA analysis has not previously been applied to ALL.
We present a simple and rapid workflow based on NanoporeMinION sequencing of PCR amplified B cell-specific rearrangement of the (IGH) locus in cfDNA from B-ALL patient samples. A cohort of 5 pediatric B-ALL patient samples was chosen for the study based on the MRD and CNS disease status.
Quantitation of IGH-variable sequences in cfDNA allowed us to detect clonal heterogeneity and track the response of individual B-ALL clones throughout treatment. cfDNA was detected in patient biofluids with clinical diagnoses of MRD and CNS disease, and leukemic clones could be detected even when diagnostic cell-count thresholds for MRD were not met. These data suggest that cfDNA assays may be useful in detecting the presence of ALL in the patient, even when blasts are not physically present in the biofluid sample.
The Nanopore IGH detection workflow to monitor cell-free DNA is a simple, rapid, and inexpensive assay that may ultimately serve as a valuable complement to traditional clinical diagnostic approaches for ALL.
Here, a set of experiments to assess the feasibility of using an invasive and widespread freshwater mussel (Dreissena rostrformis bugensis) as a sentinel species for nanoplastic detection is ...reported. Under laboratory experimental conditions, mussels ingest and retain fluorescent polystyrene (PS) beads with carboxylic acid (COOH) termination over a size range of 200–2000 nm. The number of beads the mussels ingested is quantified using fluorescence spectroscopy and the location of the beads in the mussels is imaged using fluorescence microscopy. PS beads of similar size (1000–2000 nm) to mussels' preferred food are trafficked in the ciliated food grooves of the gills. Beads of all sizes are observed in the mussels' digestive tracts, indicating that the mussels do not efficiently reject the beads as unwanted foreign material, regardless of size. Fluorescence microscopy shows all sizes of beads are concentrated in the siphons and are retained there for longer than one month postexposure. Combined atomic force microscopy–infrared spectroscopy and photothermal infrared spectroscopy are used to locate, image, and chemically identify the beads in the mussel siphons. In sum, these experiments demonstrate the potential for using mussels, specifically their siphons, to monitor environmental accumulation of aquatic nanoplastics.
Can quagga mussels (Dreissena rostriformis bugensis), a widespread and invasive freshwater species that alters local ecosystems, act as a sentinel species for detecting nanoplastics? In the laboratory, mussels ingest and retain 200–2000 nm fluorescent polystyrene beads, which are in the size range for the mussels' preferred food and are trafficked like food in the ciliated grooves of the gills.
Ikaros family DNA-binding proteins are critical regulators of B-cell development. Because the current knowledge of Ikaros targets in B-cell progenitors is limited, we have identified genes that are ...bound and regulated by Ikaros in pre-B cells. To elucidate the role of Ikaros in B-cell lineage specification and differentiation, we analyzed the differential expression of Ikaros targets during the progression of multipotent to lymphoid-restricted progenitors, B- and T-cell lineage specification, and progression along the B-cell lineage. Ikaros targets accounted for one-half of all genes up-regulated during B-cell lineage specification in vivo, explaining the essential role of Ikaros in this process. Expression of the Ikaros paralogs Ikzf1 and Ikzf3 increases incrementally during B-cell progenitor differentiation, and, remarkably, inducible Ikaros expression in cycling pre-B cells was sufficient to drive transcriptional changes resembling the differentiation of cycling to resting pre-B cells in vivo. The data suggest that Ikaros transcription factor dosage drives the progression of progenitors along a predetermined lineage by regulating multiple targets in key pathways, including pre-B–cell receptor signaling, cell cycle progression, and lymphocyte receptor rearrangement. Our approach may be of general use to map the contribution of transcription factors to cell lineage commitment and differentiation.
•We identify genes that are bound and regulated by Ikaros in pre-B cells.•Ikaros dosage drives the differentiation of cycling (Fr.C') to resting (Fr.D) pre-B cells.
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