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High-risk groups, including Indigenous people, are at risk of severe COVID-19. Here we found that Australian First Nations peoples elicit effective immune responses to COVID-19 BNT162b2 vaccination, including neutralizing antibodies, receptor-binding domain (RBD) antibodies, SARS-CoV-2 spike-specific B cells, and CD4+ and CD8+ T cells. In First Nations participants, RBD IgG antibody titers were correlated with body mass index and negatively correlated with age. Reduced RBD antibodies, spike-specific B cells and follicular helper T cells were found in vaccinated participants with chronic conditions (diabetes, renal disease) and were strongly associated with altered glycosylation of IgG and increased interleukin-18 levels in the plasma. These immune perturbations were also found in non-Indigenous people with comorbidities, indicating that they were related to comorbidities rather than ethnicity. However, our study is of a great importance to First Nations peoples who have disproportionate rates of chronic comorbidities and provides evidence of robust immune responses after COVID-19 vaccination in Indigenous people.

Nucleic acids are one of the most important cellular components. These molecules have been studied both experimentally and theoretically. As all-atom simulations are still limited to short time scales, coarse-grain modeling allows to study of those molecules on a longer time scale. Nucleic-Acid united RESidue (NARES-2P) is a low-resolution coarse-grained model with two centers of interaction per repeating unit. It has been successfully applied to study DNA self-assembly and telomeric properties. This force field enables the study of nucleic acids Behavior on a long time scale but lacks atomistic details. In this article, we present new software to reconstruct atomistic details from the NARES-2P model. It has been applied to RNA pseudoknot, nucleic acid four-way junction, G-quadruplex and DNA duplex converted to NARES-2P model and back. Moreover, it was applied to DNA structure folded and self-assembled with NARES-2P.

The goal of this paper is to provide insight about the effect of acceleration saturation in the car-following model. In this contribution, we consider a heterogeneous, mixed-traffic scenario which contains both human-driven and autonomous vehicles subjected to time delays. Corresponding stability charts are provided from which one can tune the control parameters of the automated vehicles to achieve smooth traffic flow. By taking into account the acceleration saturation, it modifies the global behaviour of the system and reduces the range of the optimal technological parameters. On a demonstrative example, we highlight the complex dynamical phenomenon induced by the saturation and we attempt to connect these nonlinear investigations to the engineering practice and point out their relevance.

The ability to manipulate light and liquids on integrated optofluidics chips has spurred a myriad of important developments in biology, medicine, chemistry and display technologies. Here we show how the convergence of optofluidics and metasurface optics can lead to conceptually new platforms for the dynamic control of light fields. We first demonstrate metasurface building blocks that display an extreme sensitivity in their scattering properties to their dielectric environment. These blocks are then used to create metasurface-based flat optics inside microfluidic channels where liquids with different refractive indices can be directed to manipulate their optical behaviour. We demonstrate the intensity and spectral tuning of metasurface colour pixels as well as on-demand optical elements. We finally demonstrate automated control in an integrated meta-optofluidic platform to open up new display functions. Combined with large-scale microfluidic integration, our dynamic-metasurface flat-optics platform could open up the possibility of dynamic display, imaging, holography and sensing applications.

TAR DNA binding protein 43 (TDP-43) pathology is a key feature of over 95% of amyotrophic lateral sclerosis (ALS) and nearly half of frontotemporal dementia (FTD) cases. The pathogenic mechanisms of TDP-43 dysfunction are poorly understood, however, activation of cell stress pathways may contribute to pathogenesis. We, therefore, sought to identify which cell stress components are critical for driving disease onset and neurodegeneration in ALS and FTD. We studied the rNLS8 transgenic mouse model, which expresses human TDP-43 with a genetically-ablated nuclear localisation sequence within neurons of the brain and spinal cord resulting in cytoplasmic TDP-43 pathology and progressive motor dysfunction. Amongst numerous cell stress-related biological pathways profiled using qPCR arrays, several critical integrated stress response (ISR) effectors, including CCAAT/enhancer-binding homologous protein (Chop/Ddit3) and activating transcription factor 4 (Atf4), were upregulated in the cortex of rNLS8 mice prior to disease onset. This was accompanied by early up-regulation of anti-apoptotic gene Bcl2 and diverse pro-apoptotic genes including BH3-interacting domain death agonist (Bid). However, pro-apoptotic signalling predominated after onset of motor phenotypes. Notably, pro-apoptotic cleaved caspase-3 protein was elevated in the cortex of rNLS8 mice at later disease stages, suggesting that downstream activation of apoptosis drives neurodegeneration following failure of early protective responses. Unexpectedly, suppression of Chop in the brain and spinal cord using antisense oligonucleotide-mediated silencing had no effect on overall TDP-43 pathology or disease phenotypes in rNLS8 mice. Cytoplasmic TDP-43 accumulation therefore causes very early activation of ISR and both anti- and pro-apoptotic signalling that switches to predominant pro-apoptotic activation later in disease. These findings suggest that precise temporal modulation of cell stress and death pathways may be beneficial to protect against neurodegeneration in ALS and FTD.

Aggregation of the RNA-binding protein, TDP-43, is the unifying hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43-related neurodegeneration involves multiple changes to normal physiological TDP-43, which undergoes nuclear depletion, cytoplasmic mislocalisation, post-translational modification, and aberrant liquid–liquid phase separation, preceding inclusion formation. Along with toxic cytoplasmic aggregation, concurrent depletion and dysfunction of normal nuclear TDP-43 in cells with TDP-43 pathology is likely a key potentiator of neurodegeneration, but is not well understood. To define processes driving TDP-43 dysfunction, we used CRISPR/Cas9-mediated fluorescent tagging to investigate how disease-associated stressors and pathological TDP-43 alter abundance, localisation, self-assembly, aggregation, solubility, and mobility dynamics of normal nuclear TDP-43 over time in live cells. Oxidative stress stimulated liquid–liquid phase separation of endogenous TDP-43 into droplet-like puncta, or spherical shell-like anisosomes. Further, nuclear RNA-binding-ablated or acetylation-mimicking TDP-43 readily sequestered and depleted free normal nuclear TDP-43 into dynamic anisosomes, in which recruited endogenous TDP-43 proteins remained soluble and highly mobile. Large, phosphorylated inclusions formed by nuclear or cytoplasmic aggregation-prone TDP-43 mutants also caused sequestration, but rendered endogenous TDP-43 immobile and insoluble, indicating pathological transition. These findings suggest that RNA-binding deficiency and post-translational modifications including acetylation exacerbate TDP-43 aggregation and dysfunction by driving sequestration, mislocalisation, and depletion of normal nuclear TDP-43 in neurodegenerative diseases.

In this contribution, we examine the evolution of surface errors during consecutive milling operations. Its description is based on a nonlinear implicit map, which is suitable to investigate the surface quality. It describes the series of consecutive Surface Location Errors (SLE) in roughing operations. As one of the principal results of the paper, bifurcations related to the fixed point of the implicit map are analyzed via normal form theorem. We determined a formula for the criticality of the bifurcation, which allows the approximate computation of the arising period-two solution. The method is demonstrated for the surface error model of milling, and the results are verified by numerical computations. Although the amplitude of the SLE would be negligible, its derivatives has a great influence in the model, which can cause stability problems.

B cells, which are critical for intestinal homeostasis, remain understudied in ulcerative colitis (UC). In this study, we recruited three cohorts of patients with UC (primary cohort, n = 145; validation cohort 1, n = 664; and validation cohort 2, n = 143) to comprehensively define the landscape of B cells during UC-associated intestinal inflammation. Using single-cell RNA sequencing, single-cell IgH gene sequencing and protein-level validation, we mapped the compositional, transcriptional and clonotypic landscape of mucosal and circulating B cells. We found major perturbations within the mucosal B cell compartment, including an expansion of naive B cells and IgG(+) plasma cells with curtailed diversity and maturation. Furthermore, we isolated an auto-reactive plasma cell clone targeting integrin αvβ6 from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing TFH-like T peripheral helper cells that were associated with the pathogenic B cell response. Finally, across all three cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that correlates with disease activity and predicts disease complications. Our data demonstrate a highly dysregulated B cell response in UC and highlight a potential role of B cells in disease pathogenesis.

To assess the accuracy of radiographs in detecting the lateral plateau involvement of medial tibial plateau fractures as well as describe the impact of CT on preoperative planning for this specific fracture morphology. Radiograph and CT imaging of patients with a Schatzker type IV tibial plateau fractures (AO/OTA 41-B1.2, B1.3 h, B2.2. B3.2, and B3.3) between January 2013 and July 2017 were reviewed by three trauma fellowship-trained orthopedic surgeons to identify fractures of the medial condyle with an intact anterolateral articular surface. Lateral plateau involvement was identified in 16 (37%) radiographs and 26 (61%) CT images (p = 0.051). Radiographic detection of lateral plateau involvement demonstrated a sensitivity of 62% and specificity of 100%, and radiographs were able to predict the recommendation for surgical intervention for lateral plateau involvement with a positive predictive value (PPV) of 75% and a negative predictive value (NPV) of 60% compared to recommendations based on CT imaging. Radiographs predicted a need for a separate surgical approach with PPV of 63% and NPV of 70% when compared to recommendations based on CT images. Radiographs are reliable in ruling in lateral plateau involvement of medial plateau fractures, but occult lateral articular extension may only be identified in CT imaging for some cases. Surgical planning may be impacted by CT imaging for this fracture morphology, but further study is warranted to evaluate the correlation between preoperative planning and clinical outcomes. III.

3D printing is an emerging educational technology that is said to prepare learners for a more technologically designed world. In this review, 3D printing studies are analyzed to identify the dominant theoretical approaches and learning outcomes associated with 3D printing in education. Five theories are identified, including situated learning (Lave & Wenger, 1991), experiential learning (Kolb & Kolb Academy of Management Learning & Education, 4, 193- 212, Kolb & Kolb, 2005), and critical making (Ratto in The Information Society, 27, 252-260, 2011), but concepts from constructionism (Papert & Harel Constructionism, 36, 1-11, 1991) and self-directed learning (Garrison Adult Education Quarterly, 48, 18-33, 1997; Knowles, 1975) are common amongst all approaches. Learning outcomes attributed to 3D printing include critical thinking, creativity, design thinking, and collaboration (Trust et al., 2018; Trust & Maloy Computers in the Schools: Interdisciplinary Journal of Practice, Theory, and Applied Research, 34, 253-266, 2017), with proponents arguing that the domain general outcomes go beyond knowing simply how to use a 3D printer. Given the identified, theoretical approaches, outcomes, and common barriers to use, recommendations are made for how educators approach and implement 3D printing in the classroom.

Silvopasture is the intentional integration of trees, forages, and livestock. Benefits of this agroforestry practice include shade for livestock, nutritious forage, and reduced wind speed in pastures, as well as ecosystem services and tree products. The literature indicate that some livestock producers are interested in silvopasture, but little is known about their establishment preferences and if they vary by demographics or operation type. This study hypothesized that producers are equally interested in planting trees in pastures (planting) and reducing forest canopy and planting forages (thinning) to establish silvopasture, and that the effects of the potential benefits of silvopasture on their preferences are similar. To test these hypotheses, 307 livestock producers in Virginia, United States of America were surveyed about whether they prefer planting or thinning. Producers also were asked about the extent to which potential benefits of silvopasture affect their preferences. Nearly 25% of the 139 respondents (response rate = 45%) were 'very interested' in thinning, compared to 8% for planting. Animal performance and welfare was their primary goal, but forest management and whole-farm productivity also were important. Guidelines are needed for maintaining stand health and productivity when thinning and for improving tree protection and growth in pastures when planting to establish silvopasture. Published version Public domain – authored by a U.S. government employee

Time sometimes feels like it is flying by or slowing down. Previous research indicates objective number of items, subjective affect, and heart rate all can influence the experience of time. While these factors are usually tested in isolation with simple stimuli in the laboratory, here we examined them together in the ecological context of a virtual subway ride. We hypothesized that subjective affective experience associated with objective crowding lengthens subjective trip duration. Participants (The online version contains supplementary material available at 10.1007/s10055-022-00713-8.

Metal ions play important biological roles e.g.: activation or deactivation of enzymatic reactions and signal transduction. Moreover, they can stabilize protein structure, or even be actively involved in the protein folding process. Therefore, accurate treatment of the ions is crucial to model and investigate biological phenomena properly. In this work the coarse-grained UNRES (UNited RESidue) force field was extended to include the interactions between proteins and four alkali or alkaline earth metal cations of biological significance, i.e. calcium, magnesium, sodium and potassium. Additionally, chloride anions were introduced as counter-ions. Parameters were derived from all-atom simulations and incorporate water in an implicit manner. The new force field was tested on the set of the proteins and was able to reproduce the ion-binding preferences.