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Von Willebrand disease (VWD), the most prevalent hereditary bleeding disorder, results from deficiency of von Willebrand factor (VWF).

The processes that govern human haematopoietic stem cell (HSC) self-renewal and engraftment are poorly understood and challenging to recapitulate in culture to reliably expand functional HSCs1–3. Here we identify MYC target 1 (MYCT1; also known as MTLC) as a crucial human HSC regulator that moderates endocytosis and environmental sensing in HSCs. MYCT1 is selectively expressed in undifferentiated human haematopoietic stem and progenitor cells (HSPCs) and endothelial cells but becomes markedly downregulated during HSC culture. Lentivirus-mediated knockdown of MYCT1prevented human fetal liver and cord blood (CB) HSPC expansion and engraftment. By contrast, restoring MYCT1 expression improved the expansion and engraftment of cultured CB HSPCs. Single-cell RNA sequencing of human CB HSPCs in which MYCT1was knocked down or overexpressed revealed that MYCT1 governs important regulatory programmes and cellular properties essential for HSC stemness, such as ETS factor expression and low mitochondrial activity. MYCT1 is localized in the endosomal membrane in HSPCs and interacts with vesicle trafficking regulators and signalling machinery. MYCT1 loss in HSPCs led to excessive endocytosis and hyperactive signalling responses, whereas restoring MYCT1 expression balanced culture-induced endocytosis and dysregulated signalling. Moreover, sorting cultured CB HSPCs on the basis of lowest endocytosis rate identified HSPCs with preserved MYCT1 expression and MYCT1-regulated HSC stemness programmes. Our work identifies MYCT1-moderated endocytosis and environmental sensing as essential regulatory mechanisms required to preserve human HSC stemness. Our data also pinpoint silencing of MYCT1 as a cell-culture-induced vulnerability that compromises human HSC expansion.

Sarcopenia is a known risk factor for adverse outcomes after esophageal cancer (EC) surgery. Robot-assisted minimally invasive esophagectomy (RAMIE) offers numerous advantages, including reduced morbidity and mortality. However, no evidence exists to date comparing the development of sarcopenia after RAMIE and open esophagectomy (OE). The objective was to evaluate whether the development of sarcopenia within the first postoperative year after esophagectomy is associated with the surgical approach: RAMIE versus OE.

Increased stress is a proposed risk factor for Alzheimer’s disease (AD). We examined cross-sectional associations between circulating stress biomarkers and multimodal measures of brain health and cognitive susceptibility to AD in older adults and sex-specific subgroups.

In life sciences, high-throughput techniques typically lead to high-dimensional data and often the number of covariates is much larger than the number of observations. This inherently comes with multicollinearity challenging a statistical analysis in a linear regression framework. Penalization methods such as the lasso, ridge regression, the group lasso, and convex combinations thereof, which introduce additional conditions on regression variables, have proven themselves effective. In this study, we introduce a novel approach by combining the lasso and the standardized group lasso leading to meaningful weighting of the predicted (“fitted”) outcome which is of primary importance, e.g., in breeding populations. This “fitted” sparse-group lasso was implemented as a proximal-averaged gradient descent method and is part of the R package “seagull” available at CRAN. For the evaluation of the novel method, we executed an extensive simulation study. We simulated genotypes and phenotypes which resemble data of a dairy cattle population. Genotypes at thousands of genomic markers were used as covariates to fit a quantitative response. The proximity of markers on a chromosome determined grouping. In the majority of simulated scenarios, the new method revealed improved prediction abilities compared to other penalization approaches and was able to localize the signals of simulated features.

In diesem Beitrag wird ein Schulungssystem für Bedienpersonal vorgestellt, das unter Nutzung von Virtueller Realität (VR) Wissen von Prozesszusammenhängen in Verarbeitungsmaschinen vermittelt. Die Kopplung der VR an ein semantisches Modell des Prozesses ermöglicht, dass sich Veränderungen von Einstellparametern durch den Lernenden realitätsgetreu auf die Visualisierung und die Animation des Prozessablaufs sowie die Produktqualität auswirken und eine Lernumgebung für effektive Aus- und Weiterbildung entsteht.

Sirtuins are protein deacylases regulating metabolism and stress responses and implicated in aging-related diseases. Modulators of the human sirtuins 1–7 are sought as chemical tools and potential therapeutics, for example, for treatment of cancer. We were able to show that 3-aryl-mercapto-succinylated- and 3-benzyl-mercapto-succinylated peptide derivatives yield selective Sirt5 inhibitors with low nM Kivalues. Here, we synthesized and characterized 3-aryl-mercapto-butyrylated peptide derivatives as effective and selective sirtuin 2 inhibitors with KDvalues in the low nanomolar range. According to kinetic measurements and microscale thermophoresis/surface plasmon resonance experiments, the respective inhibitors bind with the 3-aryl-mercapto moiety in the selectivity pocket of Sirtuin 2, inducing a rearrangement of the active site. In contrast, 3-aryl-mercapto-nonalyl or palmitoyl derivatives are characterized by a switch in the binding mode blocking both the hydrophobic channel by the fatty acyl chain and the nicotinamide pocket by the 3-aryl-mercapto moiety.

Adhesion G-protein-coupled receptors (aGPCRs) are important for organogenesis, neurodevelopment, reproduction and other processes1–6. Many aGPCRs are activated by a conserved internal (tethered) agonist sequence known as the Stachel sequence7–12. Here, we report the cryogenic electron microscopy (cryo-EM) structures of two aGPCRs in complex with Gs: GPR133 and GPR114. The structures indicate that the Stachel sequences of both receptors assume an α-helical–bulge–β-sheet structure and insert into a binding site formed by the transmembrane domain (TMD). A hydrophobic interaction motif (HIM) within the Stachel sequence mediates most of the intramolecular interactions with the TMD. Combined with the cryo-EM structures, biochemical characterization of the HIM motif provides insight into the cross-reactivity and selectivity of the Stachel sequences. Two interconnected mechanisms, the sensing of Stachel sequences by the conserved ‘toggle switch’ W6.53and the constitution of a hydrogen-bond network formed by Q7.49/Y7.49and the P6.47/V6.47φφG6.50motif (φ indicates a hydrophobic residue), are important in Stachel sequence-mediated receptor activation and Gscoupling. Notably, this network stabilizes kink formation in TM helices 6 and 7 (TM6 and TM7, respectively). A common Gs-binding interface is observed between the two aGPCRs, and GPR114 has an extended TM7 that forms unique interactions with Gs. Our structures reveal the detailed mechanisms of aGPCR activation by Stachel sequences and their Gscoupling.

The ontogeny of human haematopoietic stem cells (HSCs) is poorly defined owing to the inability to identify HSCs as they emerge and mature at different haematopoietic sites1. Here we created a single-cell transcriptome map of human haematopoietic tissues from the first trimester to birth and found that the HSC signature RUNX1+HOXA9+MLLT3+MECOM+HLF+SPINK2+distinguishes HSCs from progenitors throughout gestation. In addition to the aorta–gonad–mesonephros region, nascent HSCs populated the placenta and yolk sac before colonizing the liver at 6 weeks. A comparison of HSCs at different maturation stages revealed the establishment of HSC transcription factor machinery after the emergence of HSCs, whereas their surface phenotype evolved throughout development. The HSC transition to the liver marked a molecular shift evidenced by suppression of surface antigens reflecting nascent HSC identity, and acquisition of the HSC maturity markers CD133 (encoded by PROM1) and HLA-DR. HSC origin was tracked to ALDH1A1+KCNK17+haemogenic endothelial cells, which arose from an IL33+ALDH1A1+arterial endothelial subset termed pre-haemogenic endothelial cells. Using spatial transcriptomics and immunofluorescence, we visualized this process in ventrally located intra-aortic haematopoietic clusters. The in vivo map of human HSC ontogeny validated the generation of aorta–gonad–mesonephros-like definitive haematopoietic stem and progenitor cells from human pluripotent stem cells, and serves as a guide to improve their maturation to functional HSCs.

Microglia appear activated in the vicinity of amyloid beta (Aβ) plaques, but whether microglia contribute to Aβ propagation into unaffected brain regions remains unknown. Using transplantation of wild-type (WT) neurons, we show that Aβ enters WT grafts, and that this is accompanied by microglia infiltration. Manipulation of microglia function reduced Aβ deposition within grafts. Furthermore, in vivo imaging identified microglia as carriers of Aβ pathology in previously unaffected tissue. Our data thus argue for a hitherto unexplored mechanism of Aβ propagation.

Decreasing the activation of pathology-activated microglia is crucial to prevent chronic inflammation and tissue scarring. In this study, we used a stab wound injury model in zebrafish and identified an injury-induced microglial state characterized by the accumulation of lipid droplets and TAR DNA-binding protein of 43 kDa (TDP-43)+condensates. Granulin-mediated clearance of both lipid droplets and TDP-43+condensates was necessary and sufficient to promote the return of microglia back to the basal state and achieve scarless regeneration. Moreover, in postmortem cortical brain tissues from patients with traumatic brain injury, the extent of microglial activation correlated with the accumulation of lipid droplets and TDP-43+condensates. Together, our results reveal a mechanism required for restoring microglia to a nonactivated state after injury, which has potential for new therapeutic applications in humans.

Here, we study the hydride formation in a metastable Ti–33Zr–22Hf–11Ta (at.%) refractory high entropy alloy (RHEA). Deviating to non-equiatomic compositions of RHEAs promotes the formation of transformation-induced plasticity where the body-centered cubic phase transforms to hexagonal close-packed (HCP) phase. It is found that the phase transformation capability assists the hydride formation due to the low solubility of hydrogen within the HCP phase. In this study, hydrogen is charged via electrochemical polishing and the corresponding phase transformation is activated in the metastable RHEAs. The newly formed HCP phase interacts with hydrogen to form a face-centered cubic hydride verified by electron energy loss spectroscopy. This work provides a primary exploration of the formation of compositionally complex metal hydrides in the metastable RHEAs, which are potential candidates for future hydrogen storage material design.

This work reports the design and fabrication of novel printed single-wall carbon nanotube (SWCNT) electrothermal Joule heating devices. The devices are directly deposited on unidirectional (UD) glass fiber (GF) fabrics. The GF-SWCNT Joule heaters were integrated during manufacturing as “system” plies in carbon fiber reinforced polymer (CFRP) composite laminates. Specific secondary functions were imparted on the composite laminate endowing thus a multifunctional character. The efficient out-of-oven curing (OOC) of a CFRP laminate was demonstrated using a sandwich configuration comprising top/bottom GF-SWCNT system plies. A total power consumption of ca. 10.5 kWh for the efficient polymerization of the thermoset matrix was required. Infrared thermography (IR-T) monitoring showed a uniform and stable temperature field before and after impregnation with epoxy resin. Quasi-static three-point bending and dynamic mechanical analysis (DMA) revealed a minor knock-down effect of the OOC–CFRP laminates properties compared to oven cured CFRPs, whereas the glass transition temperature (Tg) was almost identical. The OOC–CFRP laminates were efficient in providing additional functions such as deicing and self-sensing that are highly sought in the energy and transport sectors, i.e., wind turbine blades or aircraft wings. The novel modular design provides unique opportunities for large-area applications via multiple interconnected arrays of printed devices.

Study design: Cross-sectional explorative observational study. Objectives: To identify factors which have an association to the self-perceived Quality of Life (QoL) for persons with acquired spinal cord injury (SCI). Setting: Eight specialized SCI-centers in Germany. The GerSCI survey is the German part of the International Spinal Cord Injury Survey (InSCI). Methods: Self-disclosure questionnaire, created from the InSCI group, translated and adapted for Germany. The questionnaire collects a very broad range of data and, and due to its design as a self-report, is particularly suitable for the analysis on QoL. Because of the content, which is binding for all participating states, it allows a direct comparability of the results. Included in Germany were 1479 persons with acquired SCI aged 18 years and older. Results: Various factors were identified with high associations to QoL, including changeable and unchangeable ones, such as those of particular importance: pain, sleep problems, sexual dysfunction, age, and time since onset of SCI. Some results confirmed reports of previous studies, others were surprising. Conclusion: this study provides an important basis for the planned analysis of the InSCI participating countries in the 6 WHO regions. Germany was able to contribute the largest study population. The concrete study design of InSCI allows us to directly compare data and helps us to improve ourselves within the framework of a “learning health system”. Medical measures can be orientated towards the found results, in order to ensure the best possible care and support by the therapeutic team, individually adapted to the person, place of residence and impairment.

Carbonates are excellent carriers for divalent cations such as Ca, Mg, and Sr, and knowledge about their stability and solid solutions is important to understanding the global strontium cycle. To shed light on the topology of the two-phase field between calcite-type and aragonite-type (Ca,Sr)CO3solid solutions as a function of temperature and pressure, and to learn more about the distribution of Sr and Ca between carbonates and fluid, we studied the system CaCO3-SrCO3-H2O at 600 °C in the pressure range 0.5–5 kbar. Conventional and rapid-quench hydrothermal syntheses were performed using a range of different starting materials. All bulk compositions were within the assumed/postulated two-phase field of calcite-type and aragonite-type (Ca,Sr)CO3solid solutions. The run products were analyzed by scanning electron microscopy, electron microprobe analysis, and powder X‑ray diffraction with Rietveld refinement. The results show that the heterotype solid solution is more extensive than previously assumed, with calcite incorporating up to 20 mol% SrCO3, which is twice as much as previously predicted. The compositional range of the aragonite-type solid solution was identical to that found in the literature. Using the data from this study, an updated version of the phase diagram P-X(Sr) at 600 °C for the CaCO3-SrCO3system was calculated. The phase diagram does not support a phase transition within the trigonal (Ca,Sr)CO3solid solution associated with rotational disorder of the CO3-groups. This order-disorder phase transition was previously postulated to explain some observed compositional trends in this system. Our new data are in line with other more recent studies. The distribution of Sr and Ca between the fluid and solid phases D=XSrsolid /XSrfluid $D=X_{\mathrm{Sr}}^{\text {solid }} / X_{\mathrm{Sr}}^{\text {fluid }}$is near to 1.0 for calcite-type and on average around 2.0 for aragonite-type solid solutions. This contrasts with silicate-fluid systems in which Sr typically shows a strong preference for the fluid phase compared with Ca.

This study demonstrates for the first time a structural glass fiber-reinforced polymer (GFRP) composite laminate with efficient thermal energy harvesting properties as a thermoelectric generator (TEG). This TEG laminate was fabricated by stacking unidirectional glass fiber (GF) laminae coated with p- and n-type single-wall carbon nanotube (SWCNT) inks via a blade coating technique. According to their thermoelectric (TE) response, the p- and n-type GF-SWCNT fabrics exhibited Seebeck coefficients of +23 and −29 μV/K with 60 and 118 μW/m·K2power factor values, respectively. The in-series p–n interconnection of the TE-enabled GF-SWCNT fabrics and their subsequent impregnation with epoxy resin effectively generated an electrical power output of 2.2 μW directly from a 16-ply GFRP TEG laminate exposed to a temperature difference (ΔT) of 100 K. Both experimental and modeling work validated the TE performance. The structural integrity of the multifunctional GFRP was tested by three-point bending coupled with online monitoring of the steady-state TE current (Isc) at a ΔΤof 80 K. Iscwas found to closely follow all transitions and discontinuities related to structural damage in the stress/strain curve, thus showing its potential to serve the functions of power generation and damage monitoring.

There are approximately 800 annotated G protein–coupled receptor (GPCR) genes, making these membrane receptors members of the most abundant gene family in the human genome. Besides being involved in manifold physiologic functions and serving as important pharmacotherapeutic targets, mutations in 55 GPCR genes cause about 66 inherited monogenic diseases in humans. Alterations of nine GPCR genes are causatively involved in inherited digenic diseases. In addition to classic gain- and loss-of-function variants, other aspects, such as biased signaling, trans-signaling, ectopic expression, allele variants of GPCRs, pseudogenes, gene fusion, and gene dosage, contribute to the repertoire of GPCR dysfunctions. However, the spectrum of alterations and GPCR involvement is probably much larger because an additional 91 GPCR genes contain homozygous or hemizygous loss-of-function mutations in human individuals with currently unidentified phenotypes. This review highlights the complexity of genomic alteration of GPCR genes as well as their functional consequences and discusses derived therapeutic approaches.

ABSTRACTCell lines recapitulating physiological processes can represent alternatives to animal or human studies. The 3T3-L1 cell line is used to mimic adipocyte function and differentiation. Since transfection of 3T3-L1 cells is difficult, we used a modified 3T3-L1 cell line overexpressing Cas9 for a straightforward generation of gene knock-outs. As an example, we intended to generate 3T3-L1 cell lines deficient for adhesion G protein-coupled receptors Gpr64/Adgr2and Gpr126/Adgr6using the CRISPR/Cas approach. Surprisingly, all the generated knock-out as well as scramble control cell lines were unresponsive to isoprenaline in respect to adiponectin secretion and lipolysis in contrast to the wild type 3T3-L1 cells. We, therefore, analysed the properties of these stable Cas9-overexpressing 3T3-L1 cells. We demonstrate that this commercially available cell line exhibits dysfunction in cAMP signalling pathways as well as reduced insulin sensitivity independent of gRNA transfection. We tried transient transfection of plasmids harbouring Cas9 as well as direct introduction of the Cas9 protein as alternate approaches to the stable expression of this enzyme. We find that transfection of the Cas9 protein is not only feasible but also does not impair adipogenesis and, therefore, represents a preferable alternative to achieve genetic knock-out.

There are approximately 800 annotated G protein–coupled receptor (GPCR) genes, making these membrane receptors members of the most abundant gene family in the human genome. Besides being involved in manifold physiologic functions and serving as important pharmacotherapeutic targets, mutations in 55 GPCR genes cause about 66 inherited monogenic diseases in humans. Alterations of nine GPCR genes are causatively involved in inherited digenic diseases. In addition to classic gain- and loss-of-function variants, other aspects, such as biased signaling, trans-signaling, ectopic expression, allele variants of GPCRs, pseudogenes, gene fusion, and gene dosage, contribute to the repertoire of GPCR dysfunctions. However, the spectrum of alterations and GPCR involvement is probably much larger because an additional 91 GPCR genes contain homozygous or hemizygous loss-of-function mutations in human individuals with currently unidentified phenotypes. This review highlights the complexity of genomic alteration of GPCR genes as well as their functional consequences and discusses derived therapeutic approaches.Significance StatementWith the advent of new transgenic and sequencing technologies, the number of monogenic diseases related to G protein–coupled receptor (GPCR) mutants has significantly increased, and our understanding of the functional impact of certain kinds of mutations has substantially improved. Besides the classical gain- and loss-of-function alterations, additional aspects, such as biased signaling, trans-signaling, ectopic expression, allele variants of GPCRs, uniparental disomy, pseudogenes, gene fusion, and gene dosage, need to be elaborated in light of GPCR dysfunctions and possible therapeutic strategies.

X-chromosome dosage compensation in female placental mammals is achieved by X-chromosome inactivation (XCI). Human pre-implantation embryos are an exception, in which dosage compensation occurs by X-chromosome dampening (XCD). Here, we examined whether XCD extends to human prenatal germ cells given their similarities to naive pluripotent cells. We found that female human primordial germ cells (hPGCs) display reduced X-linked gene expression before entering meiosis. Moreover, in hPGCs, both X chromosomes are active and express the long non-coding RNAs X active coating transcript (XACT) and X inactive specific transcript (XIST)—the master regulator of XCI—which are silenced after entry into meiosis. We find that XACTis a hPGC marker, describe XCD associated with XISTexpression in hPGCs and suggest that XCD evolved in humans to regulate X-linked genes in pre-implantation embryos and PGCs. Furthermore, we found a unique mechanism of X-chromosome regulation in human primordial oocytes. Therefore, future studies of human germline development must consider the sexually dimorphic X-chromosome dosage compensation mechanisms in the prenatal germline.

Background: G protein-coupled receptors (GPCR) are well-characterized regulators of a plethora of physiological functions among them the modulation of adipogenesis and adipocyte function. The class of Adhesion GPCR (aGPCR) and their role in adipose tissue, however, is poorly studied. With respect to the demand for novel targets in obesity treatment, we present a comprehensive study on the expression and function of this enigmatic GPCR class during adipogenesis and in mature adipocytes. Methods: The expression of all aGPCR representatives was determined by reanalyzing RNA-Seq data and by performing qPCR in different mouse and human adipose tissues under low- and high-fat conditions. The impact of aGPCR expression on adipocyte differentiation and lipid accumulation was studied by siRNA-mediated knockdown of all expressed members of this receptor class. The biological characteristics and function of mature adipocytes lacking selected aGPCR were analyzed by mass spectrometry and biochemical methods (lipolysis, glucose uptake, adiponectin secretion). Results: More than ten aGPCR are significantly expressed in visceral and subcutaneous adipose tissues and several aGPCR are differentially regulated under high-caloric conditions in human and mouse. Receptor knockdown of six receptors resulted in an impaired adipogenesis indicating their expression is essential for proper adipogenesis. The altered lipid composition was studied in more detail for two representatives, ADGRG2/GPR64 and ADGRG6/GPR126. While GPR126 is mainly involved in adipocyte differentiation, GPR64 has an additional role in mature adipocytes by regulating metabolic processes. Conclusions: Adhesion GPCR are significantly involved in qualitative and quantitative adipocyte lipid accumulation and can control lipolysis. Factors driving adipocyte formation and function are governed by signaling pathways induced by aGPCR yielding these receptors potential targets for treating obesity.

Study design: Survey study. Objectives: Spinal cord injury (SCI)-associated pneumonia (SCI-AP) is associated with poor functional recovery and a major cause of death after SCI. Better tackling SCI-AP requires a common understanding on how SCI-AP is defined. This survey examines clinical algorithms relevant for diagnosis and treatment of SCI-AP. Setting: All departments for SCI-care in Germany. Methods: The clinical decision-making on SCI-AP and the utility of the Centers for Disease Control and Prevention (CDC) criteria for diagnosis of ‘clinically defined pneumonia’ were assessed by means of a standardized questionnaire including eight case vignettes of suspected SCI-AP. The diagnostic decisions based on the case information were analysed using classification and regression trees (CART). Results: The majority of responding departments were aware of the CDC-criteria (88%). In the clinical vignettes, 38–81% of the departments diagnosed SCI-AP in accordance with the CDC-criteria and 7–41% diagnosed SCI-AP in deviation from the CDC-criteria. The diagnostic agreement was not associated with the availability of standard operating procedures for SCI-AP management in the departments. CART analysis identified radiological findings, fever, and worsened gas exchange as most important for the decision on SCI-AP. Frequently requested supplementary diagnostics were microbiological analyses, C-reactive protein, and procalcitonin. For empirical antibiotic therapy, the departments used (acyl-)aminopenicillins/β-lactamase inhibitors, cephalosporins, or combinations of (acyl-)aminopenicillins/β-lactamase inhibitors with fluoroquinolones or carbapenems. Conclusions: This survey reveals a diagnostic ambiguity regarding SCI-AP despite the awareness of CDC-criteria and established SOPs. Heterogeneous clinical practice is encouraging the development of disease-specific guidelines for diagnosis and management of SCI-AP.

Attempts to increase the efficiency of case management in arbitration have been around for some time. They were mainly focused on the design and use of certain procedural rules and tools. It is beneficial that this work was undertaken, but it seems to reach its limits to improve case management. More recently, the arbitration community has started to discover the wealth of psychological knowledge to better understand and manage certain aspects of the arbitration process. However, this curiosity was limited to specific issues, such as psychology of witness evidence or of decision taking. This article proposes to take a bird’s eye view based on organizational psychology and management science and asks the question: Can the established knowledge about successful teamwork be applied to arbitration? The article reviews, if such a holistic teamwork approach leads to avenues for improving the efficiency of case management in arbitration. The answer is clearly affirmative. To view the interactions between the arbitral tribunal, the parties and other participants in the arbitration as teamwork provides new perspectives and can lead to new attitudes as well as to new tools for managing cases. Arbitrations guided by a teamwork approach promise to be more efficient, to involve parties and arbitral tribunals more intensely – and to be more enriching for the participants.

The theory of grain boundary (the interface between crystallites, GB) structure has a long history1and the concept of GBs undergoing phase transformations was proposed 50 years ago2,3. The underlying assumption was that multiple stable and metastable states exist for different GB orientations4–6. The terminology ‘complexion’ was recently proposed to distinguish between interfacial states that differ in any equilibrium thermodynamic property7. Different types of complexion and transitions between complexions have been characterized, mostly in binary or multicomponent systems8–19. Simulations have provided insight into the phase behaviour of interfaces and shown that GB transitions can occur in many material systems20–24. However, the direct experimental observation and transformation kinetics of GBs in an elemental metal have remained elusive. Here we demonstrate atomic-scale GB phase coexistence and transformations at symmetric and asymmetric [111¯]tilt GBs in elemental copper. Atomic-resolution imaging reveals the coexistence of two different structures at Σ19b GBs (where Σ19 is the density of coincident sites and b is a GB variant), in agreement with evolutionary GB structure search and clustering analysis21,25,26. We also use finite-temperature molecular dynamics simulations to explore the coexistence and transformation kinetics of these GB phases. Our results demonstrate how GB phases can be kinetically trapped, enabling atomic-scale room-temperature observations. Our work paves the way for atomic-scale in situ studies of metallic GB phase transformations, which were previously detected only indirectly9,15,27–29, through their influence on abnormal grain growth, non-Arrhenius-type diffusion or liquid metal embrittlement.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1G86Rand FusΔNLS/+ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1G93Aand FusΔNLS/+mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.

Purkinje neuron degeneration characterizes spinocerebellar ataxia type 1, yet the comprehension of the impact on the broader cerebellar circuit remains incomplete. We here detail simultaneous in vivotwo-photon calcium imaging of diverse neuronal populations in the cerebellar cortex of Sca1 mice while they are navigating a virtual environment. We outline surgical procedures and protocols to chronically record from identical neurons, and we detail data post-processing and analysis to delineate disease-related alterations in neuronal activity and sensorimotor-driven response properties.

There is evidence that the fiber-matrix interaction in fiber-reinforced cementitious composites is determined by the wettability and roughness of the fibers. Due to the high ionic strength in the hydrated cement, also the surface charge or acid/base behavior of the fibers is assumed to play a role. To create fibers with alkaline and acidic surface functionalities, water-insoluble poly (vinyl alcohol) fibers were permanently modified by adsorption of various polyelectrolytes. X-ray photoelectron spectroscopy, zeta potential, and contact angle measurements revealed acidic, alkaline or amphoteric fiber surfaces with advancing water contact angles between 34° and 58°. In a first step to study the interaction with cementitious materials, the interaction of these fibers with pore solution (the liquid phase of hydrated cement) and the adsorption of calcium ions on the fiber surface were investigated. The work will be continued by studying the fiber-matrix interaction in cementitious matrices and its influence on the composite strength.

Analysis of entire transparent rodent bodies after clearing could provide holistic biological information in health and disease, but reliable imaging and quantification of fluorescent protein signals deep inside the tissues has remained a challenge. Here, we developed vDISCO, a pressure-driven, nanobody-based whole-body immunolabeling technology to enhance the signal of fluorescent proteins by up to two orders of magnitude. This allowed us to image and quantify subcellular details through bones, skin and highly autofluorescent tissues of intact transparent mice. For the first time, we visualized whole-body neuronal projections in adult mice. We assessed CNS trauma effects in the whole body and found degeneration of peripheral nerve terminals in the torso. Furthermore, vDISCO revealed short vascular connections between skull marrow and brain meninges, which were filled with immune cells upon stroke. Thus, our new approach enables unbiased comprehensive studies of the interactions between the nervous system and the rest of the body.

Liquid metal (LM) nanodroplets possess intriguing surface properties, thus offering promising potential in chemical synthesis, catalysis, and biomedicine. However, the reaction kinetics and product growth at the surface of LM nanodroplets are significantly influenced by the interface involved, which has not been thoroughly explored and understood. Here, we propose an interface engineering strategy, taking a spontaneous galvanic reaction between Ga0and AuCl4–ions as a representative example, to successfully modulate the growth of heterostructures on the surface of Ga-based LM nanodroplets by establishing a dielectric interface with a controllable thickness between LM and reactive surroundings. Combining high-resolution electron energy-loss spectroscopy (EELS) analysis and theoretical simulation, it was found that the induced charge distribution at the interface dominates the spatiotemporal distribution of the reaction sites. Employing tungsten oxide (WOx) with varying thicknesses as the demonstrated dielectric interface of LM, Ga@WOx@Au with distinct core–shell-satellite or dimer-like heterostructures has been achieved and exhibited different photoresponsive capabilities for photodetection. Understanding the kinetics of product growth and the regulatory strategy of the dielectric interface provides an experimental approach to controlling the structure and properties of products in LM nanodroplet-involved chemical processes.

Platinum-yttrium alloys (PtxY) are suggested to have superior oxygen reduction reaction (ORR) activity and long-term stability in proton exchange membrane fuel cells (PEMFCs). However, the actual ORR activity and stability of a PtxY catalyst with a high electrochemically active surface area (ECSA) in a PEMFC remains uncertain. Here, a Ketjen black (KB) carbon supported PtxY/KB catalyst with a high ECSA(∼60 m2/g) was synthesized using a carbon nitride precursor. Based on elemental analysis, XRD, electron microscopy, and a mass-balance based model, it was shown that the acid-leached PtxY nanoparticles of the catalyst consist of a ∼0.7 nm thick Pt-shell and a Pt3Y core. Rotating disk electrode (RDE) and 5 cm2single-cell PEMFC measurements indicated that the ORR activity of the acid-leached PtxY/KB catalyst is similar to an analogously synthesized Pt/KB reference catalyst with the same ECSA. Voltage-cycling accelerated stress tests (ASTs) between 0.6−1.0 V (in H2/N2at 80 °C/95% RH) in 5 cm2single-cells showed that the ORR activity and durability of the PtxY/KB catalyst is similar to that of the Pt/KB reference catalyst. Thus, the high durability of Pt-rare Earth alloys that has been claimed on the basis of RDE measurements is not observed in actual PEMFCs.

Hematopoietic stem cells (HSC) sustain life-long blood production and have the ability to recapitulate the hematopoietic system upon transplantation. This makes them therapeutically invaluable for the treatment of hematopoietic malignancies and genetic disorders. However, the regulatory processes governing HSC functional competence and engraftment ability are poorly understood and challenging to recapitulate ex vivo, making robust expansion of human HSCs difficult to achieve.