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Leguminous tree root nodule nitrogen-fixing bacteria are critical for recuperation of soil C and N cycle processes after disturbance in tropical forests, while other nodule-associated bacteria (NAB) may enhance nodule development and activity, and plant growth. However, little is known of these root nodule microbiomes. Through DNA analysis, we evaluated the bacterial taxa associated with the root nodules of the 1-year-old, 2-year-old, 13-year-old, and old growth Inga punctata trees in a cloud forest. Bradyrhizobium diazoefficiens was the dominant taxon found in all nodules at 63.16% to 85.71% mean percent sequences (MPS) of the total nodule bacterial DNA and was found in the youngest nodules examined (1 year old), suggesting that it is the primary nodular bacteria. There were 26 other NAB genera with collective MPS levels between 7.4% to 12.2%, while 15 of these genera were found in the Bulk Forest soils at collective MPS levels of 4.6%. These bacterial community compositions were different between the NAB and Bulk Forest soils, suggesting the NAB became concentrated within the root nodules, resulting in communities with different compositions from the Bulk Forest soils. Twenty-three of the 26 NAB genera were previously identified with the potential to perform 9 plant growth promoting (PGP) activities, suggesting their importance in root nodule development and plant growth. These NAB communities appeared to successionally develop over time into more complex taxonomic communities, which is consistent with the outcome of advanced microbial communities following succession. The presence of both B. diazoefficiens and the NAB communities in the nodules across all ages of tree roots, and the potential for PGP activities linked with most of the NAB genera, suggest the importance of B. diazoefficiens and the NAB community for nodule development and enhanced development and growth of I. punctata throughout its lifespan, and most critically in the younger plants.

Abstract In the present study road safety impact analysis for certain advanced driver assistance systems (ADAS) was conducted. Based on a literature review, expert interviews and current adaptations in legislation, the most promising nine ADAS were selected. The impact was analysed based on statistical crash data from Austria. Factors such as infrastructure and weather conditions, market penetration, expected functionality of sensors, user acceptance and risk homeostasis were considered. A software tool was developed to calculate the crash reduction potential of the selected ADAS for the scenarios 2025, 2030 and 2040. The results show that the ADAS related to warning/braking have the greatest future reduction potential and could lead to a reduction of up to 8,700 crashes and 70 fatalities in Austria in 2040. In addition, the Intelligent Speed Assistance system would lead to an overall crash reduction of 8% compared to current crash numbers in Austria in 2040. The Turning Assistant for heavy goods vehicles shows the lowest reduction in crashes and casualties, but due to the highest severity per crash (93 fatalities per 1,000 crashes), it nevertheless provides an important contribution to the reduction of fatalities in road traffic. However, to benefit from the ADAS safety potential, it is highly relevant that these systems are used in a correct manner. In the future, it will be necessary to provide users with more information on the correct use, benefits and limitations of the respective ADAS and to integrate the use of these systems into driver education procedures and tests.

Transcriptional profiles of Caenorhabditis elegans grown on unmethylated sterols (desMSs) or on 4α-methylsterols (4MSs) were compared using microarrays. Thirty-four genes were upregulated and 2 were downregulated >2-fold by growth on 4MSs, including 13 cuticle collagen (col) genes, 1 cuticulin gene (cut-1), 2 groundhog-like (grl) genes, and 1 groundhog gene (grd-4); col-36 and grl-20 were increased 12- and 19-fold, respectively. Fifteen of these 17 genes have been assigned to metabolic mountain 17, suggesting coordinate 4MS-mediated regulation of expression. Quantitative RT-PCR was performed on 27–51 h old animals grown on cholesterol (a desMS) or lophenol (a 4MS). col-36 and grl-20 showed similar cyclic peaks of expression in cholesterol and similar alterations in lophenol, suggesting coregulation. Of six additional grl genes, only grl-3 was upregulated on lophenol; the rest were downregulated. Cyclicity of expression was lost or altered in all six. Nuclear receptor genes nhr-23, nhr-25, nhr-41, and daf-12 all showed cyclic expression in cholesterol and significant downregulation in lophenol by RT-PCR. Expression of the insulin-like receptor daf-2 was lower in lophenol, whereas that of its major downstream target daf-16 was higher. Thus, major changes in gene expression accompany growth on 4MSs, but with surprisingly little effect on normal growth and development.

Abstract One of the major consequences of the COVID-19 pandemic has been the significant incidence of persistent fatigue following resolution of an acute infection (i.e. post-COVID fatigue). We have shown previously that, in comparison to healthy controls, those suffering from post-COVID fatigue exhibit changes in muscle physiology, cortical circuitry, and autonomic function. Whether these changes preceded infection, potentially predisposing people to developing post-COVID fatigue, or whether the changes were a consequence of infection was unclear. Here we present results of a 12-month longitudinal study of 18 participants from the same cohort of post-COVID fatigue sufferers to investigate these correlates of fatigue over time. We report improvements in self-perception of the impact of fatigue via questionnaires, as well as significant improvements in objective measures of peripheral muscle fatigue and autonomic function, bringing them closer to healthy controls. Additionally, we found reductions in muscle twitch tension rise times, becoming faster than controls, suggesting that the improvement in muscle fatigability might be due to a process of adaptation rather than simply a return to baseline function.

Neutrophils are critical for the direct eradication of Aspergillus fumigatus conidia, but whether they mediate antifungal defense beyond their role as effectors is unclear. In this study, we demonstrate that neutrophil depletion impairs the activation of protective antifungal CCR2+ inflammatory monocytes. In the absence of neutrophils, monocytes displayed limited differentiation into monocyte-derived dendritic cells, reduced formation of reactive oxygen species, and diminished conidiacidal activity. Upstream regulator analysis of the transcriptional response in monocytes predicted a loss of STAT1-dependent signals as the potential basis for the dysfunction seen in neutrophil-depleted mice. We find that conditional removal of STAT1 on CCR2+ cells results in diminished antifungal monocyte responses, whereas exogenous administration of IFN-γ to neutrophil-depleted mice restores monocyte-derived dendritic cell maturation and reactive oxygen species production. Altogether, our findings support a critical role for neutrophils in antifungal immunity not only as effectors but also as important contributors to antifungal monocyte activation, in part by regulating STAT1-dependent functions.

Abstract Background Adult T-cell leukemia (ATL) is a complex and multifaceted disease associated with human T-cell leukemia virus type 1 (HTLV-I) infection. Tax, the viral oncoprotein, is considered a major contributor to cell cycle deregulation in HTLV-I transformed cells by either directly disrupting cellular factors (protein-protein interactions) or altering their transcription profile. Tax transactivates these cellular promoters by interacting with transcription factors such as CREB/ATF, NF-κB, and SRF. Therefore by examining which factors upregulate a particular set of promoters we may begin to understand how Tax orchestrates leukemia development. Results We observed that CTLL cells stably expressing wild-type Tax (CTLL/WT) exhibited aneuploidy as compared to a Tax clone deficient for CREB transactivation (CTLL/703). To better understand the contribution of Tax transactivation through the CREB/ATF pathway to the aneuploid phenotype, we performed microarray analysis comparing CTLL/WT to CTLL/703 cells. Promoter analysis of altered genes revealed that a subset of these genes contain CREB/ATF consensus sequences. While these genes had diverse functions, smaller subsets of genes were found to be involved in G2/M phase regulation, in particular kinetochore assembly. Furthermore, we confirmed the presence of CREB, Tax and RNA Polymerase II at the p97Vcp and Sgt1 promoters in vivo through chromatin immunoprecipitation in CTLL/WT cells. Conclusion These results indicate that the development of aneuploidy in Tax-expressing cells may occur in response to an alteration in the transcription profile, in addition to direct protein interactions.

Abstract Background A major goal of cancer research is to identify discrete biomarkers that specifically characterize a given malignancy. These markers are useful in diagnosis, may identify potential targets for drug development, and can aid in evaluating treatment efficacy and predicting patient outcome. Microarray technology has enabled marker discovery from human cells by permitting measurement of steady-state mRNA levels derived from thousands of genes. However many challenging and unresolved issues regarding the acquisition and analysis of microarray data remain, such as accounting for both experimental and biological noise, transcripts whose expression profiles are not normally distributed, guidelines for statistical assessment of false positive/negative rates and comparing data derived from different research groups. This study addresses these issues using Affymetrix HG-U95A and HG-U133 GeneChip data derived from different research groups. Results We present here a simple non parametric approach coupled with noise filtering to identify sets of genes differentially expressed between the normal and cancer states in oral, breast, lung, prostate and ovarian tumors. An important feature of this study is the ability to integrate data from different laboratories, improving the analytical power of the individual results. One of the most interesting findings is the down regulation of genes involved in tissue differentiation. Conclusions This study presents the development and application of a noise model that suppresses noise, limits false positives in the results, and allows integration of results from individual studies derived from different research groups.

Abstract Long COVID, the prolonged illness and fatigue suffered by a small proportion of those infected with SARS‐CoV‐2, is placing an increasing burden on individuals and society. A Physiological Society virtual meeting in February 2022 brought clinicians and researchers together to discuss the current understanding of long COVID mechanisms, risk factors and recovery. This review highlights the themes arising from that meeting. It considers the nature of long COVID, exploring its links with other post‐viral illnesses such as myalgic encephalomyelitis/chronic fatigue syndrome, and highlights how long COVID research can help us better support those suffering from all post‐viral syndromes. Long COVID research started particularly swiftly in populations routinely monitoring their physical performance – namely the military and elite athletes. The review highlights how the high degree of diagnosis, intervention and monitoring of success in these active populations can suggest management strategies for the wider population. We then consider how a key component of performance monitoring in active populations, cardiopulmonary exercise training, has revealed long COVID‐related changes in physiology – including alterations in peripheral muscle function, ventilatory inefficiency and autonomic dysfunction. The nature and impact of dysautonomia are further discussed in relation to postural orthostatic tachycardia syndrome, fatigue and treatment strategies that aim to combat sympathetic overactivation by stimulating the vagus nerve. We then interrogate the mechanisms that underlie long COVID symptoms, with a focus on impaired oxygen delivery due to micro‐clotting and disruption of cellular energy metabolism, before considering treatment strategies that indirectly or directly tackle these mechanisms. These include remote inspiratory muscle training and integrated care pathways that combine rehabilitation and drug interventions with research into long COVID healthcare access across different populations. Overall, this review showcases how physiological research reveals the changes that occur in long COVID and how different therapeutic strategies are being developed and tested to combat this condition.

Glioblastoma (GBM) is the most common and aggressive human brain tumor. Human cytomegalovirus (HCMV) immediate-early (IE) proteins that are endogenously expressed in GBM cells are strong viral transactivators with oncogenic properties. Here, we show how HCMV IEs are preferentially expressed in glioma stem-like cells (GSC), where they colocalize with the other GBM stemness markers, CD133, Nestin, and Sox2. In patient-derived GSCs that are endogenously infected with HCMV, attenuating IE expression by an RNAi-based strategy was sufficient to inhibit tumorsphere formation, Sox2 expression, cell-cycle progression, and cell survival. Conversely, HCMV infection of HMCV-negative GSCs elicited robust self-renewal and proliferation of cells that could be partially reversed by IE attenuation. In HCMV-positive GSCs, IE attenuation induced a molecular program characterized by enhanced expression of mesenchymal markers and proinflammatory cytokines, resembling the therapeutically resistant GBM phenotype. Mechanistically, HCMV/IE regulation of Sox2 occurred via inhibition of miR-145, a negative regulator of Sox2 protein expression. In a spontaneous mouse model of glioma, ectopic expression of the IE1 gene (UL123) specifically increased Sox2 and Nestin levels in the IE1-positive tumors, upregulating stemness and proliferation markers in vivo. Similarly, human GSCs infected with the HCMV strain Towne but not the IE1-deficient strain CR208 showed enhanced growth as tumorspheres and intracranial tumor xenografts, compared with mock-infected human GSCs. Overall, our findings offer new mechanistic insights into how HCMV/IE control stemness properties in GBM cells.

Every movement ends in a period of stillness. Current models assume that commands that hold the limb at a target location do not depend on the commands that moved the limb to that location. Here, we report a surprising relationship between movement and posture in primates: on a within-trial basis, the commands that hold the arm and finger at a target location depend on the mathematical integration of the commands that moved the limb to that location. Following damage to the corticospinal tract, both the move and hold period commands become more variable. However, the hold period commands retain their dependence on the integral of the move period commands. Thus, our data suggest that the postural controller possesses a feedforward module that uses move commands to calculate a component of hold commands. This computation may arise within an unknown subcortical system that integrates cortical commands to stabilize limb posture.

Biodiversity data support conservation research and inform conservation decisions addressing the wicked problem of biodiversity loss. However, these data often need processing and compilation before use, which exceed the time availability of professional scientists. Nevertheless, scientists can recruit, train, and support a network of citizen scientists to prepare these data using online platforms. Here, we describe three citizen science projects sponsored by the Arkansas Natural Heritage Commission to transcribe and georeference historic herbarium specimens and document current biodiversity through iNaturalist for two highly biodiverse and rapidly developing counties in Northwest Arkansas, USA. Citizen science-generated data will be used in a county natural heritage inventory (CNHI) report, including a comprehensive list of taxa tied to voucher specimens and records for rare plant populations. Since the CNHI project started in 2018, citizen scientists have transcribed 8855 and georeferenced 2636 specimen records. From iNaturalist observations, 125 rare plant populations of 39 taxa have been documented. This CNHI report will determine the most critical taxa, habitats, and sites for conservation action in the region and will inform conservation stakeholders at the local, state, and federal levels as they engage in land acquisition, ecological restoration, natural resource management, planning of growth and development, and environmental review/regulation.

Mycobacterium tuberculosis the causative agent of tuberculosis affects millions of people worldwide. New tools for treatment and prevention of tuberculosis are urgently needed. We previously showed that a ferritin (bfrB) mutant of M. tuberculosis has altered iron homeostasis and increased sensitivity to antibiotics and to microbicidal effectors produced by activated macrophages. Most importantly, M. tuberculosis lacking BfrB is strongly attenuated in mice, especially, during the chronic phase of infection. In this study, we examined whether immunization with a bfrB mutant could confer protection against subsequent infection with virulent M. tuberculosis in a mouse model. The results show that the protection elicited by immunization with the bfrB mutant is comparable to BCG vaccination with respect to reduction of bacterial burden. However, significant distinctions in the disease pathology and host genome-wide lung transcriptome suggest improved containment of Mtb infection in animals vaccinated with the bfrB mutant, compared to BCG. We found that downmodulation of inflammatory response and enhanced fibrosis, compared to BCG vaccination, is associated with the protective response elicited by the bfrB mutant.

The existing literature on young and elderly drivers indicates that they have the highest crash risks compared to other age groups of drivers. This study improves our understanding of the risk factors contributing to young and elderly drivers' elevated crash risk by examining self-report data from the E -Survey of Road User's Safety Attitudes (ESRA). The primary objective of this study is to compare the attitudes and behaviours of young, elderly, and middle-age drivers in Canada, the United States, and Europe. The main focus is on the practice of driving while distracted by mobile phones and driving while fatigued, as these are two dangerous behaviours that demonstrate the impact age may have. The analyses consistently showed that there are differences in the responses attributable to age. In all regions, drivers aged 18–21 years consistently reported higher rates of distracted and fatigued driving and higher rates of perceived social and personal acceptability of these behaviours than drivers aged 35–54 years. Elderly drivers aged 65+ years reported even lower rates of these behaviours and acceptability. Young drivers were also the least likely to believe that distraction and fatigue are frequent causes of road crashes, while elderly drivers were the most likely to believe this. This pattern with respect to age repeats in the support for policy measures as well; young drivers are least likely to support zero tolerance policies for mobile phone use when driving, while elderly drivers are the most likely to support this measure. Multivariate logistic regression modeling confirmed that elderly drivers were the least likely to engage in the use of mobile phones while driving or driving while fatigued. Statistically significant results showed that the middle-age group was less likely than young drivers to read a text message/email or check social media while driving and driving while fatigued. • Young drivers (18–21 years) reported higher rates of distracted and fatigued driving than middle-age drivers (35–54 years). • Young drivers also showed higher rates of perceived social and personal acceptability of these behaviours. • Elderly drivers (65+ years) reported even lower rates of these behaviours and acceptability. • These trends are consistent across Canada, the United States, and Europe. [ABSTRACT FROM AUTHOR]

Developments in the field of automated mobility will greatly change our mobility and the possibilities to get from one place to another. This paper presents different scenarios for personal mobility in Austria, anticipating the possibilities and developments in the field of automated vehicles (AVs). The scenarios were developed using a systematically formalized scenario technique and expand the social and political discourse on automated mobility, which is currently characterized by a lack of experience and visibility as an established transport service. Using system dynamics modeling techniques, i.e., the Metropolitan Activity Relocation Simulator (MARS), impacts of the scenarios on the Austrian transportation system are estimated. The simulations show that, without suitable transport policy measures, automated mobility will lead to a significant increase in the volume of individual traffic and to modal shift effects with lower traffic volumes for public transport, walking and cycling. In addition, without a link between AVs and post-fossil propulsion systems, increases in pollutant emissions can also be expected. In contrast, the simulation results of an increased use of AVs in public transport show positive effects for the support of a more sustainable mobility. Hence, transport policy measures accompanying the introduction and development of automated vehicles will be needed in the future to reach a sustainable development.

The existing literature on young and elderly drivers indicates that they have the highest crash risks compared to other age groups of drivers. This study improves our understanding of the risk factors contributing to young and elderly drivers' elevated crash risk by examining self-report data from the E-Survey of Road User's Safety Attitudes (ESRA). The primary objective of this study is to compare the attitudes and behaviours of young, elderly, and middle-age drivers in Canada, the United States, and Europe. The main focus is on the practice of driving while distracted by mobile phones and driving while fatigued, as these are two dangerous behaviours that demonstrate the impact age may have. The analyses consistently showed that there are differences in the responses attributable to age. In all regions, drivers aged 18–21 years consistently reported higher rates of distracted and fatigued driving and higher rates of perceived social and personal acceptability of these behaviours than drivers aged 35–54 years. Elderly drivers aged 65+ years reported even lower rates of these behaviours and acceptability. Young drivers were also the least likely to believe that distraction and fatigue are frequent causes of road crashes, while elderly drivers were the most likely to believe this. This pattern with respect to age repeats in the support for policy measures as well; young drivers are least likely to support zero tolerance policies for mobile phone use when driving, while elderly drivers are the most likely to support this measure. Multivariate logistic regression modeling confirmed that elderly drivers were the least likely to engage in the use of mobile phones while driving or driving while fatigued. Statistically significant results showed that the middle-age group was less likely than young drivers to read a text message/email or check social media while driving and driving while fatigued.

Here, Colangeli et al. use a human household contact cohort to measure the rate of mutation and evolution of Mycobacterium tuberculosis strains and find that long term latency is characterized by reduced mutation rates compared to latency in the first year, coinciding with clinical risk of developing active TB.

Abstract Chimeric Antigen Receptor (CAR) immunotherapy utilizes genetically-engineered immune cells that express a unique cell surface receptor that combines tumor antigen specificity with immune cell activation. In recent clinical trials, the adoptive transfer of CAR-modified immune cells (including CAR-T and CAR-NK cells) into patients has been remarkably successful in treating multiple refractory blood cancers. To improve safety and efficacy, and expand potential applicability to other cancer types, CARs with different target specificities and sequence modifications are being developed and tested by many laboratories. Despite the overall progress in CAR immunotherapy, conventional tools to design and evaluate the efficacy and safety of CAR immunotherapies can be inaccurate, time-consuming, costly, and labor-intensive. Furthermore, existing tools cannot always determine how responsive individual patients will be to a particular CAR immunotherapy. Recent work in our laboratory suggests that the quality of the immunological synapse (IS) can accurately predict CAR-modified cell efficacy (and toxicity) that can correlate with clinical outcomes. Here we review current efforts to develop a Synapse Predicts Efficacy (SPE) system for easy, rapid and cost-effective evaluation of CAR-modified immune cell immunotherapy. Ultimately, we hypothesize the conceptual basis and clinical application of SPE will serve as an important parameter in evaluating CAR immunotherapy and significantly advance precision cancer immunotherapy. Video abstract Graphical abstract Graphic abstract for manuscript CCAS-D-20-00136 by Liu, D., et al., ‘The Role of Immunological Synapse in Predicting the Efficacy of Chimeric Antigen Receptor (CAR) Immunotherapy”. The various branches of evaluating cancer immunotherapy metaphorically represented as a Rubik’s cube. The development of a novel approach to predict the effectiveness of Chimeric Antigen Receptor (CAR)-modified cells by quantifying the quality of CAR IS will introduce a new parameter to the rapidly expanding field of cancer immunotherapy. Currently, no single parameter can predict the clinical outcome or efficacy of a specific type of CAR-modified cell. IS quality will serve as a quantifiable measure to evaluate CAR products and can be used in conjunction with other conventional parameters to form a composite clinical predictor. Much like a Rubik’s cube has countless configurations, several methods and combinations of clinical metrics have arisen for evaluating the ability of a given immunotherapeutic strategy to treat cancer. The quality of IS depicting cancer immunotherapy is metaphorically expressed as a Rubik’s cube. Each face/color represents one aspect of cancer therapy. Each grid in one face indicates one factor within that aspect of cancer therapy. For example, the green color represents the tumor microenvironment, and one out of the nine grids in the green color indicates suppressor cells (suppressors in green). Changes in one factor may completely alter the entire strategy of cancer therapy. However, the quality of IS (illuminated center red grid) makes the effectiveness of CAR immunotherapy predictable.

The potential rise of automated vehicles (AVs) may significantly impact future traffic volumes, in turn affecting urban street designs and adjacent land use. While integrated studies on potential traffic and land-use changes due to AVs largely concern issues of location choice and changing settlement patterns, assessments of how AVs may influence the quality of streets depending on the requirements of adjacent land use remain scarce. This paper presents an integrated assessment of the urban effect of AVs on traffic and neighborhoods in Vienna. It provides a methodology to assess whether changing traffic volumes are compatible with the land use of a given neighborhood to approximate street space requirements for shared automated shuttles and to visualize possible trajectories of spatial transformation by considering local development goals. The results show that the opportunities to convert street space and the risks of environmental harm due to AVs will vary across neighborhoods and street typologies. It is crucial for policymakers and planners to consider such contextual differences to gain better insight into the functional requirements and urban consequences of AVs. This assessment aims to shed light on the possible trade-offs of a system change in favor of AVs to help evaluate adequate operational conditions and inform proactive traffic and urban design policies to harness possible implications.