Human neuroscience has always been pushing the boundary of what is measurable. During the last decade, concerns about statistical power and replicability - in science in general, but also specifically in human neuroscience - have fueled an extensive debate. One important insight from this discourse is the need for larger samples, which naturally increases statistical power. An alternative is to increase the precision of measurements, which is the focus of this review. This option is often overlooked, even though statistical power benefits from increasing precision as much as from increasing sample size. Nonetheless, precision has always been at the heart of good scientific practice in human neuroscience, with researchers relying on lab traditions or rules of thumb to ensure sufficient precision for their studies. In this review, we encourage a more systematic approach to precision. We start by introducing measurement precision and its importance for well-powered studies in human neuroscience. Then, determinants for precision in a range of neuroscientific methods (MRI, M/EEG, EDA, Eye-Tracking, and Endocrinology) are elaborated. We end by discussing how a more systematic evaluation of precision and the application of respective insights can lead to an increase in reproducibility in human neuroscience.

Effective neutrophil migration to sites of inflammation is crucial for host immunity. A coordinated cascade of steps allows intravascular leukocytes to counteract the shear stress, transmigrate through the endothelial layer, and move toward the extravascular, static environment. Those events are tightly orchestrated by integrins, but, while the molecular mechanisms leading to their activation have been characterized, the regulatory pathways promoting their detachment remain elusive. In light of this, it has long been known that platelet-endothelial cell adhesion molecule (Pecam1, also known as CD31) deficiency blocks leukocyte transmigration at the level of the outer vessel wall, yet the associated cellular defects are controversial. In this study, we combined an unbiased proteomic study with in vitro and in vivo single-cell tracking in mice to study the dynamics and role of CD31 during neutrophil migration. We found that CD31 localizes to the uropod of migrating neutrophils along with closed β2-integrin and is required for essential neutrophil actin/integrin polarization. Accordingly, the uropod of Pecam1-/- neutrophils is unable to detach from the extracellular matrix, while antagonizing integrin binding to extracellular matrix components rescues this in vivo migratory defect. Conversely, we showed that sustaining CD31 co-signaling actively favors uropod detachment and effective migration of extravasated neutrophils to sites of inflammation in vivo. Altogether, our results suggest that CD31 acts as a molecular rheostat controlling integrin-mediated adhesion at the uropod of egressed neutrophils, thereby triggering their detachment from the outer vessel wall to reach the inflammatory sites.

Cell-generated forces play a major role in coordinating the large-scale behavior of cell assemblies, in particular during development, wound healing, and cancer. Mechanical signals propagate faster than biochemical signals, but can have similar effects, especially in epithelial tissues with strong cell-cell adhesion. However, a quantitative description of the transmission chain from force generation in a sender cell, force propagation across cell-cell boundaries, and the concomitant response of receiver cells is missing. For a quantitative analysis of this important situation, here we propose a minimal model system of two epithelial cells on an H-pattern ('cell doublet'). After optogenetically activating RhoA, a major regulator of cell contractility, in the sender cell, we measure the mechanical response of the receiver cell by traction force and monolayer stress microscopies. In general, we find that the receiver cells show an active response so that the cell doublet forms a coherent unit. However, force propagation and response of the receiver cell also strongly depend on the mechano-structural polarization in the cell assembly, which is controlled by cell-matrix adhesion to the adhesive micropattern. We find that the response of the receiver cell is stronger when the mechano-structural polarization axis is oriented perpendicular to the direction of force propagation, reminiscent of the Poisson effect in passive materials. We finally show that the same effects are at work in small tissues. Our work demonstrates that cellular organization and active mechanical response of a tissue are key to maintain signal strength and lead to the emergence of elasticity, which means that signals are not dissipated like in a viscous system, but can propagate over large distances.

Update of doi: 10.1101/2022.04.11.487851.

Decisions about noisy stimuli are widely understood to be made by accumulating evidence up to a decision bound that can be adjusted according to task demands. However, relatively little is known about how such mechanisms operate in continuous monitoring contexts requiring intermittent target detection. Here, we examined neural decision processes underlying detection of 1-second coherence-targets within continuous random dot motion, and how they are adjusted across contexts with Weak, Strong, or randomly Mixed Weak/Strong targets. Our prediction was that decision bounds would be set lower when Weak targets are more prevalent. Behavioural hit and false alarm rate patterns were consistent with this, and were well-captured by a bound-adjustable leaky accumulator model. However, Beta-band EEG signatures of motor preparation contradicted this, instead indicating lower bounds in the Strong-target context. We thus tested two alternative models in which decision bound dynamics were constrained directly by Beta measurements, respectively featuring leaky accumulation with adjustable leak, and non-leaky accumulation of evidence referenced to an adjustable sensory-level criterion. We found that the latter model best explained both behaviour and neural dynamics, highlighting novel means of decision policy regulation and the value of neurally-informed modelling.

Background: Although there are several efficacious vaccines against COVID-19, vaccination rates in many regions around the world remain insufficient to prevent continued high disease burden and emergence of viral variants. Repurposing of existing therapeutics that prevent or mitigate severe COVID-19 could help to address these challenges. The objective of this study was to determine whether prior use of bisphosphonates is associated with reduced incidence and/or severity of COVID-19. Methods: A retrospective cohort study utilizing payer-complete health insurance claims data from 8,239,790 patients with continuous medical and prescription insurance January 1, 2019 to June 30, 2020 was performed. The primary exposure of interest was use of any bisphosphonate from January 1, 2019 to February 29, 2020. Bisphosphonate users were identified as patients having at least one bisphosphonate claim during this period, who were then 1:1 propensity score-matched to bisphosphonate non-users by age, gender, insurance type, primary-care-provider visit in 2019, and comorbidity burden. Main outcomes of interest included: (a) any testing for SARS-CoV-2 infection; (b) COVID-19 diagnosis; and (c) hospitalization with a COVID-19 diagnosis between March 1, 2020 and June 30, 2020. Multiple sensitivity analyses were also performed to assess core study outcomes amongst more restrictive matches between BP users/non-users, as well as assessing the relationship between BP-use and other respiratory infections (pneumonia, acute bronchitis) both during the same study period as well as before the COVID outbreak. Results: 7,906,603 patients for whom continuous medical and prescription insurance information was available were selected. 450,366 bisphosphonate users were identified and 1:1 propensity score-matched to bisphosphonate non-users. Bisphosphonate users had lower odds ratios (OR) of testing for SARS-CoV-2 infection (OR=0.22; 95%CI:0.21-0.23; p<0.001), COVID-19 diagnosis (OR=0.23; 95%CI:0.22-0.24; p<0.001), and COVID-19-related hospitalization (OR=0.26; 95%CI:0.24-0.29; p<0.001). Sensitivity analyses yielded results consistent with the primary analysis. Bisphosphonate-use was also associated with decreased odds of acute bronchitis (OR=0.23; 95%CI:0.22-0.23; p<0.001) or pneumonia (OR=0.32; 95%CI:0.31-0.34; p<0.001) in 2019, suggesting that bisphosphonates may protect against respiratory infections by a variety of pathogens, including but not limited to SARS-CoV-2. Conclusions: Prior bisphosphonate-use was associated with dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations. Prospective clinical trials will be required to establish a causal role for bisphosphonate-use in COVID-19-related outcomes. Funding: This study was supported by NIH grants, AR068383 and AI155865, a grant from MassCPR (to U.H.v.A.) and a CRI Irvington postdoctoral fellowship, CRI2453 (to P.H.).

BACKGROUND: The emergence of new SARS-CoV-2 variants with significant immune-evasiveness, the relaxation of measures for reducing the number of infections, the waning of immune protection (particularly in high-risk population groups), and the low uptake of new vaccine boosters, forecast new waves of hospitalizations and admission to intensive care units. There is an urgent need for easily implementable and clinically effective Early Warning Scores (EWSs) that can predict the risk of complications within the next 24-48 hr. Although EWSs have been used in the evaluation of COVID-19 patients, there are several clinical limitations to their use. Moreover, no models have been tested on geographically distinct populations or population groups with varying levels of immune protection. METHODS: We developed and validated COVID-19 Early Warning Score (COEWS), an EWS that is automatically calculated solely from laboratory parameters that are widely available and affordable. We benchmarked COEWS against the widely used NEWS2. We also evaluated the predictive performance of vaccinated and unvaccinated patients. RESULTS: The variables of the COEWS predictive model were selected based on their predictive coefficients and on the wide availability of these laboratory variables. The final model included complete blood count, blood glucose, and oxygen saturation features. To make COEWS more actionable in real clinical situations, we transformed the predictive coefficients of the COEWS model into individual scores for each selected feature. The global score serves as an easy-to-calculate measure indicating the risk of a patient developing the combined outcome of mechanical ventilation or death within the next 48 hr.The discrimination in the external validation cohort was 0.743 (95% confidence interval [CI]: 0.703-0.784) for the COEWS score performed with coefficients and 0.700 (95% CI: 0.654-0.745) for the COEWS performed with scores. The area under the receiver operating characteristic curve (AUROC) was similar in vaccinated and unvaccinated patients. Additionally, we observed that the AUROC of the NEWS2 was 0.677 (95% CI: 0.601-0.752) in vaccinated patients and 0.648 (95% CI: 0.608-0.689) in unvaccinated patients. CONCLUSIONS: The COEWS score predicts death or MV within the next 48 hr based on routine and widely available laboratory measurements. The extensive external validation, its high performance, its ease of use, and its positive benchmark in comparison with the widely used NEWS2 position COEWS as a new reference tool for assisting clinical decisions and improving patient care in the upcoming pandemic waves. FUNDING: University of Vienna.

Communication is crucial for organismic interactions, from bacteria, to fungi, to humans. Humans may use the visual sense to monitor the environment before starting acoustic interactions. In comparison, fungi, lacking a visual system, rely on a cell-to-cell dialogue based on secreted signaling molecules to coordinate cell fusion and establish hyphal networks. Within this dialogue, hyphae alternate between sending and receiving signals. This pattern can be visualized via the putative signaling protein Soft (SofT), and the mitogen-activated protein kinase MAK-2 (MakB) which are recruited in an alternating oscillatory manner to the respective cytoplasmic membrane or nuclei of interacting hyphae. Here, we show that signal oscillations already occur in single hyphae of Arthrobotrys flagrans in the absence of potential fusion partners (cell monologue). They were in the same phase as growth oscillations. In contrast to the anti-phasic oscillations observed during the cell dialogue, SofT and MakB displayed synchronized oscillations in phase during the monologue. Once two fusion partners came into each other's vicinity, their oscillation frequencies slowed down (entrainment phase) and transit into anti-phasic synchronization of the two cells'; oscillations with frequencies of 104 +/- 28 sec and 117 +/- 19 sec, respectively. Single-cell oscillations, transient entrainment, and anti-phasic oscillations were reproduced by a mathematical model where nearby hyphae can absorb and secrete a limited molecular signaling component into a shared extra-cellular space. We show that intracellular Ca2+ concentrations oscillate in two approaching hyphae, and depletion of Ca2+ from the medium affected vesicle-driven extension of the hyphal tip, abolished the cell monologue and the anti-phasic synchronization of two hyphae. Our results suggest that single hyphae engage in a 'monologue' that may be used for exploration of the environment and can dynamically shift their extra-cellular signaling systems into a 'dialogue' to initiate hyphal fusion.

Update of doi: 10.1101/2021.11.16.468908.

Background: In most of the world, the mammography screening programmes were paused at the start of the pandemic, whilst mammography screening continued in Denmark. We examined the mammography screening participation during the COVID-19 pandemic in Denmark. Methods: The study population comprised all women aged 50-69 years old invited to participate in mammography screening from 2016-2021 in Denmark based on data from the Danish Quality Database for Mammography Screening in combination with population-based registries. Using a generalised linear model, we estimated prevalence ratios (PR) and 95% confidence intervals (CI) of mammography screening participation within 90, 180 and 365 days since invitation during the pandemic in comparison with the previous years adjusting for age, year and month of invitation. Results: The study comprised 1,828,791 invitations among 847,766 women. Before the pandemic, 80.2% of invitations resulted in participation in mammography screening within 90 days, 82.7% within 180 days and 83.1% within 365 days. At the start of the pandemic, the participation in screening within 90 days was reduced to 69.9% for those invited in pre-lockdown and to 76.5% for those invited in 1st lockdown. Extending the length of follow-up time to 365 days only a minor overall reduction was observed (PR=0.94; 95% CI: 0.93-0.95 in pre-lockdown and PR=0.97; 95% CI: 0.96-0.97 in 1st lockdown). A lower participation was; however, seen among immigrants and among women with a low income. Conclusions: The short-term participation in mammography screening was reduced at the start of the pandemic, whilst only a minor reduction in the overall participation was observed with longer follow-up time indicating that women postponed screening. Some groups of women; nonetheless, had a lower participation indicating that the social inequity in screening participation was exacerbated during the pandemic. Funding: The study was funded by the Danish Cancer Society Scientific Committee (grant number R321-A17417) and the Danish regions.

Update of doi: 10.1101/2023.01.23.525162.

Erythroblasts possess unique characteristics as they undergo differentiation from hematopoietic stem cells. During terminal erythropoiesis, these cells incorporate large amounts of iron in order to generate hemoglobin and ultimately undergo enucleation to become mature red blood cells, ultimately delivering oxygen in the circulation. Thus, erythropoiesis is a finely tuned, multifaceted process requiring numerous properly timed physiological events to maintain efficient production of 2 million red blood cells per second in steady state. Iron is required for normal functioning in all human cells, the erythropoietic compartment consuming the majority in light of the high iron requirements for hemoglobin synthesis. Recent evidence regarding the crosstalk between erythropoiesis and iron metabolism sheds light on the regulation of iron availability by erythroblasts and the consequences of insufficient as well as excess iron on erythroid lineage proliferation and differentiation. In addition, significant progress has been made in our understanding of dysregulated iron metabolism in various congenital and acquired malignant and non-malignant diseases. Finally, we report several actual as well as theoretical opportunities for translating the recently acquired robust mechanistic understanding of iron metabolism regulation to improve management of patients with disordered erythropoiesis, such as anemia of chronic inflammation, β-thalassemia, polycythemia vera, and myelodysplastic syndromes.

Update of doi: 10.1101/2021.08.12.456145.