Laser-Pulse-Length Effects in Ultrafast Laser Desorption.

Shortening the laser pulse length opens up new opportunities for laser desorption (LD) of molecules, with benefits for mass spectrometry (MS) sampling and ionization. The capability to ablate any material without the need for an absorbing matrix and the decrease of thermal damage and molecular fragmentation has promoted various applications with very different parameters and postionization techniques. However, the key issues of the optimum laser pulse length and intensity to achieve efficient and gentle desorption of molecules for postionization in MS are not resolved, although these parameters determine the costs and complexity of the required laser system. Here, we address this research gap with a systematic study on the effect of the pulse length on the LD of molecules. Keeping all other optical and ionization parameters constant, we directly compared the pulses in the femtosecond, picosecond, and nanosecond range with respect to LD-induced fragmentation and desorption efficiency. To represent real-world applications, we investigated the LD of over-the-counter medicaments naproxen and ibuprofen directly from tablets as well as the LD of retene and ship emission aerosols from a quartz filter. With our study design, we excluded interfering effects on fragmentation and LD efficiency from, for example, collisional cooling or postionization by performing the experiments in vacuum with resonance-enhanced multiphoton ionization as the postionization technique. Regarding LD-induced fragmentation, we already found benefits for the picosecond pulses. However, the efficiency of LD was found to continuously increase with decreasing pulse length, pointing to the application potential of ultrashort pulses in trace analytics. Because many interfering effects beyond the LD pulse length could be excluded in the experiment, our results may be directly transferable to the LD applied in other techniques.

Targeting Longevity Gene SLC13A5: A Novel Approach to Prevent Age-Related Bone Fragility and Osteoporosis.

Reduced expression of the plasma membrane citrate transporter SLC13A5, also known as INDY, has been linked to increased longevity and mitigated age-related cardiovascular and metabolic diseases. Citrate, a vital component of the tricarboxylic acid cycle, constitutes 1-5% of bone weight, binding to mineral apatite surfaces. Our previous research highlighted osteoblasts' specialized metabolic pathway facilitated by SLC13A5 regulating citrate uptake, production, and deposition within bones. Disrupting this pathway impairs bone mineralization in young mice. New Mendelian randomization analysis using UK Biobank data indicated that SNPs linked to reduced SLC13A5 function lowered osteoporosis risk. Comparative studies of young (10 weeks) and middle-aged (52 weeks) osteocalcin-cre-driven osteoblast-specific Slc13a5 knockout mice (Slc13a5cKO) showed a sexual dimorphism: while middle-aged females exhibited improved elasticity, middle-aged males demonstrated enhanced bone strength due to reduced SLC13A5 function. These findings suggest reduced SLC13A5 function could attenuate age-related bone fragility, advocating for SLC13A5 inhibition as a potential osteoporosis treatment.

Exploring disease-causing traits for drug repurposing in critically ill COVID-19 patients: A causal inference approach.

Despite recent development of vaccines to prevent SARS-CoV-2 infection, treatment of critically ill COVID-19 patients remains an important goal. In principle, genome-wide association studies (GWASs) provide a shortcut to the clinical evidence needed to repurpose existing drugs; however, genes identified frequently lack a causal disease link. We report an alternative method for finding drug repurposing targets, focusing on disease-causing traits beyond immediate disease genetics. Sixty blood cell types and biochemistries, and body mass index, were screened on a cohort of critically ill COVID-19 cases and controls that exhibited mild symptoms after infection, yielding high neutrophil cell count as a possible causal trait for critical illness. Our methodology identified CDK6 and janus kinase (JAK) inhibitors as treatment targets that were validated in an ex vivo neutrophil extracellular trap (NET) formation assay. Our methodology demonstrates the increased power for drug target identification by leveraging large disease-causing trait datasets.

Rooting depth and xylem vulnerability are independent woody plant traits jointly selected by aridity, seasonality, and water table depth.

Evolutionary radiations of woody taxa within arid environments were made possible by multiple trait innovations including deep roots and embolism-resistant xylem, but little is known about how these traits have coevolved across the phylogeny of woody plants or how they jointly influence the distribution of species. We synthesized global trait and vegetation plot datasets to examine how rooting depth and xylem vulnerability across 188 woody plant species interact with aridity, precipitation seasonality, and water table depth to influence species occurrence probabilities across all biomes. Xylem resistance to embolism and rooting depth are independent woody plant traits that do not exhibit an interspecific trade-off. Resistant xylem and deep roots increase occurrence probabilities in arid, seasonal climates over deep water tables. Resistant xylem and shallow roots increase occurrence probabilities in arid, nonseasonal climates over deep water tables. Vulnerable xylem and deep roots increase occurrence probabilities in arid, nonseasonal climates over shallow water tables. Lastly, vulnerable xylem and shallow roots increase occurrence probabilities in humid climates. Each combination of trait values optimizes occurrence probabilities in unique environmental conditions. Responses of deeply rooted vegetation may be buffered if evaporative demand changes faster than water table depth under climate change.

The Data Portal "Chromosome Numbers of the Flora of Germany": Progress After Five Years, Recent Developments, and Future Strategies.

Chromosome numbers and information on ploidy level are of great importance for better understanding of plant evolution and taxonomy but also for species identification. Technical developments in flow cytometry dramatically improved the measurement of genome size and triggered a renewed interest in chromosome numbers. Web-based portals make these kind of data accessible for a wide audience in both academia and citizen science. The specialised database of German plant chromosome counts and ploidy estimates comprises to date more than 14,000 records covering 52% of the German taxa. The database is accessed about 70 times per month and became an integral part of several more comprehensive initiatives. One example is the Rothmaler Flora of Germany, which now for the first time features chromosome data with verified origin from the region of interest. Another is the German plant information hub FloraWeb currently amended by several new data sources with the chromosome number database as a major component.

Human infants are aroused and concerned by moral transgressions.

Humans reason and care about ethical issues, such as avoiding unnecessary harm. But what enables us to develop a moral capacity? This question dates back at least to ancient Greece and typically results in the traditional opposition between sentimentalism (the view that morality is mainly driven by socioaffective processes) and rationalism [the view that morality is mainly driven by (socio)cognitive processes or reason]. Here, we used multiple methods (eye-tracking and observations of expressive behaviors) to assess the role of both cognitive and socioaffective processes in infants' developing morality. We capitalized on the distinction between moral (e.g., harmful) and conventional (e.g., harmless) transgressions to investigate whether 18-mo-old infants understand actions as distinctively moral as opposed to merely disobedient or unexpected. All infants watched the same social scene, but based on prior verbal interactions, an actor's tearing apart of a picture (an act not intrinsically harmful) with a tool constituted either a conventional (wrong tool), a moral (producing harm), or no violation (correct tool). Infants' anticipatory looks differentiated between conventional and no violation conditions, suggesting that they processed the verbal interactions and built corresponding expectations. Importantly, infants showed a larger increase in pupil size (physiological arousal), and more expressions indicating empathic concern, in response to a moral than to a conventional violation. Thus, infants differentiated between harmful and harmless transgressions based solely on prior verbal interactions. Together, these convergent findings suggest that human infants' moral development is fostered by both sociocognitive (inferring harm) and socioaffective processes (empathic concern for others' welfare).

CimpleG: finding simple CpG methylation signatures.

DNA methylation signatures are usually based on multivariate approaches that require hundreds of sites for predictions. Here, we propose a computational framework named CimpleG for the detection of small CpG methylation signatures used for cell-type classification and deconvolution. We show that CimpleG is both time efficient and performs as well as top performing methods for cell-type classification of blood cells and other somatic cells, while basing its prediction on a single DNA methylation site per cell type. Altogether, CimpleG provides a complete computational framework for the delineation of DNAm signatures and cellular deconvolution.

Cooling-induced expansions of Afromontane forests in the Horn of Africa since the Last Glacial Maximum.

Understanding the changing plant ecosystems that existed in East Africa over the past millennia is crucial for identifying links between habitats and past human adaptation and dispersal across the region. In the Horn of Africa, this task is hampered by the scarcity of fossil botanical data. Here we present modelled past vegetation distributions in Ethiopia from the Last Glacial Maximum (LGM) to present at high spatial and temporal resolution. The simulations show that, contrary to long-standing hypotheses, the area covered by Afromontane forests during the Late Glacial was significantly larger than at present. The combined effect of low temperatures and the relative rainfall contribution sourced from the Congo Basin and Indian Ocean, emerges as the mechanism that controlled the migration of Afromontane forests to lower elevations. This process may have enabled the development of continuous forest corridors connecting populations that are currently isolated in mountainous areas over the African continent. Starting with the Holocene, the expansion of forests began to reverse. This decline intensified over the second half of the Holocene leading to a retreat of the forests to higher elevations where they are restricted today. The simulations are consistent with proxy data derived from regional pollen records and provide a key environmental and conceptual framework for human environmental adaptation research.

YAP1 is essential for self-organized differentiation of pluripotent stem cells.

Induced pluripotent stem cells (iPSCs) form aggregates that recapitulate aspects of the self-organization in early embryogenesis. Within few days, cells undergo a transition from epithelial-like structures to organized three-dimensional embryoid bodies (EBs) with upregulation of germ layer-specific genes. However, it is largely unclear, which signaling cascades regulate self-organized differentiation. The Yes-associated protein 1 (YAP1) is a downstream effector of the Hippo pathway and essential mechanotransducer. YAP1 has been suggested to play a crucial role for early embryo development, but the relevance for early germ layer commitment of human iPSCs remains to be elucidated. To gain insights into the function of YAP1 in early cell-fate decisions, we generated YAP1 knockout (YAP-/-) iPSC lines with CRISPR/Cas9 technology and analyzed transcriptomic and epigenetic modifications. YAP-/- iPSCs showed increased expression of several YAP1 targets and of NODAL, an important regulator of cell differentiation. Furthermore, YAP1 deficiency evoked global DNA methylation changes. Directed differentiation of adherent iPSC colonies towards endoderm, mesoderm, and ectoderm could be induced, albeit endodermal and ectodermal differentiation showed transcriptomic and epigenetic changes in YAP-/- lines. Notably, in undirected self-organized YAP-/- EBs germ layer specification was clearly impaired. This phenotype was rescued via lentiviral overexpression of YAP1 and also by NODAL inhibitors. Our results demonstrate that YAP1 plays an important role during early germ layer specification of iPSCs, particularly for the undirected self-organization of EBs, and this is at least partly attributed to activation of the NODAL signaling.

Epigenetic biomarkers to track differentiation of pluripotent stem cells.

Quality control of induced pluripotent stem cells remains a challenge. For validation of the pluripotent state, it is crucial to determine trilineage differentiation potential toward endoderm, mesoderm, and ectoderm. Here, we report GermLayerTracker, a combination of site-specific DNA methylation (DNAm) assays that serve as biomarker for early germ layer specification. CG dinucleotides (CpGs) were identified with characteristic DNAm at pluripotent state and after differentiation into endoderm, mesoderm, and ectoderm. Based on this, a pluripotency score was derived that tracks reprogramming and may indicate differentiation capacity, as well as lineage-specific scores to monitor either directed differentiation or self-organized multilineage differentiation in embryoid bodies. Furthermore, we established pyrosequencing assays for fast and cost-effective analysis. In the future, the GermLayerTracker could be used for quality control of pluripotent cells and to estimate lineage-specific commitment during initial differentiation events.

How to prevent technostress at the digital workplace: a Delphi study.

Technostress is a rising issue in the changing world of digital work. Technostress can cause severe adverse outcomes for individuals and organizations. Thus, organizations face the moral, legal, and economic responsibility to prevent employees' excessive technostress. As technostress develops over time, it is crucial to prevent it throughout the process of its emergence instead of only reacting after adverse outcomes occur. Contextualizing the Theory of Preventive Stress management to technostress, we synthesize and advance existing knowledge on inhibiting technostress. We develop a set of 24 technostress prevention measures from technostress inhibitor literature, other technostress literature, and based on qualitative and quantitative contributions from a Delphi study. Based on expert feedback, we characterize each measure and, where possible, assess its relevance in addressing specific technostressors. Our paper contributes to research by transferring the Theory of Preventive Stress Management into the context of technostress and presenting specific measures to prevent technostress. This offers a complementary view to technostress inhibitors by expanding the theoretical grounding and adding a time perspective through the implementation of primary, secondary, and tertiary prevention measures. For practice, we offer a comprehensive and applicable overview of measures organizations can implement to prevent technostress.

Global patterns of vascular plant alpha diversity.

Global patterns of regional (gamma) plant diversity are relatively well known, but whether these patterns hold for local communities, and the dependence on spatial grain, remain controversial. Using data on 170,272 georeferenced local plant assemblages, we created global maps of alpha diversity (local species richness) for vascular plants at three different spatial grains, for forests and non-forests. We show that alpha diversity is consistently high across grains in some regions (for example, Andean-Amazonian foothills), but regional 'scaling anomalies' (deviations from the positive correlation) exist elsewhere, particularly in Eurasian temperate forests with disproportionally higher fine-grained richness and many African tropical forests with disproportionally higher coarse-grained richness. The influence of different climatic, topographic and biogeographical variables on alpha diversity also varies across grains. Our multi-grain maps return a nuanced understanding of vascular plant biodiversity patterns that complements classic maps of biodiversity hotspots and will improve predictions of global change effects on biodiversity.

Great apes and human children rationally monitor their decisions.

Several species can detect when they are uncertain about what decision to make-revealed by opting out of the choice, or by seeking more information before deciding. However, we do not know whether any nonhuman animals recognize when they need more information to make a decision because new evidence contradicts an already-formed belief. Here, we explore this ability in great apes and human children. First, we show that after great apes saw new evidence contradicting their belief about which of two rewards was greater, they stopped to recheck the evidence for their belief before deciding. This indicates the ability to keep track of the reasons for their decisions, or 'rational monitoring' of the decision-making process. Children did the same at 5 years of age, but not at 3 years. In a second study, participants formed a belief about a reward's location, but then a social partner contradicted them, by picking the opposite location. This time even 3-year-old children rechecked the evidence, while apes ignored the disagreement. While apes were sensitive only to the conflict in physical evidence, the youngest children were more sensitive to peer disagreement than conflicting physical evidence.

Preschoolers agree to and enforce prosocial, but not selfish, sharing norms.

Young children act prosocially in many contexts but are somewhat selfish when it comes to sharing their resources in individual decision-making situations (e.g., the dictator game). But when deciding collectively, would they make it a binding rule for themselves and others to act selfishly in a resource sharing context? Here we used a novel "group dictator game" in a norm creation paradigm to investigate whether 3- and 5-year-olds (N = 48) would agree to and enforce a selfish or prosocial sharing norm. Children from a Western cultural background were paired with two puppets at a time. Each group member had an endowment of four stickers and faced a photograph of a recipient. In the prosocial norm condition a proposer puppet suggested to share half of one's endowment, whereas in the selfish norm condition another proposer suggested to share nothing. The protagonist puppet then either followed or violated the suggested norm. We found that 5-year-olds (but not 3-year-olds) rejected selfish proposals more often than prosocial proposals. Importantly, older (but not younger) preschoolers also enforced the prosocial (but not the selfish) norm by protesting normatively and intervening when the protagonist acted selfishly (and thus violated the norm). These results indicate that a collective decision-making context may enhance preschoolers' prosociality and that moral considerations on the content of a proposed sharing rule influence preschoolers' creation and enforcement of such nonarbitrary norms.

Interaction-Based Feature Selection Algorithm Outperforms Polygenic Risk Score in Predicting Parkinson's Disease Status.

Polygenic risk scores (PRS) aggregating results from genome-wide association studies are the state of the art in the prediction of susceptibility to complex traits or diseases, yet their predictive performance is limited for various reasons, not least of which is their failure to incorporate the effects of gene-gene interactions. Novel machine learning algorithms that use large amounts of data promise to find gene-gene interactions in order to build models with better predictive performance than PRS. Here, we present a data preprocessing step by using data-mining of contextual information to reduce the number of features, enabling machine learning algorithms to identify gene-gene interactions. We applied our approach to the Parkinson's Progression Markers Initiative (PPMI) dataset, an observational clinical study of 471 genotyped subjects (368 cases and 152 controls). With an AUC of 0.85 (95% CI = [0.72; 0.96]), the interaction-based prediction model outperforms the PRS (AUC of 0.58 (95% CI = [0.42; 0.81])). Furthermore, feature importance analysis of the model provided insights into the mechanism of Parkinson's disease. For instance, the model revealed an interaction of previously described drug target candidate genes TMEM175 and GAPDHP25. These results demonstrate that interaction-based machine learning models can improve genetic prediction models and might provide an answer to the missing heritability problem.

Clinical and cardiac magnetic resonance findings in post-COVID patients referred for suspected myocarditis.

OBJECTIVES: We assessed possible myocardial involvement in previously cardiac healthy post-COVID patients referred for persisting symptoms with suspected myocarditis. BACKGROUND: Prior studies suggested myocardial inflammation in patients with coronavirus-induced disease 2019 (COVID-19). However, the prevalence of cardiac involvement among COVID patients varied between 1.4 and 78%. METHODS: A total of 56 post-COVID patients without previous heart diseases were included consecutively into this study. All patients had positive antibody titers against SARS-CoV-2. Patients were referred for persistent symptoms such as chest pain/discomfort, shortness of breath, or intolerance to activity. All patients underwent standardized cardiac assessment including electrocardiogram (ECG), cardiac biomarkers, echocardiography, and cardiac magnetic resonance (CMR). RESULTS: 56 Patients (46 ± 12 years, 54% females) presented 71 ± 66 days after their COVID-19 disease. In most patients, the course of COVID-19 was mild, with hospital treatment being necessary in five (9%). At presentation, patients most often reported persistent fatigue (75%), chest pain (71%), and shortness of breath (66%). Acute myocarditis was confirmed by T1/T2-weighed CMR and elevated NTpro-BNP levels in a single patient (2%). Left ventricular ejection fraction was 56% in this patient. Additional eight patients (14%) showed suspicious CMR findings, including myocardial edema without fibrosis (n = 3), or non-ischemic myocardial injury suggesting previous inflammation (n = 5). However, myocarditis could ultimately not be confirmed according to 2018 Lake Louise criteria; ECG, echo and lab findings were inconspicuous in all eight patients. CONCLUSIONS: Among 56 post-COVID patients with persistent thoracic complaints final diagnosis of myocarditis could be confirmed in a single patient using CMR.

DNA methylation profiling in mummified human remains from the eighteenth-century.

Reconstruction of ancient epigenomes by DNA methylation (DNAm) can shed light into the composition of cell types, disease states, and age at death. However, such analysis is hampered by impaired DNA quality and little is known how decomposition affects DNAm. In this study, we determined if EPIC Illumina BeadChip technology is applicable for specimens from mummies of the eighteenth century CE. Overall, the signal intensity on the microarray was extremely low, but for one of two samples we were able to detect characteristic DNAm signals in a subset of CG dinucleotides (CpGs), which were selected with a stringent processing pipeline. Using only these CpGs we could train epigenetic signatures with reference DNAm profiles of multiple tissues and our predictions matched the fact that the specimen was lung tissue from a 28-year-old woman. Thus, we provide proof of principle that Illumina BeadChips are applicable for DNAm profiling in ancient samples.

Root traits explain plant species distributions along climatic gradients yet challenge the nature of ecological trade-offs.

Ecological theory is built on trade-offs, where trait differences among species evolved as adaptations to different environments. Trade-offs are often assumed to be bidirectional, where opposite ends of a gradient in trait values confer advantages in different environments. However, unidirectional benefits could be widespread if extreme trait values confer advantages at one end of an environmental gradient, whereas a wide range of trait values are equally beneficial at the other end. Here, we show that root traits explain species occurrences along broad gradients of temperature and water availability, but model predictions only resembled trade-offs in two out of 24 models. Forest species with low specific root length and high root tissue density (RTD) were more likely to occur in warm climates but species with high specific root length and low RTD were more likely to occur in cold climates. Unidirectional benefits were more prevalent than trade-offs: for example, species with large-diameter roots and high RTD were more commonly associated with dry climates, but species with the opposite trait values were not associated with wet climates. Directional selection for traits consistently occurred in cold or dry climates, whereas a diversity of root trait values were equally viable in warm or wet climates. Explicit integration of unidirectional benefits into ecological theory is needed to advance our understanding of the consequences of trait variation on species responses to environmental change.