The ACE inhibitor captopril inhibits ACN-1 to control dauer formation and aging.

The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in Caenorhabditis elegans, Drosophila and rodents, but its mechanism is not well defined. Here, we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril-hypersensitive mutants. We identified a missense mutation that causes a partial loss of function of the daf-2 receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in C. elegans by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of acn-1 via captopril or RNA interference promoted dauer larvae formation, suggesting that acn-1 is a daf gene. Captopril-mediated lifespan extension was abrogated by daf-16(lf) and daf-12(lf) mutations. Our results indicate that captopril and acn-1 influence lifespan by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control.

Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia.

Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome1 (ARDS). Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from that in other types of pneumonia2. Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.

Lysosome-related organelles contain an expansion compartment that mediates delivery of zinc transporters to promote homeostasis.

Zinc is an essential nutrient-it is stored during periods of excess to promote detoxification and released during periods of deficiency to sustain function. Lysosome-related organelles (LROs) are an evolutionarily conserved site of zinc storage, but mechanisms that control the directional zinc flow necessary for homeostasis are not well understood. In Caenorhabditis elegans intestinal cells, the CDF-2 transporter stores zinc in LROs during excess. Here, we identify ZIPT-2.3 as the transporter that releases zinc during deficiency; ZIPT-2.3 transports zinc, localizes to the membrane of LROs in intestinal cells, and is necessary for zinc release from LROs and survival during zinc deficiency. In zinc excess and deficiency, the expression levels of CDF-2 and ZIPT-2.3 are reciprocally regulated at the level of mRNA and protein, establishing a fundamental mechanism for directional flow to promote homeostasis. To elucidate how the ratio of CDF-2 and ZIPT-2.3 is altered, we used super-resolution microscopy to demonstrate that LROs are composed of a spherical acidified compartment and a hemispherical expansion compartment. The expansion compartment increases in volume during zinc excess and deficiency. These results identify the expansion compartment as an unexpected structural feature of LROs that facilitates rapid transitions in the composition of zinc transporters to mediate homeostasis, likely minimizing the disturbance to the acidified compartment.

Alveolar macrophage-derived extracellular vesicles inhibit endosomal fusion of influenza virus.

Alveolar macrophages (AMs) and epithelial cells (ECs) are the lone resident lung cells positioned to respond to pathogens at early stages of infection. Extracellular vesicles (EVs) are important vectors of paracrine signaling implicated in a range of (patho)physiologic contexts. Here we demonstrate that AMs, but not ECs, constitutively secrete paracrine activity localized to EVs which inhibits influenza infection of ECs in vitro and in vivo. AMs exposed to cigarette smoke extract lost the inhibitory activity of their secreted EVs. Influenza strains varied in their susceptibility to inhibition by AM-EVs. Only those exhibiting early endosomal escape and high pH of fusion were inhibited via a reduction in endosomal pH. By contrast, strains exhibiting later endosomal escape and lower fusion pH proved resistant to inhibition. These results extend our understanding of how resident AMs participate in host defense and have broader implications in the defense and treatment of pathogens internalized within endosomes.

Nature 4.0: A networked sensor system for integrated biodiversity monitoring.

Ecosystem functions and services are severely threatened by unprecedented global loss in biodiversity. To counteract these trends, it is essential to develop systems to monitor changes in biodiversity for planning, evaluating, and implementing conservation and mitigation actions. However, the implementation of monitoring systems suffers from a trade-off between grain (i.e., the level of detail), extent (i.e., the number of study sites), and temporal repetition. Here, we present an applied and realized networked sensor system for integrated biodiversity monitoring in the Nature 4.0 project as a solution to these challenges, which considers plants and animals not only as targets of investigation, but also as parts of the modular sensor network by carrying sensors. Our networked sensor system consists of three main closely interlinked components with a modular structure: sensors, data transmission, and data storage, which are integrated into pipelines for automated biodiversity monitoring. We present our own real-world examples of applications, share our experiences in operating them, and provide our collected open data. Our flexible, low-cost, and open-source solutions can be applied for monitoring individual and multiple terrestrial plants and animals as well as their interactions. Ultimately, our system can also be applied to area-wide ecosystem mapping tasks, thereby providing an exemplary cost-efficient and powerful solution for biodiversity monitoring. Building upon our experiences in the Nature 4.0 project, we identified ten key challenges that need to be addressed to better understand and counteract the ongoing loss of biodiversity using networked sensor systems. To tackle these challenges, interdisciplinary collaboration, additional research, and practical solutions are necessary to enhance the capability and applicability of networked sensor systems for researchers and practitioners, ultimately further helping to ensure the sustainable management of ecosystems and the provision of ecosystem services.

Improving health and economic security by reducing work schedule uncertainty.

Work schedules in the service sector are routinely unstable and unpredictable, and this unpredictability may have harmful effects on health and economic insecurity. However, because schedule unpredictability often coincides with low wages and other dimensions of poor job quality, the causal effects of unpredictable work schedules are uncertain. Seattle's Secure Scheduling ordinance, enacted in 2017, mandated greater schedule predictability, providing an opportunity to examine the causal relationship between work scheduling and worker health and economic security. We draw on pre- and postintervention survey data from workers in Seattle and comparison cities to estimate the impacts of this law using a difference-in-differences approach. We find that the law had positive impacts on workers' schedule predictability and stability and led to increases in workers' subjective well-being, sleep quality, and economic security. Using the Seattle law as an instrumental variable, we also estimate causal effects of schedule predictability on well-being outcomes. We show that uncertainty about work time has a substantial effect on workers' well-being, particularly their sleep quality and economic security.

Cadmium hijacks the high zinc response by binding and activating the HIZR-1 nuclear receptor.

Cadmium is an environmental pollutant and significant health hazard that is similar to the physiological metal zinc. In Caenorhabditis elegans, high zinc homeostasis is regulated by the high zinc activated nuclear receptor (HIZR-1) transcription factor. To define relationships between the responses to high zinc and cadmium, we analyzed transcription. Many genes were activated by both high zinc and cadmium, and hizr-1 was necessary for activation of a subset of these genes; in addition, many genes activated by cadmium did not require hizr-1, indicating there are at least two mechanisms of cadmium-regulated transcription. Cadmium directly bound HIZR-1, promoted nuclear accumulation of HIZR-1 in intestinal cells, and activated HIZR-1-mediated transcription via the high zinc activation (HZA) enhancer. Thus, cadmium binding promotes HIZR-1 activity, indicating that cadmium acts as a zinc mimetic to hijack the high zinc response. To elucidate the relationships between high zinc and cadmium detoxification, we analyzed genes that function in three pathways: the pcs-1/phytochelatin pathway strongly promoted cadmium resistance but not high zinc resistance, the hizr-1/HZA pathway strongly promoted high zinc resistance but not cadmium resistance, and the mek-1/sek-1/kinase signaling pathway promoted resistance to high zinc and cadmium. These studies identify resistance pathways that are specific for high zinc and cadmium, as well as a shared pathway.

Cross-modal interactions at the audiovisual cocktail-party revealed by behavior, ERPs, and neural oscillations.

Theories of attention argue that objects are the units of attentional selection. In real-word environments such objects can contain visual and auditory features. To understand how mechanisms of selective attention operate in multisensory environments, in this pre-registered study, we created an audiovisual cocktail-party situation, in which two speakers (left and right of fixation) simultaneously articulated brief numerals. In three separate blocks, informative auditory speech was presented (a) alone or paired with (b) congruent or (c) uninformative visual speech. In all blocks, subjects localized a pre-defined numeral. While audiovisual-congruent and uninformative speech improved response times and speed of information uptake according to diffusion modeling, an ERP analysis revealed that this did not coincide with enhanced attentional engagement. Yet, consistent with object-based attentional selection, the deployment of auditory spatial attention (N2ac) was accompanied by visuo-spatial attentional orienting (N2pc) irrespective of the informational content of visual speech. Notably, an N2pc component was absent in the auditory-only condition, demonstrating that a sound-induced shift of visuo-spatial attention relies on the availability of audio-visual features evolving coherently in time. Additional exploratory analyses revealed cross-modal interactions in working memory and modulations of cognitive control.

Abdominal fat quantification using convolutional networks.

OBJECTIVES: To present software for automated adipose tissue quantification of abdominal magnetic resonance imaging (MRI) data using fully convolutional networks (FCN) and to evaluate its overall performance-accuracy, reliability, processing effort, and time-in comparison with an interactive reference method. MATERIALS AND METHODS: Single-center data of patients with obesity were analyzed retrospectively with institutional review board approval. Ground truth for subcutaneous (SAT) and visceral adipose tissue (VAT) segmentation was provided by semiautomated region-of-interest (ROI) histogram thresholding of 331 full abdominal image series. Automated analyses were implemented using UNet-based FCN architectures and data augmentation techniques. Cross-validation was performed on hold-out data using standard similarity and error measures. RESULTS: The FCN models reached Dice coefficients of up to 0.954 for SAT and 0.889 for VAT segmentation during cross-validation. Volumetric SAT (VAT) assessment resulted in a Pearson correlation coefficient of 0.999 (0.997), relative bias of 0.7% (0.8%), and standard deviation of 1.2% (3.1%). Intraclass correlation (coefficient of variation) within the same cohort was 0.999 (1.4%) for SAT and 0.996 (3.1%) for VAT. CONCLUSION: The presented methods for automated adipose-tissue quantification showed substantial improvements over common semiautomated approaches (no reader dependence, less effort) and thus provide a promising option for adipose tissue quantification. CLINICAL RELEVANCE STATEMENT: Deep learning techniques will likely enable image-based body composition analyses on a routine basis. The presented fully convolutional network models are well suited for full abdominopelvic adipose tissue quantification in patients with obesity. KEY POINTS: • This work compared the performance of different deep-learning approaches for adipose tissue quantification in patients with obesity. • Supervised deep learning-based methods using fully convolutional networks  were suited best. • Measures of accuracy were equal to or better than the operator-driven approach.

Reply to the letter "Understanding lactate and its clearance during extracorporeal membrane oxygenation for supporting refractory cardiogenic shock patients".

This is a reply to the letter titled "Understanding lactate and its clearance during extracorporeal membrane oxygenation for supporting refractory cardiogenic shock patients" by Eva Rully Kurniawati et al. In response to the concerns raised about our paper published in BMC Cardiovascular Disorders, titled "Association between serum lactate levels and mortality in patients with cardiogenic shock receiving mechanical circulatory support: a multicenter retrospective cohort study," we have addressed the confounding bias on the population included and the use of VA-ECMO and Impella CP. Furthermore, we have provided new data on the correlation of oxygen supply and lactate levels at admission of cardiogenic shock.

Racial/ethnic and gender inequities in the sufficiency of paid leave during the COVID-19 pandemic: Evidence from the service sector.

BACKGROUND: Access to paid family and medical leave (PFML), including leave to care for a seriously ill loved one or recover from one's own serious illness, conveys health and economic benefits for workers and their families. However, without a national PFML policy, access to paid leave remains limited and unequal. Previous work documenting inequitable access by socioeconomic status and race/ethnicity primarily focuses on parental leave, measures theoretical access to paid leave rather than actual leave uptake, and lacks an accounting for why workers of color and women may have less access to PFML. We extend this literature by looking at leave-taking for medical needs or caregiving among a high-risk population during the COVID-19 pandemic. METHODS: We draw on data from 2595 service-sector workers surveyed by the Shift Project in 2020 and 2021 to estimate inequities in leave uptake among workers who experienced qualifying events. We then estimate the relative importance of worker demographic characteristics, qualifying event types (medical vs. caregiving leave), proxies for access to state and employer PFML policies, job characteristics, and ultimately within-firm differences to these gaps. RESULTS: Overall, one-fifth of workers reported sufficient leave. Women are significantly more likely than men to report insufficient or no leave. Hispanic and Black workers are more likely to take insufficient or no leave, respectively, but these differences were attenuated when controlling for covariates. CONCLUSIONS: The dearth of PFML laws leaves women and workers of color without access to leave that is paid and of sufficient duration when facing a qualifying event.

Flexible transition timing in discrete-time multistate life tables using Markov chains with rewards.

Discrete-time multistate life tables are attractive because they are easier to understand and apply in comparison with their continuous-time counterparts. While such models are based on a discrete time grid, it is often useful to calculate derived magnitudes (e.g. state occupation times), under assumptions which posit that transitions take place at other times, such as mid-period. Unfortunately, currently available models allow very few choices about transition timing. We propose the use of Markov chains with rewards as a general way of incorporating information on the timing of transitions into the model. We illustrate the usefulness of rewards-based multistate life tables by estimating working life expectancies using different retirement transition timings. We also demonstrate that for the single-state case, the rewards approach matches traditional life-table methods exactly. Finally, we provide code to replicate all results from the paper plus R and Stata packages for general use of the method proposed.

Neuroergonomics on the Go: An Evaluation of the Potential of Mobile EEG for Workplace Assessment and Design.

OBJECTIVE: We demonstrate and discuss the use of mobile electroencephalogram (EEG) for neuroergonomics. Both technical state of the art as well as measures and cognitive concepts are systematically addressed. BACKGROUND: Modern work is increasingly characterized by information processing. Therefore, the examination of mental states, mental load, or cognitive processing during work is becoming increasingly important for ergonomics. RESULTS: Mobile EEG allows to measure mental states and processes under real live conditions. It can be used for various research questions in cognitive neuroergonomics. Besides measures in the frequency domain that have a long tradition in the investigation of mental fatigue, task load, and task engagement, new approaches-like blink-evoked potentials-render event-related analyses of the EEG possible also during unrestricted behavior. CONCLUSION: Mobile EEG has become a valuable tool for evaluating mental states and mental processes on a highly objective level during work. The main advantage of this technique is that working environments don't have to be changed while systematically measuring brain functions at work. Moreover, the workflow is unaffected by such neuroergonomic approaches.

The Gender Wage Gap, Between-Firm Inequality, and Devaluation: Testing a New Hypothesis in the Service Sector.

Unequal sorting of men and women into higher and lower wage firms contributes significantly to the gender wage gap according to recent analysis of national labor markets. We confirm the importance of this between-firm gender segregation in wages and examine a second outcome of hours using unique employer-employee data from the service sector. We then examine what explains the relationship between firm gender composition and wages. In contrast to prevailing economic explanations that trace between-firm differences in wages to differences in firm surplus, we find evidence consistent with devaluation and potentially a gender-specific use of "low road" employment strategies.

The Politics of Prevention: Polarization in How Workplace COVID-19 Safety Practices Shaped the Well-Being of Frontline Service Sector Workers.

The COVID-19 pandemic dramatically reshaped the labor market, especially for service sector workers. Frontline service sector workers, already coping with precarious working conditions, faced proximate risks of COVID-19 transmission on the job and navigated new workplace safety measures, including masking, social distancing, and staying home while sick, all in a polarized political environment. We examine polarization in the effects of COVID-19 workplace safety measures on workers' feelings of safety and well-being. Specifically, we examine how support for former President Trump moderates the relationship between COVID-19 safety practices (masking, social distancing, staying home while sick) and workers' feelings of safety and well-being. To do so, we draw on novel data collected by The Shift Project from 2,039 service sector workers at 89 large firms during the COVID-19 pandemic. We find that workplace safety measures are positively associated with workers' self-assessments of feeling safe and with mental health, but only for Biden voters.

Preparing for the unknown: How working memory provides a link between perception and anticipated action.

What mechanisms underlie the transfer of a working memory representation into a higher-level code for guiding future actions? Electrophysiological correlates of attentional selection and motor preparation processes within working memory were investigated in two retrospective cuing tasks. In the first experiment, participants stored the orientation and location of a grating. Subsequent feature cues (selective vs. neutral) indicated which feature would be the target for later report. The oscillatory response in the mu and beta frequency range with an estimated source in the sensorimotor cortex contralateral to the responding hand was used as correlate of motor preparation. Mu/beta suppression was stronger following the selective feature cues compared to the neutral cue, demonstrating that purely feature-based selection is sufficient to form a prospective motor plan. In the second experiment, another retrospective cue was included to study whether knowledge of the task at hand is necessary to initiate motor preparation. Following the feature cue, participants were cued to either compare the stored feature(s) to a probe stimulus (recognition task) or to adjust the memory probe to match the target feature (continuous report task). An analogous suppression of mu oscillations was observed following a selective feature cue, even ahead of task specification. Further, a subsequent selective task cue again elicited a mu/beta suppression, which was stronger after a continuous report task cue. This indicates that working memory is able to flexibly store different types of information in higher-level mental codes to provide optimal prerequisites for all required action possibilities.

Target enhancement or distractor suppression? Functionally distinct alpha oscillations form the basis of attention.

Recent advances in attention research have been propelled by the debate on target enhancement versus distractor suppression. A predominant neural correlate of attention is the modulation of alpha oscillatory power (~10 Hz), which signifies shifts of attention in time, space and between sensory modalities. However, the underspecified functional role of alpha oscillations limits the progress of tracking down the neurocognitive basis of attention. In this short opinion article, we review and critically examine a synthesis of three conceptual and methodological aspects that are indispensable for a mechanistic understanding of the role of alpha oscillations for attention. (a) Precise mapping of the anatomical source and the temporal response profile of neural signals reveals distinct alpha oscillatory processes that implement facilitatory versus suppressive components of attention. (b) A testable framework enables unanimous association of alpha modulation with either target enhancement or different forms of distractor suppression (active vs. automatic). (c) Linking anatomically specified alpha oscillations to behavior reveals the causal nature of alpha oscillations for attention. The three reviewed aspects substantially enrich study design, data analysis and interpretation of results to achieve the goal of understanding how anatomically specified and functionally relevant neural oscillations contribute to the implementation of facilitatory versus suppressive components of attention.

The role of informational content of visual speech in an audiovisual cocktail party: Evidence from cortical oscillations in young and old participants.

Age-related differences in the processing of audiovisual speech in a multi-talker environment were investigated analysing event-related spectral perturbations (ERSPs), focusing on theta, alpha and beta oscillations that are assumed to reflect conflict processing, multisensory integration and attentional mechanisms, respectively. Eighteen older and 21 younger healthy adults completed a two-alternative forced-choice word discrimination task, responding to audiovisual speech stimuli. In a cocktail-party scenario with two competing talkers (located at -15° and 15° azimuth), target words (/yes/or/no/) appeared at a pre-defined (attended) position, distractor words at the other position. In two audiovisual conditions, acoustic speech was combined either with informative or uninformative visual speech. While a behavioural benefit for informative visual speech occurred for both age groups, differences between audiovisual conditions in the theta and beta band were only present for older adults. A stronger increase in theta perturbations for stimuli containing uninformative visual speech could be associated with early conflict processing, while a stronger suppression in beta perturbations for informative visual speech could be associated to audiovisual integration. Compared to the younger group, the older group showed generally stronger beta perturbations. No condition differences in the alpha band were found. Overall, the findings suggest age-related differences in audiovisual speech integration in a multi-talker environment. While the behavioural benefit of informative visual speech was unaffected by age, older adults had a stronger need for cognitive control when processing conflicting audiovisual speech input. Furthermore, mechanisms of audiovisual integration are differently activated depending on the informational content of the visual information.

Alternatives to animal models and their application in the discovery of species susceptibility to SARS-CoV-2 and other respiratory infectious pathogens: A review.

The emergence of the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) inspired rapid research efforts targeting the host range, pathogenesis and transmission mechanisms, and the development of antiviral strategies. Genetically modified mice, rhesus macaques, ferrets, and Syrian golden hamsters have been frequently used in studies of pathogenesis and efficacy of antiviral compounds and vaccines. However, alternatives to in vivo experiments, such as immortalized cell lines, primary respiratory epithelial cells cultured at an air-liquid interface, stem/progenitor cell-derived organoids, or tissue explants, have also been used for isolation of SARS-CoV-2, investigation of cytopathic effects, and pathogen-host interactions. Moreover, initial proof-of-concept studies for testing therapeutic agents can be performed with these tools, showing that animal-sparing cell culture methods could significantly reduce the need for animal models in the future, following the 3R principles of replace, reduce, and refine. So far, only few studies using animal-derived primary cells or tissues have been conducted in SARS-CoV-2 research, although natural infection has been shown to occur in several animal species. Therefore, the need for in-depth investigations on possible interspecies transmission routes and differences in susceptibility to SARS-CoV-2 is urgent. This review gives an overview of studies employing alternative culture systems like primary cell cultures, tissue explants, or organoids for investigations of the pathophysiology and reverse zoonotic potential of SARS-CoV-2 in animals. In addition, future possibilities of SARS-CoV-2 research in animals, including previously neglected methods like the use of precision-cut lung slices, will be outlined.

What's to Like? Facebook as a Tool for Survey Data Collection.

In this paper, we explore the use of Facebook targeted advertisements for the collection of survey data. We illustrate the potential of survey sampling and recruitment on Facebook through the example of building a large employee-employer linked dataset as part of The Shift Project. We describe the workflow process of targeting, creating, and purchasing survey recruitment advertisements on Facebook. We address concerns about sample selectivity, and apply post-stratification weighting techniques to adjust for differences between our sample and that of "gold-standard" data sources. We then compare univariate and multi-variate relationships in the Shift data against the Current Population Survey and the National Longitudinal Survey of Youth-1997. Finally, we provide an example of the utility of the firm-level nature of the data by showing how firm-level gender composition is related to wages. We conclude by discussing some important remaining limitations of the Facebook approach, as well as highlighting some unique strengths of the Facebook targeting advertisement approach, including the ability for rapid data collection in response to research opportunities, rich and flexible sample targeting capabilities, and low cost, and we suggest broader applications of this technique.