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Derailed cytokine and immune cell networks account for the organ damage and the clinical severity of COVID-19 (refs. .sup.1-4). Here we show that SARS-CoV-2, like other viruses, evokes cellular senescence as a primary stress response in infected cells. Virus-induced senescence (VIS) is indistinguishable from other forms of cellular senescence and is accompanied by a senescence-associated secretory phenotype (SASP), which comprises pro-inflammatory cytokines, extracellular-matrix-active factors and pro-coagulatory mediators.sup.5-7. Patients with COVID-19 displayed markers of senescence in their airway mucosa in situ and increased serum levels of SASP factors. In vitro assays demonstrated macrophage activation with SASP-reminiscent secretion, complement lysis and SASP-amplifying secondary senescence of endothelial cells, which mirrored hallmark features of COVID-19 such as macrophage and neutrophil infiltration, endothelial damage and widespread thrombosis in affected lung tissue.sup.1,8,9. Moreover, supernatant from VIS cells, including SARS-CoV-2-induced senescence, induced neutrophil extracellular trap formation and activation of platelets and the clotting cascade. Senolytics such as navitoclax and a combination of dasatinib plus quercetin selectively eliminated VIS cells, mitigated COVID-19-reminiscent lung disease and reduced inflammation in SARS-CoV-2-infected hamsters and mice. Our findings mark VIS as a pathogenic trigger of COVID-19-related cytokine escalation and organ damage, and suggest that senolytic targeting of virus-infected cells is a treatment option against SARS-CoV-2 and perhaps other viral infections. Virus-induced senescence is a central pathogenic feature in COVID-19, and senolytics, which promote apoptosis of senescent cells, can reduce disease severity in hamsters,mice, as well as humans infected with SARS-CoV-2., Author(s): Soyoung Lee [sup.1] [sup.2] [sup.3] , Yong Yu [sup.4] , Jakob Trimpert [sup.5] , Fahad Benthani [sup.4] , Mario Mairhofer [sup.4] , Paulina Richter-Pechanska [sup.1] , Emanuel Wyler [sup.2] [...]

Multi-axis mechanical stress sensors have become an important tool in numerous fields. To characterize the quality and resolution of a new stress sensor, researchers use test platforms to apply controlled amounts of shear and normal stresses. Since commercially available multi-axis test platforms are expensive, in many cases researchers end up needing to build their own sensor characterization platforms. In this study, we describe a cost-effective multi-axis stress sensor characterization platform to reduce development time, enable accurate benchmarking and provide an open source standard for stress sensor characterization for other researchers. In our design, we combined a 3-axis translational stage and a 3-axis force and torque (F/T) sensor through custom hardware and software. Our platform is cost effective and can reach the limits of the F/T sensor (Fxy = ±65 N and Fz = ±200 N) without losing any accuracy to structural bending. We provide detailed construction and operation instructions as well as results of extensive static and cyclic load experiments. To further validate our system, we show characterization results from a custom stress sensor as a case study. The modular nature of our platform also enables other researchers to customize this characterization platform for their unique experimental requirements. Keywords: Mechanical characterization, Stress sensor design, Testing stage, Stress sensor calibration

Stress can modulate the recruitment of multiple memory systems during learning, favouring dorsal striatal "habit" learning over hippocampal "cognitive" learning. Here, we tested whether stress may also bias the engagement of "cognitive" and "habit" systems during retrieval and thereby affect the nature of remembering. To this end, participants first performed a probabilistic classification learning task that can be solved by both the "cognitive" and the "habit" system. Twenty‐four hours later, participants underwent either a stress manipulation or a non‐stressful control procedure before they completed a retention test for the previously learned task in the MRI scanner. During this retention test, stress‐induced cortisol levels were linked to a relative bias towards behavioural strategies indicative for the "habit" system. At the neural level, stress led to increased dorsal striatal activity during retrieval. Elevated cortisol levels were directly correlated with increased activity in the dorsal striatum and further linked to reduced functional connectivity between the hippocampus and the amygdala, which is assumed to orchestrate the stress‐related shift from "cognitive" to "habitual" control. Together, our data suggest that stress may bias the contributions of multiple memory systems also at retrieval, in a manner that promotes dorsal striatal "habit" processes and most likely driven by cortisol. [ABSTRACT FROM AUTHOR]

Although the generalization of fear to stimuli resembling a threatening stimulus is an adaptive mechanism, fear overgeneralization is maladaptive and thought to play a key role in anxiety‐related disorders. Since there is typically a delay between an initial fear experience and a situation in which fear (over)generalization may occur, we assessed delayed fear generalization and its neural signature. Moreover, as stress is known to affect fear learning, we further tested whether acute stress modulates fear generalization. Therefore, we conducted a two‐day fear generalization study, with initial fear acquisition on Day 1 and a fear generalization test after a 24‐hr delay in the MRI scanner. Prior to fear generalization testing, participants were exposed to a stressor or a control manipulation. Our behavioral data showed the expected generalization of fear. At a neural level, fear generalization was accompanied by increased fear‐signaling for stimuli that resembled the conditioned stimulus in the bilateral insula and frontal operculum, whereas activity declined in frontal, hippocampal, and temporal regions, including the ventromedial prefrontal cortex, as stimuli became more similar to the conditioned stimulus. Importantly, stress did not modulate fear generalization, neither on a behavioral nor on a neural level. Interestingly, in an explorative comparison to two other studies that used the same paradigm but tested generalization immediately after acquisition, we observed increased fear generalization in the delayed relative to the immediate generalization test. In sum, our results suggest that stress leaves fear generalization and its neural signature unaffected but that a temporal delay might increase the extent to which fear responses are generalized to stimuli resembling the threatening stimulus. Our results add new information on the (neural) process of fear generalization. We show that an experience of acute stress shortly before a test of fear generalization does not seem to have an effect on fear generalization and its neural underpinnings in a population of healthy young individuals. Interestingly, however, compared to an immediate test, delayed fear generalization appeared to be increased on a behavioral and neural level, whereas the underlying neural mechanisms remain the same as in an immediate test of fear generalization. These results point to the potential importance of time in fear generalization. [ABSTRACT FROM AUTHOR]

Over the past three decades, functional magnetic resonance imaging (fMRI) has become crucial to study how cognitive processes are implemented in the human brain. However, the question of whether participants recruited into fMRI studies differ from participants recruited into other study contexts has received little to no attention. This is particularly pertinent when effects fail to generalize across study contexts: for example, a behavioural effect discovered in a non-imaging context not replicating in a neuroimaging environment. Here, we tested the hypothesis, motivated by preliminary findings (N  = 272), that fMRI participants differ from behaviour-only participants on one fundamental individual difference variable: trait anxiety. Analysing trait anxiety scores and possible confounding variables from healthy volunteers across multiple institutions (N  = 3317), we found robust support for lower trait anxiety in fMRI study participants, consistent with a sampling or self-selection bias. The bias was larger in studies that relied on phone screening (compared with full in-person psychiatric screening), recruited at least partly from convenience samples (compared with community samples), and in pharmacology studies. Our findings highlight the need for surveying trait anxiety at recruitment and for appropriate screening procedures or sampling strategies to mitigate this bias. [ABSTRACT FROM AUTHOR]

Background: Applicability of thrombin generation tests to clinical routine has been sought for many years. The aim of this study was to compare thrombin generation measured in fresh platelet poor plasma (f-PPP) and frozenthawed platelet poor plasma (ft-PPP) to prove the consistency of results. Methods: In this prospective study, thrombin generation was measured in twenty-fold repetitions in 3.2% citrate PPP obtained from male healthy blood donors aged 19 - 39 years (n = 54 donations). The tests were performed with fresh PPP and repeated after storing the PPP at -60°C. In two subgroup analyses, the effect of higher and lower normal baseline platelet counts on the Calibrated Automated Thrombogram (CAT) assay and the influence of ABO blood groups on thrombin generation were analyzed. Results: Referring to the parameters of thrombin generation most frequently used in studies, peak thrombin of f- PPP and ft-PPP agreed in about 50% of the samples. Endogenous thrombin potential (ETP) of f-PPP and ft-PPP agreed in nearly two-thirds of the samples. A slightly but significantly slower kinetic was found in the thrombin generation of ft-PPP compared with f-PPP. At least in f-PPP, ETP correlates with baseline platelet counts of the whole blood sample. Peak thrombin was significantly higher in non-O blood groups compared to O blood group. Conclusions: A low level of agreement between the results of f-PPP and ft-PPP is shown. In terms of practicability of sample collection using semi-automated thrombin-generation assays ft-PPP should be preferred over f-PPP. We therefore recommend using ft-PPP in clinical studies. [ABSTRACT FROM AUTHOR]

Glucocorticoids and noradrenaline can enhance memory consolidation but impair memory retrieval. Beyond their effects on quantitative memory performance, these major stress mediators bias the engagement of multiple memory systems toward "habitual" control during learning. However, if and how glucocorticoids and noradrenaline may also affect which memory system is recruited during recall, thereby affecting the control of retrieval, remain largely unknown. To address these questions, we trained healthy participants in a probabilistic classification learning task, which can be supported both by cognitive and habitual strategies. Approximately 24 hr later, participants received a placebo, hydrocortisone, yohimbine (an α2-adrenoceptor antagonist increasing noradrenergic stimulation), or both drugs before they completed a recall test for the probabilistic classification learning task. During training, all groups showed a practice-dependent shift toward more habitual strategies, reflecting an "automatization" of behavior. In the recall test, after a night of sleep, this automatization was even more pronounced in the placebo group, most likely due to offline consolidation processes and with beneficial effects on recall performance. Hydrocortisone or yohimbine intake abolished this further automatization, preventing the shift to a more efficient memory system and leading, in particular in the hydrocortisone group, to impaired recall performance. Our results suggest that glucocorticoids and noradrenergic stimulation may modulate the engagement of different strategies at recall and link the well-known stress hormone-induced retrieval deficit to a change in the system controlling memory retrieval. [ABSTRACT FROM AUTHOR]

The flow in a fan rest-riff is studied with combined experimental and numerical methods, with a focus on the tip-leakage flow. A zonal RANS/LES approach is introduced for the simulation: the region of interest at tip is computed with full large-eddy simulation (LES), while Reynolds-averaged Navier-Stokes (RANS) is used at inner radii. Detailed comparisons with the experiment show that the simulation gives a good description of the flow. In the region of interest at tip, a remarkable prediction of the velocity spectrum is achieved, over about six decades of energy. The simulation precisely captures both the tonal and broadband contents. Furthermore, a detailed analysis of the simulation allows identifying a tip-leakage vortex (TLV) wandering, whose influence onto the spectrum is also observed in the experiment. This phenomenon might be due to excitation by upstream turbulence from the casing boundary layer and/or the adjacent TLV. It may be a precursor of rotating instability. Finally, considering the outlet duct acoustic spectrum, the vortex wandering appears to be a major contribution to noise radiation. [ABSTRACT FROM AUTHOR]