Search

Abstract Oncolytic virotherapy is a promising form of cancer treatment that uses viruses to infect and kill cancer cells. In addition to their direct effects on cancer cells, the viruses stimulate various immune responses partly directed against the tumour. Efforts are made to genetically engineer oncolytic viruses to enhance their immunogenic potential. However, the interplay between tumour growth, viral infection, and immune responses is complex and not fully understood, leading to variable and sometimes counterintuitive therapeutic outcomes. Here, we employ a spatio-temporal model to shed more light on this interplay. We investigate systematically how the properties of virus-induced immunogenic signals (their half-life, rate of spread, and potential to promote T-cell-mediated cytotoxicity) affect the therapeutic outcome. Our simulations reveal that strong immunogenic signals, combined with faster diffusion rates, improve the spread of immune activation, leading to better tumour eradication. However, replicate simulations suggest that the outcome of virotherapy is more stochastic than generally appreciated. Our model shows that virus-induced immune responses can interfere with virotherapy, by targeting virus-infected cancer cells and/or by impeding viral spread. In the presence of immune responses, the mode of virus introduction is important, with systemic viral delivery throughout the tumour yielding the most favourable outcomes. The timing of virus introduction also plays a critical role; depending on the efficacy of the immune response, a later start of virotherapy can be advantageous. Overall, our results emphasise that the rational design of oncolytic viruses requires optimising virus-induced immunogenic signals and strategies that balance viral spread with immune activity for improved therapeutic success.

Abstract Attosecond science has demonstrated that electrons can be controlled on the sub-cycle time scale of an optical waveform, paving the way towards optical frequency electronics. However, these experiments historically relied on high-energy laser pulses and detection not suitable for microelectronic integration. For practical optical frequency electronics, a system suitable for integration and capable of generating detectable signals with low pulse energies is needed. While current from plasmonic nanoantenna emitters can be driven at optical frequencies, low charge yields have been a significant limitation. In this work we demonstrate that large-scale electrically connected plasmonic nanoantenna networks, when driven in concert, enable charge yields sufficient for single-shot carrier-envelope phase detection at repetition rates exceeding tens of kilohertz. We not only show that limitations in single-shot CEP detection techniques can be overcome, but also demonstrate a flexible approach to optical frequency electronics in general, enabling future applications such as high sensitivity petahertz-bandwidth electric field sampling or logic-circuits.

Bacterial contamination of angiographic materials and fluids has been shown to occur during human angiographic procedures. Angiographic examinations and experiments must be performed under sterile conditions to avoid complications due to contamination and possible subsequent infections. However, data regarding the frequency and the clinical consequences are limited. Our aim was to investigate the incidence of bacterial contamination during experimental angiographies. We tested angiographic fluids, syringes and endovascular materials from the angiographic supply tables for bacterial contamination, collecting 252 samples during 18 experimental angiographies in pigs. After sterile filtration, samples were cultured on media, and individual colony-forming units were identified by matrix-assisted laser desorption ionization-time of flight mass spectrometry. Contamination was detected in the majority of samples (60%). There was no angiography in which all samples remained sterile. The highest contamination rates (94%) were found in fluids from the working bowls and on the outer surface of syringes (85%) at the end of angiography. At this time, working bowls were significantly more frequently and extensively contaminated than the control bowls. Among the samples, the frequency and extent of contamination increased with the duration of the experimental angiographic procedures. Our findings show that bacterial contamination during angiography is common and the manipulation of endovascular working materials as well as the duration of angiographic procedures both increase bacterial contamination. While the clinical impact on the laboratory animal remains unclear, the quality of biomedical research mandates that efforts to minimize bacterial contamination should be taken as far as possible.

Abstract One of the most widely used techniques in microbiota research is 16S-rRNA-sequencing. Several laboratory processes have been shown to impact sequencing results, especially in low biomass samples. Low biomass samples are prone to off-target amplification, where instead of bacterial DNA, host DNA is erroneously amplified. Knowledge on the laboratory processes influencing off-target amplification and detection is however scarce. We here expand on previous findings by demonstrating that off-target amplification is not limited to invasive biopsy samples, but is also an issue in low bacterial biomass respiratory (mucosal) samples, especially when below 0.3 pg/μL. We show that off-target amplification can partly be mitigated by using gel-based library purification methods. Importantly, we report a higher off-target amplicon detection rate when using MiSeq reagent kit v3 compared to v2 (mean 13.3% vs 0.1% off-target reads/sample, respectively), possibly as a result of differences in reagents or sequencing recipes. However, since after bioinformatic removal of off-target reads, MiSeq reagent kit v3 still results in a twofold higher number of reads when compared to v2, v3 is still preferred over v2. Together, these results add to the growing knowledge base on off-target amplification and detection, allowing researchers to anticipate this problem in 16S-rRNA-based microbiome studies involving low biomass samples.

Abstract Reflecting the first wave COVID-19 pandemic in Central Europe (i.e. March 16th–April 15th, 2020) the neurosurgical community witnessed a general diminution in the incidence of emergency neurosurgical cases, which was impelled by a reduced number of traumatic brain injuries (TBI), spine conditions, and chronic subdural hematomas (CSDH). This appeared to be associated with restrictions imposed on mobility within countries but also to possible delayed patient introduction and interdisciplinary medical counseling. In response to one year of COVID-19 experience, also mapping the third wave of COVID-19 in 2021 (i.e. March 16 to April 15, 2021), we aimed to reevaluate the current prevalence and outcomes for emergency non-elective neurosurgical cases in COVID-19-negative patients across Austria and the Czech Republic. The primary analysis was focused on incidence and 30-day mortality in emergency neurosurgical cases compared to four preceding years (2017–2020). A total of 5077 neurosurgical emergency cases were reviewed. The year 2021 compared to the years 2017–2019 was not significantly related to any increased odds of 30 day mortality in Austria or in the Czech Republic. Recently, there was a significant propensity toward increased incidence rates of emergency non-elective neurosurgical cases during the third COVID-19 pandemic wave in Austria, driven by their lower incidence during the first COVID-19 wave in 2020. Selected neurosurgical conditions commonly associated with traumatic etiologies including TBI, and CSDH roughly reverted to similar incidence rates from the previous non-COVID-19 years. Further resisting the major deleterious effects of the continuing COVID-19 pandemic, it is edifying to notice that the neurosurgical community´s demeanor to the recent third pandemic culmination keeps the very high standards of non-elective neurosurgical care alongside with low periprocedural morbidity. This also reflects the current state of health care quality in the Czech Republic and Austria.

The relationship between virulence and pathogen clearance is not well understood. Here, using bacterial infections in Drosophila melanogaster as a model system, the authors demonstrate an approach to disentangle the drivers of virulence and assess their relation to pathogen clearance rate.

The knowledge needed to tackle future environmental and societal challenges can only be generated through exchange between science and society. The conventional distinction made between natural and cultural heritage in museums and other institutions is no longer appropriate in the Anthropocene. Museums must rethink the social and cultural dimensions of existing museum collections and reinvent the organization of knowledge production for our present. In three workshops at the Museum für Naturkunde Berlin, practitioners and interdisciplinary theorists discussed the concept of “Anthropocenic objects” and considered how they create opportunities for the emergence of new collecting practices involving participatory research and open exchange between research, society, and conservation institutions.

Abstract Degradation and fragmentation of plastics in the environment are still poorly understood. This is partly caused by the lack of long-term studies and methods that determine weathering duration. We here present a novel study object that preserves information on plastic age: microplastic (MP) resin pellets from the wreck of the SS Hamada, a ship that foundered twenty-nine years ago at the coast of Wadi el Gemal national park, Egypt. Its sinking date enabled us to precisely determine how long MP rested in the wreck and a nearby beach, on which part of the load was washed off. Pellets from both sampling sites were analyzed by microscopy, X-ray tomography, spectroscopy, calorimetry, gel permeation chromatography, and rheology. Most pellets were made of low-density polyethylene, but a minor proportion also consisted of high-density polyethylene. MP from inside the wreck showed no signs of degradation compared to pristine reference samples. Contrary, beached plastics exhibited changes on all structural levels, which sometimes caused fragmentation. These findings provide further evidence that plastic degradation under saltwater conditions is comparatively slow, whereas UV radiation and high temperatures on beaches are major drivers of that process. Future long-term studies should focus on underlying mechanisms and timescales of plastic degradation.

Measurement(s) air temperature • air humidity • air pressure • global radiation • precipitation • Grain yield • nitrous oxide concentrations (gas field measurements) • emissions of NH3 • soil moisture • ammonium in soil • nitrate in soil Technology Type(s) weather station • Weighing • static closed chamber technique • method of calibrated Passive sampling • SENTEK sensor • Extraction with 0.0125 M CaCl2 solution or 0.1 M KCl (VDLUFA method handbook I A 6.1.4.1) Factor Type(s) Fertilizer Sample Characteristic - Environment gaseous field emissions Sample Characteristic - Location Germany

Abstract New recommendations on evaluation of peritoneal membrane function suggest ruling out catheter dysfunction when evaluating patients with low ultrafiltration capacity. We introduce the use of a combination of parameters obtained from the cycler software PD Link with HomeChoicePro (Baxter International Inc., Illinois, United States) cyclers for predicting catheter dysfunction in automated peritoneal dialysis patients (APD). Out of 117 patients treated at the Medical University of Vienna between 2015 and 2021, we retrospectively identified all patients with verified catheter dysfunction (n = 14) and compared them to controls without clinical evidence of mechanical catheter problems and a recent X-ray confirming PD catheter tip in the rectovesical/rectouterine space (n = 19). All patients had a coiled single-cuff PD catheter, performed tidal PD, and received neutral pH bicarbonate/lactate-buffered PD fluids with low-glucose degradation products on APD. Icodextrin-containing PD fluids were used for daytime dwells. We retrieved cycler data for seven days each and tested parameters' predictive capability of catheter dysfunction. Total number of alarms/week > 7 as single predictive parameter of catheter dislocation identified 85.7% (sensitivity) of patients with dislocated catheter, whereas 31.6% (1-specificity) of control patients were false positive. A combination of parameters (number of alarms/week > 7, total drain time > 22 min, ultrafiltration of last fill

Abstract Although X‐ray contrast agents offer specific characteristics in terms of targeting and attenuation, their accumulation in the tissue on a cellular level is usually not known and difficult to access, as it requires high resolution and sensitivity. Here, quantitative near‐field ptychographic X‐ray computed tomography is demonstrated to assess the location of X‐ray stains at a resolution sufficient to identify intracellular structures by means of a basis material decomposition. On the example of two different X‐ray stains, the nonspecific iodine potassium iodide, and eosin Y, which mostly interacts with proteins and peptides in the cell cytoplasm, the distribution of the stains within the cells in murine kidney samples is assessed and compared to unstained samples with similar structural features. Quantitative nanoscopic stain concentrations are in good agreement with dual‐energy micro computed tomography measurements, the state‐of‐the‐art modality for material‐selective imaging. The presented approach can be applied to a variety of X‐ray stains advancing the development of X‐ray contrast agents.

Abstract The high‐frequency and low‐voltage operation of organic thin‐film transistors (OTFTs) is a key requirement for the commercial success of flexible electronics. Significant progress has been achieved in this regard by several research groups highlighting the potential of OTFTs to operate at several tens or even above 100 MHz. However, technology maturity, including scalability, integrability, and device reliability, is another crucial point for the semiconductor industry to bring OTFT‐based flexible electronics into mass production. These requirements are often not met by high‐frequency OTFTs reported in the literature as unconventional processes, such as shadow‐mask patterning or alignment with unrealistic tolerances for production, are used. Here, ultra‐short channel vertical organic field‐effect transistors (VOFETs) with a unity current gain cut‐off frequency (fT) up to 43.2 MHz (or 4.4 MHz V−1) operating below 10 V are shown. Using state‐of‐the‐art manufacturing techniques such as photolithography with reliable fabrication procedures, the integration of such devices down to the size of only 12 × 6 µm2 is shown, which is important for the adaption of this technology in high‐density circuits (e.g., display driving). The intrinsic channel transconductance is analyzed and demonstrates that the frequencies up to 430 MHz can be reached if the parasitic electrode overlap is minimized.

Membrane lipids, and especially phosphoinositides, are differentially enriched within the eukaryotic endomembrane system. This generates a landmark code by modulating the properties of each membrane. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] specifically accumulates at the plasma membrane in yeast, animal, and plant cells, where it regulates a wide range of cellular processes including endocytic trafficking. However, the functional consequences of mispatterning PI(4,5)P2 in plants are unknown. Here, we functionally characterized the putative phosphoinositide phosphatase SUPPRESSOR OF ACTIN9 (SAC9) in Arabidopsis thaliana (Arabidopsis). We found that SAC9 depletion led to the ectopic localization of PI(4,5)P2 on cortical intracellular compartments, which depends on PI4P and PI(4,5)P2 production at the plasma membrane. SAC9 localizes to a subpopulation of trans-Golgi Network/early endosomes that are enriched in a region close to the cell cortex and that are coated with clathrin. Furthermore, it interacts and colocalizes with Src Homology 3 Domain Protein 2 (SH3P2), a protein involved in endocytic trafficking. In the absence of SAC9, SH3P2 localization is altered and the clathrin-mediated endocytosis rate is reduced. Together, our results highlight the importance of restricting PI(4,5)P2 at the plasma membrane and illustrate that one of the consequences of PI(4,5)P2 misspatterning in plants is to impact the endocytic trafficking.

Signal-anchored (SA) proteins are anchored into the mitochondrial outer membrane (OM) via a single transmembrane segment at their N-terminus while the bulk of the proteins is facing the cytosol. These proteins are encoded by nuclear DNA, translated on cytosolic ribosomes, and are then targeted to the organelle and inserted into its OM by import factors. Recently, research on the insertion mechanisms of these proteins into the mitochondrial OM have gained a lot of attention. In contrast, the early cytosolic steps of their biogenesis are unresolved. Using various proteins from this category and a broad set of in vivo, in organello, and in vitro assays, we reconstituted the early steps of their biogenesis. We identified a subset of molecular (co)chaperones that interact with newly synthesized SA proteins, namely, Hsp70 and Hsp90 chaperones and co-chaperones from the Hsp40 family like Ydj1 and Sis1. These interactions were mediated by the hydrophobic transmembrane segments of the SA proteins. We further demonstrate that interfering with these interactions inhibits the biogenesis of SA proteins to a various extent. Finally, we could demonstrate direct interaction of peptides corresponding to the transmembrane segments of SA proteins with the (co)chaperones and reconstitute in vitro the transfer of such peptides from the Hsp70 chaperone to the mitochondrial Tom70 receptor. Collectively, this study unravels an array of cytosolic chaperones and mitochondrial import factors that facilitates the targeting and membrane integration of mitochondrial SA proteins.

Los Pleurobranchida son babosas marinas que agrupan alrededor de 100 especies distribuidas en los mares a nivel mundial, pero con una mayor diversidad en ambientes costeros tropicales y templados. En el Pacífico Oriental se han reportado 2 familias, 4 géneros y más de 10 especies de Pleurobranchida. La especie Berthellina ilisima Marcus & Marcus 1967 común en la Provincia del Pacifico Oriental Tropical se registra formalmente en aguas costeras de Tumbes, Perú. Se describe la anatomía de los sistemas digestivo, circulatorio, reproductor y nervioso de B. ilisima, el cual constituye la primera descripción de la anatomía interna de un Pleurobranchida para Perú.

Summary: LRH-1/NR5A2 is implicated in islet morphogenesis postnatally, and its activation using the agonist BL001 protects islets against apoptosis, reverting hyperglycemia in mouse models of Type 1 Diabetes Mellitus. Islet transcriptome profiling revealed that the expression of PTGS2/COX2 is increased by BL001. Herein, we sought to define the role of LRH-1 in postnatal islet morphogenesis and chart the BL001 mode of action conferring beta cell protection. LRH-1 ablation within developing beta cells impeded beta cell proliferation, correlating with mouse growth retardation, weight loss, and hypoglycemia leading to lethality. LRH-1 deletion in adult beta cells abolished the BL001 antidiabetic action, correlating with beta cell destruction and blunted Ptgs2 induction. Islet PTGS2 inactivation led to reduced PGE2 levels and loss of BL001 protection against cytokines as evidenced by increased cytochrome c release and cleaved-PARP. The PTGER1 antagonist—ONO-8130—negated BL001-mediated islet survival. Our results define the LRH-1/PTGS2/PGE2/PTGER1 signaling axis as a key pathway mediating BL001 survival properties.

Cryogenic optical localization in three dimensions (COLD) was recently shown to resolve up to four binding sites on a single protein. However, because COLD relies on intensity fluctuations that result from the blinking behavior of fluorophores, it is limited to cases where individual emitters show different brightness. This significantly lowers the measurement yield. To extend the number of resolved sites as well as the measurement yield, we employ partial labeling and combine it with polarization encoding in order to identify single fluorophores during their stochastic blinking. We then use a particle classification scheme to identify and resolve heterogenous subsets and combine them to reconstruct the three-dimensional arrangement of large molecular complexes. We showcase this method (polarCOLD) by resolving the trimer arrangement of proliferating cell nuclear antigen (PCNA) and six different sites of the hexamer protein Caseinolytic Peptidase B (ClpB) of Thermus thermophilus in its quaternary structure, both with Angstrom resolution. The combination of polarCOLD and single-particle cryogenic electron microscopy (cryoEM) promises to provide crucial insight into intrinsic heterogeneities of biomolecular structures. Furthermore, our approach is fully compatible with fluorescent protein labeling and can, thus, be used in a wide range of studies in cell and membrane biology.

We use high resolution, ground-based observations of ice displacement to investigate ice deformation across the floating left-lateral shear margin of Priestley Glacier, Terra Nova Bay, Antarctica. Bare ice conditions allow us to fix survey marks directly to the glacier surface. A combination of continuous positioning of a local reference mark, and repeat positioning of a network of 33 stakes installed across a 2 km width of the shear margin are used to quantify shear strain rates and the ice response to tidal forcing over an 18-day period. Along-flow velocity observed at a continuous Global Navigation Satellite Systems (GNSS) station within the network varies by up to ∼30% of the mean speed (±28 m a−1) over diurnal tidal cycles, with faster flow during the falling tide and slower flow during the rising tide. Long-term deformation in the margin approximates simple shear with a small component of flow-parallel shortening. At shorter timescales, precise optical techniques allow high-resolution observations of across-flow bending in response to the ocean tide, including across-flow strains on the order of 10–5. An elastodynamic model informed by the field observations is used to simulate the across-flow motion and deformation. Flexure is concentrated in the shear margin, such that a non-homogeneous elastic modulus is implied to best account for the combined observations. The combined pattern of ice displacement and ice strain also depends on the extent of coupling between the ice and valley sidewall. These conclusions suggest that investigations of elastic properties made using vertical ice motion, but neglecting horizontal displacement and surface strain, will lead to incorrect conclusions about the elastic properties of ice and potentially over-simplified assumptions about the sidewall boundary condition.

Response activation and inhibition are functions fundamental to executive control that are disrupted in Parkinson disease (PD). We used magnetoencephalography to examine event related changes in oscillatory power amplitude, peak latency and frequency in cortical networks subserving these functions and identified abnormalities associated with PD. Participants (N = 18 PD, 18 control) performed a cue/target task that required initiation of an un-cued movement (activation) or inhibition of a cued movement. Reaction times were variable but similar across groups. Task related responses in gamma, alpha, and beta power were found across cortical networks including motor cortex, supplementary and pre- supplementary motor cortex, posterior parietal cortex, prefrontal cortex and anterior cingulate. PD-related changes in power and latency were noted most frequently in the beta band, however, abnormal power and delayed peak latency in the alpha band in the pre-supplementary motor area was suggestive of a compensatory mechanism. PD peak power was delayed in pre-supplementary motor area, motor cortex, and medial frontal gyrus only for activation, which is consistent with deficits in un-cued (as opposed to cued) movement initiation characteristic of PD.

Data used to train supervised machine learning models are commonly split into independent training, validation, and test sets. This paper illustrates that complex data leakage cases have occurred in the no-reference image and video quality assessment literature. Recently, papers in several journals reported performance results well above the best in the field. However, our analysis shows that information from the test set was inappropriately used in the training process in different ways and that the claimed performance results cannot be achieved. When correcting for the data leakage, the performances of the approaches drop even below the state-of-the-art by a large margin. Additionally, we investigate end-to-end variations to the discussed approaches, which do not improve upon the original.

In preterm and term infants who require intermediate or intensive care Methicillin-resistant Staphylococcus aureus (MRSA) infection can lead to significant morbidity. In this study MRSA colonization and infection were assessed in a mixed tertiary neonatal intensive and intermediate care unit in Germany over an 8-year period (2013-2020). We investigated patient-related factors, associated with nosocomial MRSA acquisition, and we discuss our infection control concept for MRSA. Of 3488 patients treated during the study period, 24 were MRSA positive patients, corresponding to 26 patient hospital stays. The incidence was 0.7 MRSA patients per 100 patients. The incidence density was 0.4 MRSA patient hospital stays per 1000 patient days. Twelve patients (50%) acquired MRSA in the hospital. One patient developed a hospital acquired MRSA bloodstream infection 9 days after birth (i.e., 0.03% of all patients on the ward during the study period). A total of 122 patients had to be screened to detect one MRSA positive patient. In a logistic regression model, the use of 3rd generation intravenous cephalosporin (cefotaxim) was associated with nosocomial MRSA acquisition compared with matched control patients who did not acquire MRSA. In sum, the burden of MRSA colonization and infection in the ward was low during the study period. A comprehensive infection control concept that included microbiologic colonization screening, prospective infection surveillance together with isolation and emphasis on basic hygiene measures is essential to handle MRSA in this specialized setting.

Recently there have been tremendous efforts to develop statistical procedures which allow to determine subgroups of patients for which certain treatments are effective. This article focuses on the selection of prognostic and predictive genetic biomarkers based on a relatively large number of candidate Single Nucleotide Polymorphisms (SNPs). We consider models which include prognostic markers as main effects and predictive markers as interaction effects with treatment. We compare different high-dimensional selection approaches including adaptive lasso, a Bayesian adaptive version of the Sorted L-One Penalized Estimator (SLOBE) and a modified version of the Bayesian Information Criterion (mBIC2). These are compared with classical multiple testing procedures for individual markers. Having identified predictive markers we consider several different approaches how to specify subgroups susceptible to treatment. Our main conclusion is that selection based on mBIC2 and SLOBE has similar predictive performance as the adaptive lasso while including substantially fewer biomarkers.

Making the knowledge contained in scientific papers machine-readable and formally computable would allow researchers to take full advantage of this information by enabling integration with other knowledge sources to support data analysis and interpretation. Here we describe Biofactoid, a web-based platform that allows scientists to specify networks of interactions between genes, their products, and chemical compounds, and then translates this information into a representation suitable for computational analysis, search and discovery. We also report the results of a pilot study to encourage the wide adoption of Biofactoid by the scientific community.

Enzymerhodopsins represent a recently discovered class of rhodopsins which includes histidine kinase rhodopsin, rhodopsin phosphodiesterases, and rhodopsin guanylyl cyclases (RGCs). The regulatory influence of the rhodopsin domain on the enzyme activity is only partially understood and holds the key for a deeper understanding of intra-molecular signaling pathways. Here, we present a UV-Vis and FTIR study about the light-induced dynamics of a RGC from the fungus Catenaria anguillulae, which provides insights into the catalytic process. After the spectroscopic characterization of the late rhodopsin photoproducts, we analyzed truncated variants and revealed the involvement of the cytosolic N-terminus in the structural rearrangements upon photo-activation of the protein. We tracked the catalytic reaction of RGC and the free GC domain independently by UV-light induced release of GTP from the photolabile NPE-GTP substrate. Our results show substrate binding to the dark-adapted RGC and GC alike and reveal differences between the constructs attributable to the regulatory influence of the rhodopsin on the conformation of the binding pocket. By monitoring the phosphate rearrangement during cGMP and pyrophosphate formation in light-activated RGC, we were able to confirm the M state as the active state of the protein. The described setup and experimental design enable real-time monitoring of substrate turnover in light-activated enzymes on a molecular scale, thus opening the pathway to a deeper understanding of enzyme activity and protein-protein interactions.

Psychoactive drugs can transiently perturb brain physiology while preserving brain structure. The role of physiological state in shaping neural function can therefore be investigated through neuroimaging of pharmacologically induced effects. Previously, using pharmacological neuroimaging, we found that neural and experiential effects of lysergic acid diethylamide (LSD) are attributable to agonism of the serotonin-2A receptor (Preller et al., 2018). Here, we integrate brain-wide transcriptomics with biophysically based circuit modeling to simulate acute neuromodulatory effects of LSD on human cortical large-scale spatiotemporal dynamics. Our model captures the inter-areal topography of LSD-induced changes in cortical blood oxygen level-dependent (BOLD) functional connectivity. These findings suggest that serotonin-2A-mediated modulation of pyramidal-neuronal gain is a circuit mechanism through which LSD alters cortical functional topography. Individual-subject model fitting captures patterns of individual neural differences in pharmacological response related to altered states of consciousness. This work establishes a framework for linking molecular-level manipulations to systems-level functional alterations, with implications for precision medicine.

Difficulties in advancing effective patient-specific therapies for psychiatric disorders highlight a need to develop a stable neurobiologically grounded mapping between neural and symptom variation. This gap is particularly acute for psychosis-spectrum disorders (PSD). Here, in a sample of 436 PSD patients spanning several diagnoses, we derived and replicated a dimensionality-reduced symptom space across hallmark psychopathology symptoms and cognitive deficits. In turn, these symptom axes mapped onto distinct, reproducible brain maps. Critically, we found that multivariate brain-behavior mapping techniques (e.g. canonical correlation analysis) do not produce stable results with current sample sizes. However, we show that a univariate brain-behavioral space (BBS) can resolve stable individualized prediction. Finally, we show a proof-of-principle framework for relating personalized BBS metrics with molecular targets via serotonin and glutamate receptor manipulations and neural gene expression maps derived from the Allen Human Brain Atlas. Collectively, these results highlight a stable and data-driven BBS mapping across PSD, which offers an actionable path that can be iteratively optimized for personalized clinical biomarker endpoints.

The search for the chemical origins of life represents a long-standing and continuously debated enigma. Despite its exceptional complexity, in the last decades the field has experienced a revival, also owing to the exponential growth of the computing power allowing for efficiently simulating the behavior of matter—including its quantum nature—under disparate conditions found, e.g., on the primordial Earth and on Earth-like planetary systems (i.e., exoplanets). In this minireview, we focus on some advanced computational methods capable of efficiently solving the Schrödinger equation at different levels of approximation (i.e., density functional theory)—such as ab initio molecular dynamics—and which are capable to realistically simulate the behavior of matter under the action of energy sources available in prebiotic contexts. In addition, recently developed metadynamics methods coupled with first-principles simulations are here reviewed and exploited to answer to old enigmas and to propose novel scenarios in the exponentially growing research field embedding the study of the chemical origins of life.

Development and aging of the cerebral cortex show similar topographic organization and are governed by the same genes. It is unclear whether the same is true for subcortical regions, which follow fundamentally different ontogenetic and phylogenetic principles. We tested the hypothesis that genetically governed neurodevelopmental processes can be traced throughout life by assessing to which degree brain regions that develop together continue to change together through life. Analyzing over 6000 longitudinal MRIs of the brain, we used graph theory to identify five clusters of coordinated development, indexed as patterns of correlated volumetric change in brain structures. The clusters tended to follow placement along the cranial axis in embryonic brain development, suggesting continuity from prenatal stages, and correlated with cognition. Across independent longitudinal datasets, we demonstrated that developmental clusters were conserved through life. Twin-based genetic correlations revealed distinct sets of genes governing change in each cluster. Single-nucleotide polymorphisms-based analyses of 38,127 cross-sectional MRIs showed a similar pattern of genetic volume–volume correlations. In conclusion, coordination of subcortical change adheres to fundamental principles of lifespan continuity and genetic organization.

Nitriding can significantly increase the load carrying properties of gears. While the diffusion layer is primarily responsible for improving the tooth root and flank load carrying capacity, the compound layer mainly determines the tribological properties of the gear surface. In the present work, the influence of the compound layer on the tribological load carrying capacity of nitrided gears in the N/N pairing was investigated. For this purpose, compound layers with different thickness, porosity and phase composition were produced and their micro-pitting and wear behavior were investigated in load stage and speed stage tests. The test results confirm that the properties of the compound layer are decisive for the micro-pitting and wear resistance of nitrided gears. For a high micro-pitting resistance, the presence of pores in the near-surface area of the compound layer is of high importance, since no micro-pitting occurred as long as pores were present. With regard to the wear behavior, no dependence on the compound layer thickness or the porous zone thickness was found while the phase composition of the compound layer shows a decisive influence.

Because of the impact of lubrication on the efficiency and the lifecycle cost and emissions, the lubricating-oil consumption (LOC) is one of the key indicators in the research and development of internal combustion engines. State-of-the-art methods for LOC measurement are based on the use of a certain tracer to track the oil consumption. However, all of the currently available tracers have their downsides (e.g., the use of a radioactive tracer, corrosive emissions, etc.). Therefore, in the course of this research project, a new tracer substance that is based on a stable nonradioactive isotope of hydrogen—deuterium—was developed and tested thoroughly. The LOC is monitored by a hydrogen/deuterium isotopic ration in the exhaust gas by using an isotopic water analyzer. Tribologically important properties, such as the viscosity, stability, and compatibility of the tracer were investigated by laboratory experiments by using several tools, such as infrared spectroscopy, gas chromatography, thermogravimetry, etc. The properties relevant to the applicability of the method, such as the accuracy and the reproducibility, were investigated by engine test-bench experiments. Finally, long-term stability tests of the tracer were conducted with a field test.

Evolution is full of coevolving systems characterized by complex spatio-temporal interactions that lead to intertwined processes of adaptation. Yet, how adaptation across multiple levels of temporal scales and biological complexity is achieved remains unclear. Here, we formalize how evolutionary multi-scale processing underlying adaptation constitutes a form of metacognition flowing from definitions of metaprocessing in machine learning. We show (1) how the evolution of metacognitive systems can be expected when fitness landscapes vary on multiple time scales, and (2) how multiple time scales emerge during coevolutionary processes of sufficiently complex interactions. After defining a metaprocessor as a regulator with local memory, we prove that metacognition is more energetically efficient than purely object-level cognition when selection operates at multiple timescales in evolution. Furthermore, we show that existing modeling approaches to coadaptation and coevolution—here active inference networks, predator–prey interactions, coupled genetic algorithms, and generative adversarial networks—lead to multiple emergent timescales underlying forms of metacognition. Lastly, we show how coarse-grained structures emerge naturally in any resource-limited system, providing sufficient evidence for metacognitive systems to be a prevalent and vital component of (co-)evolution. Therefore, multi-scale processing is a necessary requirement for many evolutionary scenarios, leading to de facto metacognitive evolutionary outcomes.

The explosion in population genomic data demands ever more complex modes of analysis, and increasingly, these analyses depend on sophisticated simulations. Recent advances in population genetic simulation have made it possible to simulate large and complex models, but specifying such models for a particular simulation engine remains a difficult and error-prone task. Computational genetics researchers currently re-implement simulation models independently, leading to inconsistency and duplication of effort. This situation presents a major barrier to empirical researchers seeking to use simulations for power analyses of upcoming studies or sanity checks on existing genomic data. Population genetics, as a field, also lacks standard benchmarks by which new tools for inference might be measured. Here, we describe a new resource, stdpopsim, that attempts to rectify this situation. Stdpopsim is a community-driven open source project, which provides easy access to a growing catalog of published simulation models from a range of organisms and supports multiple simulation engine backends. This resource is available as a well-documented python library with a simple command-line interface. We share some examples demonstrating how stdpopsim can be used to systematically compare demographic inference methods, and we encourage a broader community of developers to contribute to this growing resource.

Drosophila blood cells, called hemocytes, are classified into plasmatocytes, crystal cells, and lamellocytes based on the expression of a few marker genes and cell morphologies, which are inadequate to classify the complete hemocyte repertoire. Here, we used single-cell RNA sequencing (scRNA-seq) to map hemocytes across different inflammatory conditions in larvae. We resolved plasmatocytes into different states based on the expression of genes involved in cell cycle, antimicrobial response, and metabolism together with the identification of intermediate states. Further, we discovered rare subsets within crystal cells and lamellocytes that express fibroblast growth factor (FGF) ligand branchless and receptor breathless, respectively. We demonstrate that these FGF components are required for mediating effective immune responses against parasitoid wasp eggs, highlighting a novel role for FGF signaling in inter-hemocyte crosstalk. Our scRNA-seq analysis reveals the diversity of hemocytes and provides a rich resource of gene expression profiles for a systems-level understanding of their functions.

Abstract The treatment of bone defects with recombinant bone morphogenetic protein‐2 (BMP‐2) requires high doses precluding broad clinical application. Here, a bioengineering approach is presented that strongly improves low‐dose BMP‐2‐based bone regeneration by mobilizing healing‐associated mesenchymal progenitor cells (MPCs). Smart synthetic hydrogels are used to trap and study endogenous MPCs trafficking to bone defects. Hydrogel‐trapped and prospectively isolated MPCs differentiate into multiple lineages in vitro and form bone in vivo. In vitro screenings reveal that platelet‐derived growth factor BB (PDGF‐BB) strongly recruits prospective MPCs making it a promising candidate for the engineering of hydrogels that enrich endogenous MPCs in vivo. However, PDGF‐BB inhibits BMP‐2‐mediated osteogenesis both in vitro and in vivo. In contrast, smart two‐way dynamic release hydrogels with fast‐release of PDGF‐BB and sustained delivery of BMP‐2 beneficially promote the healing of bone defects. Collectively, it is shown that modulating the dynamics of endogenous progenitor cells in vivo by smart synthetic hydrogels significantly improves bone healing and holds great potential for other advanced applications in regenerative medicine.

Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high-throughput screen identified two structurally distinct TPC2 agonists. One of these evoked robust Ca2+-signals and non-selective cation currents, the other weaker Ca2+-signals and Na+-selective currents. These properties were mirrored by the Ca2+-mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P2, respectively. Agonist action was differentially inhibited by mutation of a single TPC2 residue and coupled to opposing changes in lysosomal pH and exocytosis. Our findings resolve conflicting reports on the permeability and gating properties of TPC2 and they establish a new paradigm whereby a single ion channel mediates distinct, functionally-relevant ionic signatures on demand.

There is an urgent need to develop new methods for male contraception, however a major barrier to drug discovery has been the lack of validated targets and the absence of an effective high-throughput phenotypic screening system. To address this deficit, we developed a fully-automated robotic screening platform that provided quantitative evaluation of compound activity against two key attributes of human sperm function: motility and acrosome reaction. In order to accelerate contraceptive development, we screened the comprehensive collection of 12,000 molecules that make up the ReFRAME repurposing library, comprising nearly all the small molecules that have been approved or have undergone clinical development, or have significant preclinical profiling. We identified several compounds that potently inhibit motility representing either novel drug candidates or routes to target identification. This platform will now allow for major drug discovery programmes that address the critical gap in the contraceptive portfolio as well as uncover novel human sperm biology.

Background: Severe aortic valve stenosis (AS) is associated with pulmonary hypertension (PH) and has been shown to limit patient survival. Soluble suppression of tumorigenicity-2 (sST2) is a cardiovascular biomarker that has proven to be an important prognostic marker for survival in patients undergoing transcatheter aortic valve replacement (TAVR). The aim of this study was to assess the importance of the sST2 biomarker for risk stratification in patients with severe AS in presence or absence of PH. Methods: In 260 patients with severe AS undergoing TAVR procedure, sST2 serum level concentrations were analyzed. Right heart catheter measurements were performed in 152 patients, with no PH detection in 43 patients and with PH detection in 109 patients. Correlation analyses according to Spearman, AUROC analyses and Kaplan–Meier curves were calculated. Results: Patients with severe AS and PH showed significantly higher serum sST2 concentrations (p = 0.006). The sST2 cut-off value for non-PH patients regarding 1-year survival yielded 5521.15 pg/mL, whereas the cut-off value of PH patients was at a considerably higher level of 10,268.78 pg/mL. A cut-off value of 6990.12 pg/mL was related with a significant probability of PH presence. Survival curves showed that patients with severe AS and PH not only had higher 1-year mortality, but also that increased levels of sST2 plasma concentration were associated with earlier death. Conclusion: sST2 definitely has the potential to provide information about the presence of PH in patients with severe AS, in a noninvasive way.

The authors wish to make the following corrections to this paper [...]

Comparing neuronal microcircuits across different brain regions, species and individuals can reveal common and divergent principles of network computation. Simultaneous patch-clamp recordings from multiple neurons offer the highest temporal and subthreshold resolution to analyse local synaptic connectivity. However, its establishment is technically complex and the experimental performance is limited by high failure rates, long experimental times and small sample sizes. We introduce an in vitro multipatch setup with an automated pipette pressure and cleaning system facilitating recordings of up to 10 neurons simultaneously and sequential patching of additional neurons. We present hardware and software solutions that increase the usability, speed and data throughput of multipatch experiments which allowed probing of 150 synaptic connections between 17 neurons in one human cortical slice and screening of over 600 connections in tissue from a single patient. This method will facilitate the systematic analysis of microcircuits and allow unprecedented assessment of inter-individual variability.

The Plankton, Aerosol, Cloud, ocean Ecosystem (PACE) mission will carry into space the Ocean Color Instrument (OCI), a spectrometer measuring at 5 nm spectral resolution in the ultraviolet (UV) to near infrared (NIR) with additional spectral bands in the shortwave infrared (SWIR), and two multi-angle polarimeters that will overlap the OCI spectral range and spatial coverage, i. e., the Spectrometer for Planetary Exploration (SPEXone) and the Hyper-Angular Rainbow Polarimeter (HARP2). These instruments, especially when used in synergy, have great potential for improving estimates of water reflectance in the post Earth Observing System (EOS) era. Extending the top-of-atmosphere (TOA) observations to the UV, where aerosol absorption is effective, adding spectral bands in the SWIR, where even the most turbid waters are black and sensitivity to the aerosol coarse mode is higher than at shorter wavelengths, and measuring in the oxygen A-band to estimate aerosol altitude will enable greater accuracy in atmospheric correction for ocean color science. The multi-angular and polarized measurements, sensitive to aerosol properties (e.g., size distribution, index of refraction), can further help to identify or constrain the aerosol model, or to retrieve directly water reflectance. Algorithms that exploit the new capabilities are presented, and their ability to improve accuracy is discussed. They embrace a modern, adapted heritage two-step algorithm and alternative schemes (deterministic, statistical) that aim at inverting the TOA signal in a single step. These schemes, by the nature of their construction, their robustness, their generalization properties, and their ability to associate uncertainties, are expected to become the new standard in the future. A strategy for atmospheric correction is presented that ensures continuity and consistency with past and present ocean-color missions while enabling full exploitation of the new dimensions and possibilities. Despite the major improvements anticipated with the PACE instruments, gaps/issues remain to be filled/tackled. They include dealing properly with whitecaps, taking into account Earth-curvature effects, correcting for adjacency effects, accounting for the coupling between scattering and absorption, modeling accurately water reflectance, and acquiring a sufficiently representative dataset of water reflectance in the UV to SWIR. Dedicated efforts, experimental and theoretical, are in order to gather the necessary information and rectify inadequacies. Ideas and solutions are put forward to address the unresolved issues. Thanks to its design and characteristics, the PACE mission will mark the beginning of a new era of unprecedented accuracy in ocean-color radiometry from space.

Kinetochores are macromolecular protein complexes at centromeres that ensure accurate chromosome segregation by attaching chromosomes to spindle microtubules and integrating safeguard mechanisms. The inner kinetochore is assembled on CENP-A nucleosomes and has been implicated in establishing a kinetochore-associated pool of Aurora B kinase, a chromosomal passenger complex (CPC) subunit, which is essential for chromosome biorientation. By performing crosslink-guided in vitro reconstitution of budding yeast kinetochore complexes we showed that the Ame1/Okp1CENP-U/Q heterodimer, which forms the COMA complex with Ctf19/Mcm21CENP-P/O, selectively bound Cse4CENP-A nucleosomes through the Cse4 N-terminus. The Sli15/Ipl1INCENP/Aurora-B core-CPC interacted with COMA in vitro through the Ctf19 C-terminus whose deletion affected chromosome segregation fidelity in Sli15 wild-type cells. Tethering Sli15 to Ame1/Okp1 rescued synthetic lethality upon Ctf19 depletion in a Sli15 centromere-targeting deficient mutant. This study shows molecular characteristics of the point-centromere kinetochore architecture and suggests a role for the Ctf19 C-terminus in mediating CPC-binding and accurate chromosome segregation.

The Alphaproteobacteria is an extraordinarily diverse and ancient group of bacteria. Previous attempts to infer its deep phylogeny have been plagued with methodological artefacts. To overcome this, we analyzed a dataset of 200 single-copy and conserved genes and employed diverse strategies to reduce compositional artefacts. Such strategies include using novel dataset-specific profile mixture models and recoding schemes, and removing sites, genes and taxa that are compositionally biased. We show that the Rickettsiales and Holosporales (both groups of intracellular parasites of eukaryotes) are not sisters to each other, but instead, the Holosporales has a derived position within the Rhodospirillales. A synthesis of our results also leads to an updated proposal for the higher-level taxonomy of the Alphaproteobacteria. Our robust consensus phylogeny will serve as a framework for future studies that aim to place mitochondria, and novel environmental diversity, within the Alphaproteobacteria.

The meiotic chromosome axis plays key roles in meiotic chromosome organization and recombination, yet the underlying protein components of this structure are highly diverged. Here, we show that ‘axis core proteins’ from budding yeast (Red1), mammals (SYCP2/SYCP3), and plants (ASY3/ASY4) are evolutionarily related and play equivalent roles in chromosome axis assembly. We first identify ‘closure motifs’ in each complex that recruit meiotic HORMADs, the master regulators of meiotic recombination. We next find that axis core proteins form homotetrameric (Red1) or heterotetrameric (SYCP2:SYCP3 and ASY3:ASY4) coiled-coil assemblies that further oligomerize into micron-length filaments. Thus, the meiotic chromosome axis core in fungi, mammals, and plants shares a common molecular architecture, and likely also plays conserved roles in meiotic chromosome axis assembly and recombination control.

Our article proposes a set of six criteria for analysing science-technology-society-environment (STSE) issues in regular textbooks as to how they are expected to contribute to students’ scientific literacy. We chose genetics and gene technology as fields prolific in STSE issues. We derived our criteria (including 26 sub-criteria) from a literature review of the debate in science education on how to increase scientific literacy. We inspected the textbooks regarding the relationships between science, technology, society, and environment, and considered the presence of the decontextualized and socially neutral view of science as distorted view. We, qualitatively and quantitatively, applied our set of criteria to two German Biology textbooks and identified, in total, 718 STSE statements. Based on the frequencies of different criteria and sub-criteria in the textbooks, we drew conclusions concerning STSE issues and the underlying conceptions of science and technology, which might hinder the furtherance of scientific literacy. The applicability of our approach in other science education contexts is discussed.

For a tribological experiment involving a steel shaft sliding in a self-lubricating bronze bearing, a semi-supervised machine learning method for the classification of the state of operation is proposed. During the translatory oscillating motion, the system may undergo different states of operation from normal to critical, showing self-recovering behaviour. A Random Forest classifier was trained on individual cycles from the lateral force data from four distinct experimental runs in order to distinguish between four states of operation. The labelling of the individual cycles proved to be crucial for a high prediction accuracy of the trained RF classifier. The proposed semi-supervised approach allows choosing within a range between automatically generated labels and full manual labelling by an expert user. The algorithm was at the current state used for ex post classification of the state of operation. Considering the results from the ex post analysis and providing a sufficiently sized training dataset, online classification of the state of operation of a system will be possible. This will allow taking active countermeasures to stabilise the system or to terminate the experiment before major damage occurs.