Long-range fiber-optic earthquake sensing by active phase noise cancellation.

We present a long-range fiber-optic environmental deformation sensor based on active phase noise cancellation (PNC) in metrological frequency dissemination. PNC sensing exploits recordings of a compensation frequency that is commonly discarded. Without the need for dedicated measurement devices, it operates synchronously with metrological services, suggesting that existing phase-stabilized metrological networks can be co-used effortlessly as environmental sensors. The compatibility of PNC sensing with inline amplification enables the interrogation of cables with lengths beyond 1000 km, making it a potential contributor to earthquake detection and early warning in the oceans. Using spectral-element wavefield simulations that accurately account for complex cable geometry, we compare observed and computed recordings of the compensation frequency for a magnitude 3.9 earthquake in south-eastern France and a 123 km fiber link between Bern and Basel, Switzerland. The match in both phase and amplitude indicates that PNC sensing can be used quantitatively, for example, in earthquake detection and characterization.

The origin of Neolithic copper on the central Northern European plain and in Southern Scandinavia: Connectivities on a European scale.

The production, distribution and use of copper objects and the development of metallurgical skills in Neolithic Northern Central Europe and Southern Scandinavia are linked to early centres of copper metallurgy of South East Central Europe and Southeast Europe. A total of 45 Neolithic copper objects, until now the largest sample of Early Neolithic objects from the Northern Central European Plain and Southern Scandinavia, were selected for new lead isotope analyses. They aided in the identification of the origin of the copper: These new analyses indicate that the copper ore deposits in Southeastern Europe, especially from the Serbian mining areas, were used for the Early Neolithic northern artefacts (ca. 4100-3300 BC). The most likely sources of copper for the few Middle Neolithic artefacts (ca. 3300-2800 BC) seem to be from the Slovak Ore Mountains, the Serbian mining areas and the Eastern Alps, whereas deposits of the Slovak Ore Mountains and the Alpine region were used for the Late Neolithic and the Early Bronze Age (ca. 2300-1700 BC) artefacts. For the artefacts dated after 2000 BC, the Great Orme mine in Wales also appears to have been the source of copper for the analysed metals. The use of copper from different regions of Europe probably reflects changing social and cultural connectivities on a European scale and the changing chronology of copper exploitation.

To kill or not to kill - The role of the tumor microenvironment in shaping group 1 ILC functions.

Group 1 innate lymphoid cells (ILC) comprise two major IFN-γ producing populations, namely Natural Killer (NK) cells, and ILC1s. Recent studies have revealed a complex and diverse composition of group 1 ILC subsets infiltrating different tumors. In this review, we will outline the commonalities and differences between group 1 ILC subsets in both mice and humans, discuss how the tissue and tumor microenvironment shapes their phenotype and functions, as well as describe their contrasting roles in the response to different cancers.

Pharmacokinetics of Nirmatrelvir and Ritonavir in COVID-19 Patients with End-Stage Renal Disease on Intermittent Hemodialysis.

Nirmatrelvir/ritonavir is an effective antiviral therapy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Use is not recommended in patients with end-stage renal disease (ESDR) due to a lack of data. We investigated the pharmacokinetics of nirmatrelvir/ritonavir (150 mg/100 mg twice a day) in four patients with ESRD undergoing hemodialysis. Nirmatrelvir peak concentrations ranged from 4,563 to 7,898 ng/mL and declined after hemodialysis. Concentrations were up to 4-fold higher but still within the range known from patients without ESRD, without accumulation of nirmatrelvir after the end of treatment.

A proteomic survival predictor for COVID-19 patients in intensive care.

Global healthcare systems are challenged by the COVID-19 pandemic. There is a need to optimize allocation of treatment and resources in intensive care, as clinically established risk assessments such as SOFA and APACHE II scores show only limited performance for predicting the survival of severely ill COVID-19 patients. Additional tools are also needed to monitor treatment, including experimental therapies in clinical trials. Comprehensively capturing human physiology, we speculated that proteomics in combination with new data-driven analysis strategies could produce a new generation of prognostic discriminators. We studied two independent cohorts of patients with severe COVID-19 who required intensive care and invasive mechanical ventilation. SOFA score, Charlson comorbidity index, and APACHE II score showed limited performance in predicting the COVID-19 outcome. Instead, the quantification of 321 plasma protein groups at 349 timepoints in 50 critically ill patients receiving invasive mechanical ventilation revealed 14 proteins that showed trajectories different between survivors and non-survivors. A predictor trained on proteomic measurements obtained at the first time point at maximum treatment level (i.e. WHO grade 7), which was weeks before the outcome, achieved accurate classification of survivors (AUROC 0.81). We tested the established predictor on an independent validation cohort (AUROC 1.0). The majority of proteins with high relevance in the prediction model belong to the coagulation system and complement cascade. Our study demonstrates that plasma proteomics can give rise to prognostic predictors substantially outperforming current prognostic markers in intensive care.

Differences in executive abilities rather than associative processes contribute to memory development.

Children's learning capabilities change while growing up. One framework that describes the cognitive and neural development of children's growing learning abilities is the two-component model. It distinguishes processes that integrate separate features into a coherent memory representation (associative component) and executive abilities, such as elaboration, evaluation, and monitoring, that support memory processing (strategic component). In an fMRI study using an object-location association paradigm, we investigated how the two components influence memory performance across development. We tested children (10-12 years, n = 31), late adolescents (18 years, n = 29), and adults (25+ years, n = 30). For studying the associative component, we also probed how the utilisation of prior knowledge (schemas) facilitates memory across age groups. Children had overall lower retrieval performance, while adolescents and adults did not differ from each other. All groups benefitted from schemas, but this effect did not differ between groups. Performance differences between groups were associated with deactivation of the dorsal medial prefrontal cortex (dmPFC), which in turn was linked to executive functioning. These patterns were stronger in adolescents and adults and seemed absent in children. Thus, the children's executive system, the strategic component, is not as mature and thus cannot facilitate memory performance in the same way as in adolescents/adults. In contrast, we did not find age-related differences in the associative component; with activity in the angular gyrus predicting memory performance systematically across groups. Overall, our results suggest that differences of executive rather than associative abilities explain memory differences between children, adolescents, and adults.

An in vitro platform supports generation of human innate lymphoid cells from CD34+ hematopoietic progenitors that recapitulate ex vivo identity.

Innate lymphoid cells (ILCs) are critical effectors of innate immunity and inflammation, whose development and activation pathways make for attractive therapeutic targets. However, human ILC generation has not been systematically explored, and previous in vitro investigations relied on the analysis of few markers or cytokines, which are suboptimal to assign lineage identity. Here, we developed a platform that reliably generated human ILC lineages from CD34+ hematopoietic progenitors derived from cord blood and bone marrow. We showed that one culture condition is insufficient to generate all ILC subsets, and instead, distinct combination of cytokines and Notch signaling are essential. The identity of natural killer (NK)/ILC1s, ILC2s, and ILC3s generated in vitro was validated by protein expression, functional assays, and both global and single-cell transcriptome analysis, recapitulating the signatures and functions of their ex vivo ILC counterparts. These data represent a resource to aid in clarifying ILC biology and differentiation.

Development of Vasoinhibin-Specific Monoclonal Antibodies.

Vasoinhibin is a protein hormone with antiangiogenic, antivasodilatatory, and antivasopermeability effects generated by the proteolytic cleavage of prolactin. The discovery of its role in diabetic retinopathy and peripartum cardiomyopathy led to the evaluation of new pharmacological treatments in clinical interventional trials. However, the quantitative evaluation of vasoinhibin in biological samples from patients has not been possible due to the lack of vasoinhibin-specific antibodies. Recently, loop 1 of vasoinhibin was identified to have a different three-dimensional structure compared to PRL, and thus to contain vasoinhibin-specific epitopes. Here, we report the development of two sets of vasoinhibin-specific monoclonal antibodies against two neighboring regions of the vasoinhibin loop 1. An experimental sandwich ELISA with two monoclonal anti-vasoinhibin antibodies was developed, which had no cross-reactivity to recombinant human full-length prolactin. The ELISA had a quantitation limit of 100 ng/ml, and intra-assay- and inter-assay coefficients of variation of 12.5% and 14%, respectively. The evaluation of 15 human serum samples demonstrated concentrations of below limit of detection (n=3), below limit of quantitation (n=1) and between 0.23 µg/ml (230 ng/ml) to 605 µg/ml (n=12) in the quantifiable range. Despite the high specificity of the monoclonal-monoclonal antibody sandwiches which discriminate vasoinhibin from PRL, there might be cross-reactivities by serum proteins other than vasoinhibin. A fully established vasoinhibin ELISA may support diagnostic and therapeutic measures in vascular diseases.

Soil Thermophysical Properties Near the InSight Lander Derived From 50 Sols of Radiometer Measurements.

Measurements from the InSight lander radiometer acquired after landing are used to characterize the thermophysical properties of the Martian soil in Homestead hollow. This data set is unique as it stems from a high measurement cadence fixed platform studying a simple well-characterized surface, and it benefits from the environmental characterization provided by other instruments. We focus on observations acquired before the arrival of a regional dust storm (near Sol 50), on the furthest observed patch of soil (i.e., ∼3.5 m away from the edge of the lander deck) where temperatures are least impacted by the presence of the lander and where the soil has been least disrupted during landing. Diurnal temperature cycles are fit using a homogenous soil configuration with a thermal inertia of 183 ± 25 J m-2 K-1 s-1/2 and an albedo of 0.16, corresponding to very fine to fine sand with the vast majority of particles smaller than 140 µm. A pre-landing assessment leveraging orbital thermal infrared data is consistent with these results, but our analysis of the full diurnal temperature cycle acquired from the ground further indicates that near surface layers with different thermophysical properties must be thin (i.e., typically within the top few mm) and deep layering with different thermophysical properties must be at least below ∼4 cm. The low thermal inertia value indicates limited soil cementation within the upper one or two skin depths (i.e., ∼4-8 cm and more), with cement volumes <<1%, which is challenging to reconcile with visible images of overhangs in pits.

A new approach to the temporal significance of house orientations in European Early Neolithic settlements.

This paper shows that local differences in house orientation in settlements from the Early Neolithic in Central Europe reflect a regular chronological trajectory based on Bayesian calibration of 14C-series. This can be used to extrapolate the dating of large-scale settlement plans derived from, among other methods, geophysical surveys. In the southwest Slovakian settlement of Vráble, we observed a progressive counter-clockwise rotation in house orientation from roughly 32° to 4° over a 300 year period. A survey of published and dated village plans from other LBK regions confirms that this counter-clockwise rotation per settlement is a wider Central European trend. We explain this observation as an unintentional, unconscious but systematic leftward deviation in the house builders' cardinal orientation, which has been termed "pseudoneglect" in studies of human perception. This means that whenever houses were intended to be oriented towards a specific direction and be parallel to each other, there was an error in perception causing slight counter-clockwise rotation. This observation is used as a basis to reconstruct dynamics of Early Neolithic settlement in the Slovakian Zitava valley, showing a rapid colonization, followed by increased agglomeration into large villages consisting of strongly autonomous farmsteads.

Induction and Relief of Curiosity Elicit Parietal and Frontal Activity.

Curiosity is a basic biological drive, but little is known about its behavioral and neural mechanisms. We can be curious about several types of information. On the one hand, curiosity is a function of the expected value of information, serving primarily to help us maximize reward. On the other hand, curiosity can be a function of the uncertainty of information, helping us to update what we know. In the current studies, we aimed to disentangle the contribution of information uncertainty and expected value of rewards to curiosity in humans. To this end, we designed a lottery task in which uncertainty and expected value of trial outcomes were manipulated independently and examined how neural activity and behavioral measures of curiosity were modulated by these factors. Curiosity increased linearly with increased outcome uncertainty, both when curiosity was explicitly probed as well as when it was implicitly tested by people's willingness to wait. Increased expected value, however, did not strongly relate to these curiosity measures. Neuroimaging results showed greater BOLD response with increasing outcome uncertainty in parietal cortex at the time of curiosity induction. Outcome updating when curiosity was relieved resulted in an increased signal in the insula, orbitofrontal cortex, and parietal cortex. Furthermore, the insula showed a linear increase corresponding to the size of the information update. These results suggest that curiosity is monotonically related to the uncertainty about one's current world model, the induction and relief of which are associated with activity in parietal and insular cortices, respectively.SIGNIFICANCE STATEMENT Humans are curious by nature. When you hear your phone beep, you probably feel the urge to check the message right away, even though the message itself likely does not give you a direct reward. In this study, we demonstrated that curiosity can be driven by outcome uncertainty, over and above of reward. The induction of curiosity was accompanied by increased activity in the parietal cortex, whereas the information update at the time of curiosity relief was associated with activity in insular cortex. These findings advance our understanding of the behavioral and neural constituents of curiosity, which lies at the core of human information seeking and serves to optimize the individual's current world model.

Hippocampal-caudate nucleus interactions support exceptional memory performance.

Participants of the annual World Memory Championships regularly demonstrate extraordinary memory feats, such as memorising the order of 52 playing cards in 20 s or 1000 binary digits in 5 min. On a cognitive level, memory athletes use well-known mnemonic strategies, such as the method of loci. However, whether these feats are enabled solely through the use of mnemonic strategies or whether they benefit additionally from optimised neural circuits is still not fully clarified. Investigating 23 leading memory athletes, we found volumes of their right hippocampus and caudate nucleus were stronger correlated with each other compared to matched controls; both these volumes positively correlated with their position in the memory sports world ranking. Furthermore, we observed larger volumes of the right anterior hippocampus in athletes. Complementing these structural findings, on a functional level, fMRI resting state connectivity of the anterior hippocampus to both the posterior hippocampus and caudate nucleus predicted the athletes rank. While a competitive interaction between hippocampus and caudate nucleus is often observed in normal memory function, our findings suggest that a hippocampal-caudate nucleus cooperation may enable exceptional memory performance. We speculate that this cooperation reflects an integration of the two memory systems at issue-enabling optimal combination of stimulus-response learning and map-based learning when using mnemonic strategies as for example the method of loci.

Chronic Inflammation Increases the Sensitivity of Mouse Treg for TNFR2 Costimulation.

TNF receptor type 2 (TNFR2) has gained attention as a costimulatory receptor for T cells and as critical factor for the development of regulatory T cells (Treg) and myeloid suppressor cells. Using the TNFR2-specific agonist TNCscTNF80, direct effects of TNFR2 activation on myeloid cells and T cells were investigated in mice. In vitro, TNCscTNF80 induced T cell proliferation in a costimulatory fashion, and also supported in vitro expansion of Treg cells. In addition, activation of TNFR2 retarded differentiation of bone marrow-derived immature myeloid cells in culture and reduced their suppressor function. In vivo application of TNCscTNF80-induced mild myelopoiesis in naïve mice without affecting the immune cell composition. Already a single application expanded Treg cells and improved suppression of CD4 T cells in mice with chronic inflammation. By contrast, multiple applications of the TNFR2 agonist were required to expand Treg cells in naïve mice. Improved suppression of T cell proliferation depended on expression of TNFR2 by T cells in mice repeatedly treated with TNCscTNF80, without a major contribution of TNFR2 on myeloid cells. Thus, TNFR2 activation on T cells in naïve mice can lead to immune suppression in vivo. These findings support the important role of TNFR2 for Treg cells in immune regulation.

Mnemonic Training Reshapes Brain Networks to Support Superior Memory.

Memory skills strongly differ across the general population; however, little is known about the brain characteristics supporting superior memory performance. Here we assess functional brain network organization of 23 of the world's most successful memory athletes and matched controls with fMRI during both task-free resting state baseline and active memory encoding. We demonstrate that, in a group of naive controls, functional connectivity changes induced by 6 weeks of mnemonic training were correlated with the network organization that distinguishes athletes from controls. During rest, this effect was mainly driven by connections between rather than within the visual, medial temporal lobe and default mode networks, whereas during task it was driven by connectivity within these networks. Similarity with memory athlete connectivity patterns predicted memory improvements up to 4 months after training. In conclusion, mnemonic training drives distributed rather than regional changes, reorganizing the brain's functional network organization to enable superior memory performance.

Transient medial prefrontal perturbation reduces false memory formation.

Knowledge extracted across previous experiences, or schemas, benefit encoding and retention of congruent information. However, they can also reduce specificity and augment memory for semantically related, but false information. A demonstration of the latter is given by the Deese-Roediger-McDermott (DRM) paradigm, where the studying of words that fit a common semantic schema are found to induce false memories for words that are congruent with the given schema, but were not studied. The medial prefrontal cortex (mPFC) has been ascribed the function of leveraging prior knowledge to influence encoding and retrieval, based on imaging and patient studies. Here, we used transcranial magnetic stimulation (TMS) to transiently perturb ongoing mPFC processing immediately before participants performed the DRM-task. We observed the predicted reduction in false recall of critical lures after mPFC perturbation, compared to two control groups, whereas veridical recall and recognition memory performance remained similar across groups. These data provide initial causal evidence for a role of the mPFC in biasing the assimilation of new memories and their consolidation as a function of prior knowledge.

Motor Skills Enhance Procedural Memory Formation and Protect against Age-Related Decline.

The ability to consolidate procedural memories declines with increasing age. Prior knowledge enhances learning and memory consolidation of novel but related information in various domains. Here, we present evidence that prior motor experience-in our case piano skills-increases procedural learning and has a protective effect against age-related decline for the consolidation of novel but related manual movements. In our main experiment, we tested 128 participants with a sequential finger-tapping motor task during two sessions 24 hours apart. We observed enhanced online learning speed and offline memory consolidation for piano players. Enhanced memory consolidation was driven by a strong effect in older participants, whereas younger participants did not benefit significantly from prior piano experience. In a follow up independent control experiment, this compensatory effect of piano experience was not visible after a brief offline period of 30 minutes, hence requiring an extended consolidation window potentially involving sleep. Through a further control experiment, we rejected the possibility that the decreased effect in younger participants was caused by training saturation. We discuss our results in the context of the neurobiological schema approach and suggest that prior experience has the potential to rescue memory consolidation from age-related cognitive decline.

Myeloid suppressor cells require membrane TNFR2 expression for suppressive activity.

TNF and TNF receptor type 2 (TNFR2) have been shown to be important for generation of myeloid-derived suppressor cells (MDSC). In order to analyze whether and how TNFR2 passes the effect of TNF on, myeloid cells from TNFR2-deficient mice were compared to respective cells from wild-type mice. Primary TNFR2-deficient myeloid cells showed reduced production of NO and IL-6 which was attributable to CD11b(+) CD11c(-) Ly6C(+) Ly6G(-) immature monocytic MDSC. TNFR2-deficient MDSC isolated from bone marrow were less suppressive for T cell proliferation compared to WT-derived MDSC. These differences on myeloid cells between the two mouse lines were still observed after co-culture of bone marrow cells from the two mouse lines together during myeloid cell differentiation, which demonstrated that the impaired functional capacity of TNFR2-deficient cells was independent of soluble factors but required membrane expression of TNFR2. Similarly, adoptive transfer of TNFR2-deficient bone marrow cells into wild-type hosts did not rescue the TNFR2-specific phenotype of bone marrow-derived myeloid cells. Therefore, membrane TNFR2 expression determines generation and function of monocytic MDSC.

Whole brain, high resolution multiband spin-echo EPI fMRI at 7 T: a comparison with gradient-echo EPI using a color-word Stroop task.

A whole brain, multiband spin-echo (SE) echo planar imaging (EPI) sequence employing a high spatial (1.5 mm isotropic) and temporal (TR of 2 s) resolution was implemented at 7 T. Its overall performance (tSNR, sensitivity and CNR) was assessed and compared to a geometrically matched gradient-echo (GE) EPI multiband sequence (TR of 1.4 s) using a color-word Stroop task. PINS RF pulses were used for refocusing to reduce RF amplitude requirements and SAR, summed and phase-optimized standard pulses were used for excitation enabling a transverse or oblique slice orientation. The distortions were minimized with the use of parallel imaging in the phase encoding direction and a post-acquisition distortion correction. In general, GE-EPI shows higher efficiency and higher CNR in most brain areas except in some parts of the visual cortex and superior frontal pole at both the group and individual-subject levels. Gradient-echo EPI was able to detect robust activation near the air/tissue interfaces such as the orbito-frontal and subcortical regions due to reduced intra-voxel dephasing because of the thin slices used and high in-plane resolution.

Genetic, morphological, and feather isotope variation of migratory willow warblers show gradual divergence in a ring.

The circular distribution of the willow warbler Phylloscopus trochilus around the Baltic Sea shares many features with the classic examples of ring species; however, the system is much younger. It has previously been shown that a secondary contact zone is located in central Scandinavia, where there are narrow clines for several morphological traits coincident with a migratory divide. Here we analyse multiple traits and genes from > 1700 males captured on breeding territories at 77 sites spread around the Baltic Sea to test the following hypothesis. If the secondary contact zone in Scandinavia is a result of divergence in two allopatric refuge populations during the last glaciation, we expect to find a similar secondary contact zone somewhere else around the circular distribution. Our results show that the trait clines were wider and displaced from each other along the eastern side of the Baltic Sea. Analyses of 12 microsatellite loci confirmed that the genome is very similar between the terminal forms (F(ST) = 0). Two AFLP-derived markers filtered out from a genomic scan instead appear to be maintained by selection. These markers exhibited steep clines at the secondary contact zone in Scandinavia, but as for the phenotypic traits, had vastly different cline centres east of the Baltic Sea. The trait clines along the ring distribution outside the Scandinavian secondary contact zone thus seem to have been shaped by independent action of selection or drift during the process of postglacial colonization.

In-hospital delays to stroke thrombolysis: paradoxical effect of early arrival.

OBJECTIVE: To determine the causes of in-hospital delays for thrombolysis. METHODS: We performed a 4 year retrospective chart analysis of i.v. tPA-treated patients at an academic medical center. Data collected included age, stroke severity by the National Institutes of Health Stroke Scale (NIHSS) and the following time points: symptom onset, hospital arrival, computed tomography (CT), i.v. tPA order and i.v. tPA initiation of infusion. RESULTS: Thirty-one cases with sufficient information for analysis were identified. Mean time from onset to arrival was 58 minutes, from arrival to brain CT was 32 minutes, and from onset to i.v. rtPA infusion was 169 minutes. The mean delay between i.v. tPA order and infusion was 32 minutes. Delay between order and administration of i.v. tPA resulted in treatment after 3 hours in 9/31 cases. An inverse relationship between early hospital arrival and delayed thrombolysis was noted. Age and stroke severity did not impact treatment times. CONCLUSION: An unexpected delay between order and actual initiation of i.v. tPA infusion resulted in almost one-third of patients receiving thrombolytics after 3 hours from symptom onset. The cause of this delay could not be discerned by this study. The paradoxical effect between early arrival to hospital and delayed treatment may be related to a sense of urgency in those arriving close to 3 hours after onset. Critical reviews such as this permit identification of hospital delays in stroke treatment, thus allowing institution of appropriate strategies to ensure prompt treatment.