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High-order harmonic generation (HHG) based transient extreme ultraviolet (XUV) absorption spectroscopy is an emerging technique to trace photoinduced charge carrier dynamics in condensed phase materials with femtosecond and even attosecond temporal resolution and elemental specificity. However, its application to nanoparticulate samples that are relevant, for example, for novel photocatalytic light harvesting concepts, has been limited. This is in part due to the challenge to produce residual-free samples on ultrathin, XUV-transparent substrates as well as a widespread understanding that sparsely distributed nanoparticles do not provide sufficient contrast for XUV absorption measurements. Here, we present static XUV absorption spectra of partially oxidized Co nanowire-structures with diameters of approximately 4.5 nm and lengths between 10 and 40 nm, recorded with an ultrashort pulse HHG light source. Nanoparticles are synthesized by the agglomeration of Co atoms inside superfluid helium droplets, followed by surface deposition and oxidation in ambient air. The method is uniquely suited for residual-free synthesis of transition metal nanowires and their deposition on ultrathin substrates. Analysis by high-resolution transmission electron microscopy reveals the formation of CoO nanowires with regions of unoxidized Co in their interior. The nanoparticle samples are investigated in an HHG-driven ultrafast XUV absorption setup. Despite the low surface coverage of only 23%, the recorded spectrum exhibits a distinct absorption feature at the Co M2,3(2p) edge near 60 eV with a peak height of about 40 mOD. The results support the feasibility of table-top ultrafast transient XUV absorption studies of photoinduced dynamics in transition metal oxide nanoparticles with sub-monolayer surface coverage.

Background: Vesicoureteral reflux (VUR) is common in children and adolescents undergoing kidney transplantation (KTx) and may adversely affect allograft kidney function. Methods: To explore the current management of symptomatic native and allograft VUR in pediatric KTx recipients, an online survey was distributed to European surgical transplant professionals. Results: Surgeons from 40 pediatric KTx centers in 18 countries participated in this survey. Symptomatic native kidney VUR was treated before or during KTx by 68% of the centers (all/selected patients: 33%/67%; before/during KTx: 89%/11%), with a preference for endoscopic treatment (59%). At KTx, 90% favored an anti‐reflux ureteral reimplantation procedure (extravesical/transvesical approach: 92%/8%; preferred extravesical technique: Lich‐Gregoir [85%]). Management strategies for symptomatic allograft VUR included surgical repair (90%), continuous antibiotic prophylaxis (51%), bladder training (49%), or noninterventional surveillance (21%). Redo ureteral implantation and endoscopic intervention for allograft VUR were equally reported (51%/49%). Conclusions: This survey shows uniformity in some surgical aspects of the pediatric KTx procedure. However, with regard to VUR, there is a significant variation in practice patterns that need to be addressed by future well‐designed and prospective studies. In this way, more robust data could be translated into consensus guidelines for a more standardized and evidence‐based management of this common condition in pediatric KTx. [ABSTRACT FROM AUTHOR]

BackgroundCentral blood pressure (cBP) is a better indicator of cardiovascular morbidity and mortality than peripheral BP (pBP). However, direct cBP measurement requires invasive techniques and indirect cBP measurement is based on rigid and empirical transfer functions applied to pBP. Thus, development of a personalized and well-validated method for non-invasive derivation of cBP from pBP is necessary to facilitate the clinical routine. The purpose of the present study was to develop a novel blind source separation tool to separate a single recording of pBP into their pressure waveforms composing its dynamics, to identify the compounds that lead to pressure waveform distortion at the periphery, and to estimate the cBP. The approach is patient-specific and extracts the underlying blind pressure waveforms in pBP without additional brachial cuff calibration or any a priori assumption on the arterial model.MethodsThe intra-arterial femoral BPfe and intra-aortic pressure BPao were anonymized digital recordings from previous routine cardiac catheterizations of eight patients at the German Heart Centre Berlin. The underlying pressure waveforms in BPfe were extracted by the single-channel independent component analysis (SCICA). The accuracy of the SCICA model to estimate the whole cBP waveform was evaluated by the mean absolute error (MAE), the root mean square error (RMSE), the relative RMSE (RRMSE), and the intraclass correlation coefficient (ICC). The agreement between the intra-aortic and estimated parameters including systolic (SBP), diastolic (DBP), mean arterial pressure (MAP), and pulse pressure (PP) was evaluated by the regression and Bland–Altman analyses.ResultsThe SCICA tool estimated the cBP waveform non-invasively from the intra-arterial BPfe with an MAE of 0.159 ± 1.629, an RMSE of 5.153 ± 0.957 mmHg, an RRMSE of 5.424 ± 1.304%, and an ICC of 0.94, as well as two waveforms contributing to morphological distortion at the femoral artery. The regression analysis showed a strong linear trend between the estimated and intra-aortic SBP, DBP, MAP, and PP with high coefficient of determination R2 of 0.98, 0.99, 0.99, and 0.97 respectively. The Bland–Altman plots demonstrated good agreement between estimated and intra-aortic parameters with a mean error and a standard deviation of difference of −0.54 ± 2.42 mmHg [95% confidence interval (CI): −5.28 to 4.20] for SBP, −1.97 ± 1.62 mmHg (95% CI: −5.14 to 1.20) for DBP, −1.49 ± 1.40 mmHg (95% CI: −4.25 to 1.26) for MAP, and 1.43 ± 2.79 mmHg (95% CI: −4.03 to 6.90) for PP.ConclusionsThe SCICA approach is a powerful tool that identifies sources contributing to morphological distortion at peripheral arteries and estimates cBP.

Recent progress in digital health data recording, advances in computing power, and methodological approaches that extract information from data as artificial intelligence are expected to have a disruptive impact on technology in medicine. One of the potential benefits is the ability to extract new and essential insights from the vast amount of data generated during health care delivery every day. Cardiovascular imaging is boosted by new intelligent automatic methods to manage, process, segment, and analyze petabytes of image data exceeding historical manual capacities. Algorithms that learn from data raise new challenges for regulatory bodies. Partially autonomous behavior and adaptive modifications and a lack of transparency in deriving evidence from complex data pose considerable problems. Controlling new technologies requires new controlling techniques and ongoing regulatory research. All stakeholders must participate in the quest to find a fair balance between innovation and regulation. The regulatory approach to artificial intelligence must be risk-based and resilient. A focus on unknown emerging risks demands continuous surveillance and clinical evaluation during the total product life cycle. Since learning algorithms are data-driven, high-quality data is fundamental for good machine learning practice. Mining, processing, validation, governance, and data control must account for bias, error, inappropriate use, drifts, and shifts, particularly in real-world data. Regulators worldwide are tackling twenty-first century challenges raised by “learning” medical devices. Ethical concerns and regulatory approaches are presented. The paper concludes with a discussion on the future of responsible artificial intelligence.

Abstract Background Obesity is associated with cardiovascular complications, including pulmonary hypertension (PH). Reports suggest that peroxisome proliferator-activated receptor-γ (PPARγ) has direct action in preventing vascular remodelling in PH. Here we dissected the specific role of high-fat-diet (HFD)-induced obesity and vascular smooth muscle cell (VSMC)-PPARγ for remodelling of small pulmonary arteries. Methods Wild-type (WT) and VSMC-specific PPARγ-knockout (SmPparγ −/−) mice were fed a low-fat-diet (LFD, 10% kcal from fat) or HFD (60% kcal from fat) for 24 weeks. Mice were metabolically phenotyped (e.g. weight development, insulin/glucose tolerance) at the beginning, and after 12 and 24 weeks, respectively. At 24 weeks additionally pulmonary pressure, heart structure, pulmonary vascular muscularization together with gene and protein expression in heart and lung tissues were determined. Results HFD increased right ventricular systolic pressure (RVSP) to a similar extent in WT and SmPparγ −/− mice. HFD decreased glucose tolerance and insulin sensitivity in both WT and SmPparγ −/− mice. Importantly, the increase in RVSP correlated with the degree of insulin resistance. However, VSMC-PPARγ deficiency increased pulmonary vascular muscularization independently of the diet-induced rise in RVSP. This increase was associated with elevated expression of early growth response protein 1 in heart and osteopontin in lung tissue. Conclusions Here we demonstrate a correlation of insulin resistance and pulmonary pressure. Further, deficiency of PPARγ in VSMCs diet-independently leads to increased pulmonary vascular muscularization.

Background Animal studies demonstrated that serelaxin lessens fibrosis in heart failure. This study assessed its effect on myocardial deformation using cardiac magnetic resonance and elucidated its relationship to gene regulation and histology in a mouse heart failure model. Methods and Results C57BL/6J mice were subjected to SHAM (n=4) or transverse aortic constriction (TAC). At week 10, TAC mice were randomized to receive either serelaxin (0.5 mg/kg per day; n=11) or vehicle (n=13) for 4 weeks. Cardiac magnetic resonance imaging was performed at baseline and repeated at the end of the study (week 14). Cine images were used to calculate left ventricular (LV) global longitudinal, circumferential, and radial strain. Hearts were examined for histology and gene expression. Compared with SHAM, mice 10 weeks after TAC showed increased LV mass with significant decreases in LV deformation parameters, indicating subclinical deterioration of myocardial function. At week 14, TAC mice given serelaxin demonstrated significant improvements in all LV strain parameters and no decrease in LV stroke volume and ejection fraction compared with TAC mice given vehicle. A significant positive correlation between global circumferential strain and the extent of myocardial fibrosis was found, and global circumferential strain correlated significantly with the expression of heart failure genes in serelaxin‐treated mice. Conclusions Serelaxin improved cardiac magnetic resonance–derived myocardial deformation parameters as well as histomorphometric and gene expression findings in mice with heart failure. Cardiac magnetic resonance–derived myocardial mechanics correlate with histology and gene expression, stressing its utilization in myocardial remodeling.

Aims: Subclinical diastolic dysfuntion in patients with preclinical heart failure with preserved ejection fraction (HFpEF) has been demonstrated in patients with Marfan syndrome (MFS). We investigated the relationship between diastolic dysfunction and NT-proBNP levels in patients with MFS. Methods and results: NT-proBNP, C-reactive protein (CRP) and diastolic function were assessed in 217 patients with MFS (31 ± 16 y, 110 f. and in 339 patients referred for suspected MFS in whom the diagnosis was ruled out according to the Ghent nosology (30 ± 15 y, 154 f). Assessment of cardiovascular remodeling, diastolic function in echocardiography, and NT-proBNP was analyzed with univariate analysis and multi-parameter analysis of covariance (MANCOVA). NT-proBNP was 70.6 ± 74.8 pg/ml in patients with Marfan syndrome and 58.4 ± 100.3 pg/ml in controls (p = 0.002, Kolmogorov–Smirnov). There were significant intergroup differences regarding end-diastolic left ventricular volume (p

Objective: Insulin resistance can be triggered by enhanced dephosphorylation of the insulin receptor or downstream components in the insulin signaling cascade through protein tyrosine phosphatases (PTPs). Downregulating density-enhanced phosphatase-1 (DEP-1) resulted in an improved metabolic status in previous analyses. This phenotype was primarily caused by hepatic DEP-1 reduction. Methods: Here we further elucidated the role of DEP-1 in glucose homeostasis by employing a conventional knockout model to explore the specific contribution of DEP-1 in metabolic tissues. Ptprj−/− (DEP-1 deficient) and wild-type C57BL/6 mice were fed a low-fat or high-fat diet. Metabolic phenotyping was combined with analyses of phosphorylation patterns of insulin signaling components. Additionally, experiments with skeletal muscle cells and muscle tissue were performed to assess the role of DEP-1 for glucose uptake. Results: High-fat diet fed-Ptprj−/− mice displayed enhanced insulin sensitivity and improved glucose tolerance. Furthermore, leptin levels and blood pressure were reduced in Ptprj−/− mice. DEP-1 deficiency resulted in increased phosphorylation of components of the insulin signaling cascade in liver, skeletal muscle and adipose tissue after insulin challenge. The beneficial effect on glucose homeostasis in vivo was corroborated by increased glucose uptake in skeletal muscle cells in which DEP-1 was downregulated, and in skeletal muscle of Ptprj−/− mice. Conclusion: Together, these data establish DEP-1 as novel negative regulator of insulin signaling.

The design and generation of an optimal expression construct is the first and essential step in in the characterization of a protein of interest. Besides evaluation and optimization of process parameters (e.g. selection of the best expression host or cell line and optimal induction conditions and time points), the design of the expression construct itself has a major impact. However, the path to this final expression construct is often not straight forward and includes multiple learning cycles accompanied by design variations and retesting of construct variants, since multiple, functional DNA sequences of the expression vector backbone, either coding or non-coding, can have a major impact on expression yields. To streamline the generation of defined expression constructs of otherwise difficult to express proteins, the Modular Protein Expression Toolbox (MoPET) has been developed. This cloning platform allows highly efficient DNA assembly of pre-defined, standardized functional DNA modules with a minimal cloning burden. Combining these features with a standardized cloning strategy facilitates the identification of optimized DNA expression constructs in shorter time. The MoPET system currently consists of 53 defined DNA modules divided into eight functional classes and can be flexibly expanded. However, already with the initial set of modules, 792,000 different constructs can be rationally designed and assembled. Furthermore, this starting set was used to generate small and mid-sized combinatorial expression optimization libraries. Applying this screening approach, variants with up to 60-fold expression improvement have been identified by MoPET variant library screening.

AimTo study the effects of RD on renal artery wall function non-invasively using magnetic resonance.Methods and results32 patients undergoing RD were included. A 3.0 Tesla magnetic resonance of the renal arteries was performed before RD and after 6-month. We quantified the vessel sharpness of both renal arteries using a quantitative analysis tool (Soap-Bubble®). In 17 patients we assessed the maximal and minimal cross-sectional area of both arteries, peak velocity, mean flow, and renal artery distensibility. In a subset of patients wall shear stress was assessed with computational flow dynamics. Neither renal artery sharpness nor renal artery distensibility differed significantly. A significant increase in minimal and maximal areas (by 25.3%, p = 0.008, and 24.6%, p = 0.007, respectively), peak velocity (by 16.9%, p = 0.021), and mean flow (by 22.4%, p = 0.007) was observed after RD. Wall shear stress significantly decreased (by 25%, p = 0.029). These effects were observed in blood pressure responders and non-responders.ConclusionsRD is not associated with adverse effects at renal artery level, and leads to an increase in cross-sectional areas, velocity and flow and a decrease in wall shear stress.

Postoperative nausea and vomiting (PONV) is one of the most common and distressing complications after general anesthesia and surgery, with young non-smoking females receiving postoperative opioids being high-risk patients. This register-based study aims to evaluate the effect of low-dose haloperidol (0.5 mg intravenously) directly after induction of general anesthesia to reduce the incidence of PONV in the postoperative anesthesiological care unit (PACU).Multivariable regression models were used to investigate the association between low-dose haloperidol and the occurrence of PONV using a patient registry containing 2,617 surgical procedures carried out at an university hospital.Haloperidol 0.5 mg is associated with a reduced risk of PONV in the total collective (adjusted odds ratio = 0.75, 95% confidence interval: [0.56, 0.99], p = 0.05). The results indicate that there is a reduced risk in male patients (adjusted odds ratio = 0.45, 95% confidence interval: [0.28, 0.73], p = 0.001) if a dose of 0.5 mg haloperidol was administered while there seems to be no effect in females (adjusted odds ratio = 1.02, 95% confidence interval: [0.71, 1.46], p = 0.93). Currently known risk factors for PONV such as female gender, duration of anesthesia and the use of opioids were confirmed in our analysis.This study suggests that low-dose haloperidol has an antiemetic effect in male patients but has no effect in female patients. A confirmation of the gender-specific effects we have observed in this register-based cohort study might have major implications on clinical daily routine.

La disección aguda de aorta tipo A es una enfermedad grave de obligado tratamiento quirúrgico. El tratamiento quirúrgico tiene morbimortalidad elevada. No hay acuerdo general acerca de la mejor forma de tratamiento. Para obtener información que permita definir las mejores estrategias operatorias y de manejo global, el Grupo de Trabajo de Cirugía de la Aorta y Cirugía Vascular Intervencionista de la Sociedad Alemana de Cirugía Torácica y Cardiovascular (GSTCVS) creó el Registro Alemán de la Disección Aguda Tipo A (GERAADA). Desde 2006, 44 centros han incluido 1.610 casos, con información completa en 1.558. La mortalidad a 30 días ha sido del 16% y la tasa de accidentes neurológicos del 10%. Tras la experiencia inicial con el registro, se desea desarrollar un Registro Europeo de las Enfermedades de la Aorta (European Registry for aortic Diseases [EuRADa]) bajo los auspicios del vascular domain de la european association for Cardiothoracic Surgery (EACTS).

INTRODUCTION: Congenital glaucoma is frequently associated with visual impairment due to optic nerve damage, corneal opacities, cataracts and amblyopia. Poor vision in childhood is related to global developmental problems, and referral to vision habilitation/rehabilitation services should be without delay to promote efficient management of the impaired vision. OBJECTIVE: To analyze data concerning visual response, the use of optical correction and prescribed low vision aids in a population of children with congenital glaucoma. METHOD: The authors analyzed data from 100 children with congenital glaucoma to assess best corrected visual acuity, prescribed optical correction and low vision aids. RESULTS: Fifty-five percent of the sample were male, 43% female. The mean age was 6.3 years. Two percent presented normal visual acuity levels, 29% mild visual impairment, 28% moderate visual impairment, 15% severe visual impairment, 11% profound visual impairment, and 15% near blindness. Sixty-eight percent received optical correction for refractive errors. Optical low vision aids were adopted for distance vision in 34% of the patients and for near vision in 6%. A manual monocular telescopic system with 2.8 × magnification was the most frequently prescribed low vision aid for distance, and for near vision a +38 diopter illuminated stand magnifier was most frequently prescribed. DISCUSSION AND CONCLUSION: Careful low vision assessment and the appropriate prescription of optical corrections and low vision aids are mandatory in children with congenital glaucoma, since this will assist their global development, improving efficiency in daily life activities and promoting social and educational inclusion.

OBJECTIVE: To evaluate the safety and effectiveness of trabeculectomy with mitomycin C in the management of childhood glaucoma. INTRODUCTION: The use of antifibrotic agents enhances the success of trabeculectomy performed in both adults and children. METHODS: A retrospective chart review (1991-2001) of 114 patients (114 eyes) from 0-14 years of age with congenital or developmental glaucoma. These patients underwent trabeculectomy with mitomycin but had not been previously treated with any antifibrotic agent. RESULTS: The mean patient age was 57.36 51.14 months (range: 0.5-168 months). Treatment was considered successful in 63 eyes (55.26%), with a mean intraocular pressure of 12.11 3.98 mmHg. For patients categorized as successfully treated, the mean follow-up time was 61.16 26.13 months (range 12-113 months). A post-surgical intraocular pressure of < 16 was observed in 47 eyes. The life-table success rates for intraocular pressure control at 24, 36, 48, and 60 months were 90.2%, 78.7%, 60.7% and 50.8%, respectively. The cumulative probability of failure was 40.8% at 12 months. Following surgery, endophthalmitis appeared in eight eyes (4.88%) after an average 36.96 months (range: 1.7-106 months). Other complications included expulsive hemorrhage, flat anterior chamber and bleb leak. DISCUSSION: It has been reported in pediatric patients that trabeculectomy without adjunctive antimetabolites achieves a successful outcome in 30% to 50% of cases. In our study, treatment was considered successful in 63 eyes (55.26%) within 61.16 26.13 months of follow-up. CONCLUSIONS: Trabeculectomy with mitomycin is safe and effective for short-term or long-term treatment of congenital or developmental glaucoma. The frequency of bleb-related endophthalmitis was no higher in these patients than that described in adults.

The plant-pathogenic bacterium Xanthomonas campestris pv. vesicatoria possesses a type III secretion (T3S) system which is encoded in the 23-kb hypersensitive response and pathogenicity (hrp) gene cluster. The T3S system is essential for pathogenicity in susceptible hosts and the induction of the hypersensitive response in resistant plants. In this study, we revisited the operon structure of the right part of the hrp gene cluster. Based on complementation experiments of transposon insertions and reverse-transcription polymerase chain reaction analyses, the hrpD operon contains hrcQ, hrcR, hrcS, and hpaA, whereas hrcD, hrpD6, and hrpE belong to the hrpE operon. We determined the transcriptional start site of the hrpE operon and showed that there is a promoter upstream of hrcD containing a plant-inducible promoter box. Conserved secondary mRNA structures in the intergenic region between hrpD6 and hrpE suggest a posttranscriptional regulated expression of hrpE. Based on comparisons of different hrp gene clusters and the analysis of evolutionary rates, we propose that the hrpE transcriptional unit was integrated into the hrp gene cluster at a later time.

We sought to evaluate the impact of ischemic burden for the prediction of hard cardiac events (cardiac death or nonfatal myocardial infarction) in patients with known or suspected CAD who undergo dobutamine stress cardiac magnetic resonance imaging (DCMR).We included 3166 patients (pts.), mean age 63 ± 12 years, 27% female, who underwent DCMR in 3 tertiary cardiac centres (University Hospital Heildelberg, German Heart Institute and Kings College London). Pts. were separated in groups based on the number of ischemic segments by wall motion abnormalities (WMA) as follows: 1. no ischemic segment, 2. one ischemic segment, 3. two ischemic segments and 4. ≥ three ischemic segments. Cardiac death and nonfatal myocardial infarction were registered as hard cardiac events. Pts. with an "early" revascularization procedure (in the first three months after DCMR) were not included in the final survival analysis.Pts. were followed for a median of 3.1 years (iqr 2-4.5 years). 187 (5.9%) pts. experienced hard cardiac events. 2349 (74.2%) had no inducible ischemia, 189 (6%) had ischemia in 1 segment, 292 (9.2%) in 2 segments and 336 (10.6%) ≥ 3 segments. Patients with only 1 ischemic segment showed a high rate of hard cardiac events of ∼ 6% annually, which was 10-fold higher compared to those without ischemia (0.6% annually, p < 0.001) but similar to those with 2 and ≥ 3 ischemic segments (∼ 5.5% and ∼ 7%, p = NS).The presence of inducible ischemia even in a single 'culprit' myocardial segment during DCMR is enough to predict hard cardiac events in patients with known or suspected CAD.

Matrix metalloproteinase (MMP)-dependent extracellular matrix (ECM) remodeling is a key feature in cardiometabolic syndrome-associated adipogenesis and atherosclerosis. Activation of membrane-tethered (MT) 1-MMP depends on furin (PCSK3). However, the regulation and function of the natural furin-inhibitor serpinB8 and thus furin/MT1-MMP-activity in obesity-related tissue inflammation/remodeling is unknown. Here we aimed to determine the role of serpinB8/furin in obesity-associated chronic inflammation.Monocyte → macrophage transformation was characterized by decreases in serpinB8 and increases in furin/MT1-MMP. Rescue of serpinB8 by protein overexpression inhibited furin-dependent pro-MT1-MMP activation in macrophages, supporting its role as a furin-inhibitor. Obese white adipose tissue-facilitated macrophage migration was inhibited by furin- and MMP-inhibition, stressing the importance of the furin-MMP axis in fat tissue inflammation/remodeling. Monocytes from obese patients (body mass index (BMI) >30kg/m(2)) had higher furin, MT1-MMP, and resistin gene expression compared to normal weight individuals (BMI

The field of synthetic biology promises to revolutionize biotechnology through the design of organisms with novel phenotypes useful for medicine, agriculture and industry. However, a limiting factor is the ability of current methods to assemble complex DNA molecules encoding multiple genetic elements in various predefined arrangements. We present here a hierarchical modular cloning system that allows the creation at will and with high efficiency of any eukaryotic multigene construct, starting from libraries of defined and validated basic modules containing regulatory and coding sequences. This system is based on the ability of type IIS restriction enzymes to assemble multiple DNA fragments in a defined linear order. We constructed a 33 kb DNA molecule containing 11 transcription units made from 44 individual basic modules in only three successive cloning steps. This modular cloning (MoClo) system can be readily automated and will be extremely useful for applications such as gene stacking and metabolic engineering.

Generation of customized DNA binding domains targeting unique sequences in complex genomes is crucial for many biotechnological applications. The recently described DNA binding domain of the transcription activator-like effectors (TALEs) from Xanthomonas consists of a series of repeats arranged in tandem, each repeat binding a nucleotide of the target sequence. We present here a strategy for engineering of TALE proteins with novel DNA binding specificities based on the 17.5 repeat-containing AvrBs3 TALE as a scaffold. For each of the 17 full repeats, four module types were generated, each with a distinct base preference. Using this set of 68 repeat modules, recognition domains for any 17 nucleotide DNA target sequence of choice can be constructed by assembling selected modules in a defined linear order. Assembly is performed in two successive one-pot cloning steps using the Golden Gate cloning method that allows seamless fusion of multiple DNA fragments. Applying this strategy, we assembled designer TALEs with new target specificities and tested their function in vivo.

Surface plasmon polaritons (SPPs) can confine and guide light in nanometer volumes and are ideal tools for achieving electric field enhancement and the construction of nanophotonic circuitry. The realization of the highest field strengths and fastest switching requires confinement also in the temporal domain. Here, we demonstrate a tapered plasmonic waveguide with an optimized grating structure that supports few-cycle surface plasmon polaritons with >70 THz bandwidth while achieving >50% light-field-to-plasmon coupling efficiency. This enables us to observe the─to our knowledge─shortest reported SPP wavepackets. Using time-resolved photoelectron microscopy with suboptical-wavelength spatial and sub-10 fs temporal resolution, we provide full spatiotemporal imaging of co- and counter-propagating few-cycle SPP wavepackets along tapered plasmonic waveguides. By comparing their propagation, we track the evolution of the laser-plasmon phase, which can be controlled via the coupling conditions.

Diamondoid molecules and their derivatives have attracted attention as fascinating building blocks for advanced functional materials. Depending on the balance between hydrogen bonds and London dispersion interactions, they can self-organize in different cluster structures with functional groups tailored for various applications. Here, we present a new approach to supramolecular aggregation where self-assembly of diamondoid acids and alcohols in the ultracold environment of superfluid helium nanodroplets (HNDs) was analyzed by a combination of time-of-flight mass spectrometry and computational tools. Experimentally observed magic numbers of the assembled cluster sizes were successfully identified and computed cluster structures gave valuable insights into a different conglomeration mode when compared to previously explored less-polar diamondoid derivatives. We have confirmed that functional groups acting as good hydrogen bond donors completely take over the self-organization process, resulting in fascinating pair-wise or cyclic supramolecular assemblies. Particularly noteworthy is that mono- and bis-substituted diamondoid derivatives of both series engage in completely different modes of action, which is reflected in differing non-covalent cluster geometries. Additionally, formed cyclic clusters with a polar cavity in the center and a non-polar diamondoid outer layer can be of high interest in porous material design and provide insights into the structural requirements needed to produce bulk materials with desired properties.

Diamondoid ethers were introduced into superfluid helium nanodroplets and the resulting clusters were analyzed by time-of-flight mass spectrometry. Clusters of higher abundances (magic number clusters) were identified and the corresponding potential cluster geometries were obtained from GFN2-xTB and DFT computations. We found that the studied diamondoid ethers readily self-assemble in helium nanodroplets and that London dispersion attraction between hydrocarbon subunits acts as a driving force for cluster formation. On the other hand, hydrogen bonding between ether oxygens and trace water molecules fosters the eventual breakdown of the initial supramolecular aggregate.

Nanoparticles with diameters in the range of a few nanometers, consisting of gold and vanadium oxide, are synthesized by sequential doping of cold helium droplets in a molecular beam apparatus and deposited on solid carbon substrates. After surface deposition, the samples are removed and various measurement techniques are applied to characterize the created particles: scanning transmission electron microscopy (STEM) at atomic resolution, temperature dependent STEM and TEM up to 650 °C, energy-dispersive X-ray spectroscopy (EDXS) and electron energy loss spectroscopy (EELS). In previous experiments we have shown that pure V 2 O 5 nanoparticles can be generated by sublimation from the bulk and deposited without affecting their original stoichiometry. Interestingly, our follow-up attempts to create Au@V 2 O 5 core@shell particles do not yield the expected encapsulated structure. Instead, Janus particles of Au and V 2 O 5 with diameters between 10 and 20 nm are identified after deposition. At the interface of the Au and the V 2 O 5 parts we observe an epitaxial-like growth of the vanadium oxide next to the Au structure. To test the temperature stability of these Janus-type particles, the samples are heated in situ during the STEM measurements from room temperature up to 650 °C, where a reduction from V 2 O 5 to V 2 O 3 is followed by a restructuring of the gold atoms to form a Wulff-shaped cluster layer. The temperature dependent dynamic interplay between gold and vanadium oxide in structures of only a few nanometer size is the central topic of this contribution to the Faraday Discussion.

While parallel segments in the Fermi level contours, often found at the surfaces of topological insulators (TIs), would imply "strong" nesting conditions, the existence of charge-density waves (CDWs)-periodic modulations of the electron density-has not been verified up to now. Here, we report the observation of a CDW at the surface of the TI Bi2Te2Se(111), below ≈350K, by helium-atom scattering and, thus, experimental evidence for a CDW involving Dirac topological electrons. Deviations of the order parameter observed below 180K, and a low-temperature break of time reversal symmetry, suggest the onset of a spin-density wave with the same period as the CDW in the presence of a prominent electron-phonon interaction, originating from Rashba spin-orbit coupling.

The ever-increasing global threat of common infections developing resistance to current therapeutics is rapidly accelerating the onset of a primitive post-antibiotic era in medicine. The prevention of further antimicrobial resistance development is unlikely due to the continued misuse of antibiotics, augmented by the lack of discovery of novel antibiotics. Screening large libraries of synthetic compounds have yet to offer effective replacements for current antibiotics. Due to historical successes, discovery from large and diverse natural sources and, more specifically, environmental bacteria, may still yield novel alternative antibiotics. However, the process of antibiotic discovery from natural sources is laborious and time-consuming as a result of outdated methodologies. Therefore, we have developed a simple and rapid preliminary screening assay to identify antibacterial-producing bacteria from natural sources. In brief, the assay utilizes the presence or absence of luminescence in bioluminescent reporter bacteria and test bacterium co-cultures in a 96-well plate format to determine the absence or presence of antibacterial compound production. Our assay, called the bioluminescent simultaneous antagonism (BSLA) assay, can accurately distinguish between known antibacterial-producing and non-producing test bacteria. The BSLA assay was validated by screening 264 unknown soil isolates which resulted in the identification of 10 antibacterial-producing isolates, effectively decreasing the pool of isolates for downstream analysis by 96%. By design, the assay is simple and requires only general laboratory equipment; however, we have shown that the assay can be scaled to automated high-throughput screening systems. Taken together, the BSLA assay allows for the rapid pre-screening of unknown bacterial isolates which, when coupled with innovative downstream dereplication and identification technologies, can effectively fast-track antimicrobial discovery.

Large-area single-crystal monolayers of two-dimensional (2D) materials such as graphene and hexagonal boron nitride (h-BN) can be grown by chemical vapour deposition (CVD). However, the high temperatures and fast timescales at which the conversion from a gas-phase precursor to the 2D material appears, make it extremely challenging to simultaneously follow the atomic arrangements. We utilise helium atom scattering to discover and control the growth of novel 2D h-BN nanoporous phases during the CVD process. We find that prior to the formation of h-BN from the gas-phase precursor, a metastable (3 × 3) structure is formed, and that excess deposition on the resulting 2D h-BN leads to the emergence of a (3 × 4) structure. We illustrate that these nanoporous structures are produced by partial dehydrogenation and polymerisation of the borazine precursor upon adsorption. These steps are largely unexplored during the synthesis of 2D materials and we unveil the rich phases during CVD growth. Our results provide significant foundations for 2D materials engineering in CVD, by adjusting or carefully controlling the growth conditions and thus exploiting these intermediate structures for the synthesis of covalent self-assembled 2D networks.

Background: There is increasing attention on machine learning (ML)-based clinical decision support systems (CDSS), but their added value and pitfalls are very rarely evaluated in clinical practice. We implemented a CDSS to aid general practitioners (GPs) in treating patients with urinary tract infections (UTIs), which are a significant health burden worldwide., Objective: This study aims to prospectively assess the impact of this CDSS on treatment success and change in antibiotic prescription behavior of the physician. In doing so, we hope to identify drivers and obstacles that positively impact the quality of health care practice with ML., Methods: The CDSS was developed by Pacmed, Nivel, and Leiden University Medical Center (LUMC). The CDSS presents the expected outcomes of treatments, using interpretable decision trees as ML classifiers. Treatment success was defined as a subsequent period of 28 days during which no new antibiotic treatment for UTI was needed. In this prospective observational study, 36 primary care practices used the software for 4 months. Furthermore, 29 control practices were identified using propensity score-matching. All analyses were performed using electronic health records from the Nivel Primary Care Database. Patients for whom the software was used were identified in the Nivel database by sequential matching using CDSS use data. We compared the proportion of successful treatments before and during the study within the treatment arm. The same analysis was performed for the control practices and the patient subgroup the software was definitely used for. All analyses, including that of physicians' prescription behavior, were statistically tested using 2-sided z tests with an α level of .05., Results: In the treatment practices, 4998 observations were included before and 3422 observations (of 2423 unique patients) were included during the implementation period. In the control practices, 5044 observations were included before and 3360 observations were included during the implementation period. The proportion of successful treatments increased significantly from 75% to 80% in treatment practices (z=5.47, P<.001). No significant difference was detected in control practices (76% before and 76% during the pilot, z=0.02; P=.98). Of the 2423 patients, we identified 734 (30.29%) in the CDSS use database in the Nivel database. For these patients, the proportion of successful treatments during the study was 83%-a statistically significant difference, with 75% of successful treatments before the study in the treatment practices (z=4.95; P<.001)., Conclusions: The introduction of the CDSS as an intervention in the 36 treatment practices was associated with a statistically significant improvement in treatment success. We excluded temporal effects and validated the results with the subgroup analysis in patients for whom we were certain that the software was used. This study shows important strengths and points of attention for the development and implementation of an ML-based CDSS in clinical practice., Trial Registration: ClinicalTrials.gov NCT04408976; https://clinicaltrials.gov/ct2/show/NCT04408976., (©Willem Ernst Herter, Janine Khuc, Giovanni Cinà, Bart J Knottnerus, Mattijs E Numans, Maryse A Wiewel, Tobias N Bonten, Daan P de Bruin, Thamar van Esch, Niels H Chavannes, Robert A Verheij. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 04.05.2022.)

The surface of Bi(114) is a striking example where the reduced dimensionality gives rise to structural rearrangement and new states at the surface. Here, we present a study of the surface structure and electronic corrugation of this quasi one-dimensional topological metal based on helium atom scattering (HAS) measurements. In contrast to low-index metal surfaces, upon scattering from the stepped (114) truncation of Bi, a large proportion of the incident beam is scattered into higher order diffraction channels which in combination with the large surface unit cell makes an analysis challenging. The surface electronic corrugation of Bi(114) is determined, using measurements upon scattering normal to the steps, together with quantum mechanical scattering calculations. Therefore, minimisation routines that vary the shape of the corrugation are employed, in order to minimise the deviation between the calculations and experimental scans. Furthermore, we illustrate that quantum mechanical scattering calculations can be used to determine the orientation of the in- and outgoing beam with respect to the stepped surface structure.

Surface colonization by microorganisms, combined with the rise in antibiotic resistance, is the main cause of production failures in various industries. Self-sterilising materials are deemed the best prevention of surface colonization. However, current screening methods for these sterilising materials are laborious and time-consuming. The disk diffusion antimicrobial assay and the Japanese industrial standard method for antimicrobial activity on solid surfaces, JIS Z 2801, were compared to our modified solid surface antimicrobial assay in terms of detecting the activity of antibiotic-containing cellulose disks against four bacterial pathogens. Our novel assay circumvents the long incubation times by utilising the metabolic active dye, resazurin, to shorten the time in which antibacterial results are obtained to less than 4 h. This assay allows for increased screening to identify novel sterilising materials for combatting surface colonisation.•Disk diffusion assay could only detect the activity of small compounds that leached from the material over 20-24 h.•JIS Z 2801 was also able to detect the surface activity of non-polar compounds, thought to be inactive based on the disk diffusion results.•The resazurin solid surface antimicrobial assay could obtain the same results as the JIS Z 2801, within a shorter time and in a high-throughput 96-well plate setup., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors. Published by Elsevier B.V.)

Diamantane clusters formed inside superfluid helium nanodroplets were analyzed by time-of-flight mass spectrometry. Distinct cluster sizes were identified as "magic numbers" and the corresponding feasible structures for clusters consisting of up to 19 diamantane molecules were derived from meta-dynamics simulations and subsequent DFT computations. The obtained interaction energies were attributed to London dispersion attraction. Our findings demonstrate that diamantane units readily form assemblies even at low pressures and near-zero Kelvin temperatures, confirming the importance of the intermolecular dispersion effect for condensation of matter.

Metal clusters have drawn continuous interest because of their high potential for the assembly of matter with special properties that may significantly differ from the corresponding bulk. Controlled combination of particular elements in one nanoparticle can increase the options for the creation of new materials for photonic, catalytic, or electronic applications. Superfluid helium droplets provide confinement and ultralow temperature, i.e. an ideal environment for the atom-by-atom aggregation of a new nanoparticle. This perspective presents a review of the current research progress on the synthesis of tailored metal and metal oxide clusters including core-shell designs, their characterization within the helium droplet beam, deposition on various solid substrates, and analysis via surface diagnostics. Special attention is given to the thermal properties of mixed metal clusters and questions about alloy formation on the nanoscale. Experimental results are accompanied by theoretical approaches employing computational chemistry, molecular dynamics simulations and He density functional theory.

Helium Atom Scattering (HAS) and Helium Spin-Echo scattering (HeSE), together helium scattering, are well established, but non-commercial surface science techniques. They are characterised by the beam inertness and very low beam energy (<0.1 eV) which allows essentially all materials and adsorbates, including fragile and/or insulating materials and light adsorbates such as hydrogen to be investigated on the atomic scale. At present there only exist an estimated less than 15 helium and helium spin-echo scattering instruments in total, spread across the world. This means that up till now the techniques have not been readily available for a broad scientific community. Efforts are ongoing to change this by establishing a central helium scattering facility, possibly in connection with a neutron or synchrotron facility. In this context it is important to clarify what information can be obtained from helium scattering that cannot be obtained with other surface science techniques. Here we present a non-exclusive overview of a range of material properties particularly suited to be measured with helium scattering: (i) high precision, direct measurements of bending rigidity and substrate coupling strength of a range of 2D materials and van der Waals heterostructures as a function of temperature, (ii) direct measurements of the electron-phonon coupling constant λ exclusively in the low energy range (<0.1 eV, tuneable) for 2D materials and van der Waals heterostructures (iii) direct measurements of the surface boson peak in glassy materials, (iv) aspects of polymer chain surface dynamics under nano-confinement (v) certain aspects of nanoscale surface topography, (vi) central properties of surface dynamics and surface diffusion of adsorbates (HeSE) and (vii) two specific science case examples - topological insulators and superconducting radio frequency materials, illustrating how combined HAS and HeSE are necessary to understand the properties of quantum materials. The paper finishes with (viii) examples of molecular surface scattering experiments and other atom surface scattering experiments which can be performed using HAS and HeSE instruments.

We present an experimental study of inelastic scattering processes on the (111) surface of the topological insulator Sb 2 Te 3 using helium atom scattering. In contrast to other binary topological insulators such as Bi 2 Se 3 and Bi 2 Te 3 , Sb 2 Te 3 is much less studied and the as-grown Sb 2 Te 3 sample turns out to be p-doped, with the Fermi-level located below the Dirac-point as confirmed by angle-resolved photoemission spectroscopy. We report the surface phonon dispersion along both high symmetry directions in the energy region below 11 meV, where the Rayleigh mode exhibits the strongest intensity. The experimental data is compared with a study based on density functional perturbation theory calculations, providing good agreement except for a set of additional peculiar inelastic events below the Rayleigh mode. In addition, an analysis of angular scans with respect to a number of additional inelastic events is presented, including resonance enhancement, kinematical focusing, focused inelastic resonance and surfing. In the latter case, phonon-assisted adsorption of the incident helium atom gives rise to a bound state where the helium atom rides the created Rayleigh wave.

The phenomenology of resonant scattering has been known since the earliest experiments upon scattering of atomic beams from surfaces and is a means of obtaining experimental information about the fundamentals of weak adsorption systems in the van der Waals regime. We provide an overview of the experimental approach based on new experimental data for the He-Sb 2 Te 3 (111) system, followed by a comparative overview and perspective of recent results for topological semimetal and insulator surfaces. Moreover, we shortly discuss the perspectives of calculating helium-surface interaction potentials from ab initio calculations. Our perspective demonstrates that atom-surface scattering provides direct experimental information about the atom-surface interaction in the weak physisorption regime and can also be used to determine the lifetime and mean free path of the trapped atom. We further discuss the effects of elastic and inelastic scattering on the linewidth and lifetime of the trapped He atom with an outlook on future developments and applications.

Nanoparticles consisting of three different materials in a layered core@shell@shell structure are synthesized in cold helium droplets by sequential doping. Upon the formation of Au core particles, a first shell layer is formed by adding either Ar, isopropyl alcohol, or hexane. Subsequently, the droplets are doped with rhodamine B (RB) molecules; fluorescence spectra recorded upon laser excitation at 532 nm provide insight into the structure of the formed complexes. For the two-component Au@RB system, the RB fluorescence is quenched in the presence of the Au core. If an intermediate isolating shell layer is introduced (Au@shell@RB), the fluorescence increases again. The results demonstrate that shell-isolated nanoparticles can be formed inside He nanodroplets and functionalized in situ with additional molecules. As the structure of the particles depends on the pickup sequence, the approach can be exploited for the synthesis and investigation of a large variety of different combinations of plasmonic metals, intermediate layers, and molecules.

The temperature-induced structural changes of Fe-, Co-, and Ni-Au core-shell nanoparticles with diameters around 5 nm are studied via atomically resolved transmission electron microscopy. We observe structural transitions from local toward global energy minima induced by elevated temperatures. The experimental observations are accompanied by a computational modeling of all core-shell particles with either centralized or decentralized core positions. The embedded atom model is employed and further supported by density functional theory calculations. We provide a detailed comparison of vacancy formation energies obtained for all materials involved in order to explain the variations in the restructuring processes which we observe in temperature-programmed TEM studies of the particles., Competing Interests: The authors declare no competing financial interest., (Copyright © 2020 American Chemical Society.)

He atom scattering has been demonstrated to be a sensitive probe of the electron-phonon interaction parameter λ at metal and metal-overlayer surfaces. Here it is shown that the theory linking λ to the thermal attenuation of atom scattering spectra (the Debye-Waller factor) can be applied to topological semimetal surfaces, such as the quasi-one-dimensional charge-density-wave system Bi(114) and the layered pnictogen chalcogenides. The electron-phonon coupling, as determined for several topological insulators belonging to the class of bismuth chalcogenides, suggests a dominant contribution of the surface quantum well states over the Dirac electrons in terms of λ.

The response of a molecule to photoexcitation is governed by the coupling of its electronic states. However, if the energetic spacing between the electronically excited states at the Franck-Condon window becomes sufficiently small, it is infeasible to selectively excite and monitor individual states with conventional time-resolved spectroscopy, preventing insight into the energy transfer and relaxation dynamics of the molecule. Here, we demonstrate how the combination of time-resolved spectroscopy and extensive surface hopping dynamics simulations with a global fit approach on individually excited ensembles overcomes this limitation and resolves the dynamics in the n3p Rydberg states in acetone. Photoelectron transients of the three closely spaced states n3p x , n3p y , and n3p z are used to validate the theoretical results, which in turn allow retrieving a comprehensive kinetic model describing the mutual interactions of these states for the first time.

Vanadium oxide clusters with a mean diameter below 10 nm are investigated by high resolution Scanning Transmission Electron Microscopy (STEM), Electron Energy Loss Spectroscopy (EELS) and UV-vis absorption spectroscopy. The clusters are synthesised by sublimation from bulk vanadium(v) oxide, in combination with a pick-up by superfluid helium droplets. The latter act as reaction chambers which enable cluster growth under fully inert and solvent-free conditions. High-resolution STEM images of deposited vanadium oxide particles allowing for the determination of lattice constants, clearly indicate a dominating presence of V 2 O 5 . This finding is further supported by UV-vis absorption spectra of nanoparticles after deposition on fused silica substrates, which indicates that the oxidation state of the material is preserved over the entire process. From the results of the UV-vis measurement, the band gap of the nanosized V 2 O 5 could be determined to be 3.3 eV. The synthesis approach provides a route to clean V 2 O 5 clusters as it does not involve any surfactant or solvents, which is crucial for an unbiased measurement of intrinsic catalyst properties.

Structural changes of Ni-Au core-shell nanoparticles with increasing temperature are studied at atomic resolution. The bimetallic clusters, synthesized in superfluid helium droplets, show a centralized Ni core, which is an intrinsic feature of the growth process inside helium. After deposition on SiN x , the nanoparticles undergo a programmed temperature treatment in vacuum combined with an in situ transmission electron microscopy study of structural changes. We observe not only full alloying far below the actual melting temperature, but also a significantly higher stability of core-shell structures with decentralized Ni cores. Explanations are provided by large-scale molecular dynamics simulations on model structures consisting of up to 3000 metal atoms. Two entirely different diffusion processes can be identified for both types of core-shell structures, strikingly illustrating how localized, atomic features can still dictate the overall behavior of a nanometer-sized particle., Competing Interests: The authors declare no competing financial interest.

We present a study of the atom-surface interaction potential for the He-Bi 2 Se 3 (111) system. Using selective adsorption resonances, we are able to obtain the complete experimental band structure of atoms in the corrugated surface potential of the topological insulator Bi 2 Se 3 . He atom scattering spectra show several selective adsorption resonance features that are analyzed, starting with the free-atom approximation and a laterally averaged atom-surface interaction potential. Based on quantum mechanical calculations of the He-surface scattering intensities and resonance processes, we are then considering the three-dimensional atom-surface interaction potential, which is further refined to reproduce the experimental data. Following this analysis, the He-Bi 2 Se 3 (111) interaction potential is best represented by a corrugated Morse potential with a well depth of D = (6.54 ± 0.05) meV, a stiffness of κ = (0.58 ± 0.02) Å -1 , and a surface electronic corrugation of (5.8 ± 0.2)% of the lattice constant. The experimental data may also be used as a challenging benchmark system to analyze the suitability of several van der Waals approaches: the He-Bi 2 Se 3 (111) interaction captures the fundamentals of weak adsorption systems where the binding is governed by long-range electronic correlations., Competing Interests: The authors declare no competing financial interest., (Copyright © 2019 American Chemical Society.)

The 0.4 K internal temperature of superfluid helium nanodroplets is believed to guarantee a corresponding ground-state population of dopant atoms and molecules inside this cryogenic matrix. We have recorded 6s ← 5p excitation spectra of indium atoms in helium droplets and found two absorption bands separated by about 2000 cm - 1 , a value close to the spin-orbit (SO) splitting of the In 2 P ground state. The intensities of the bands agree with a thermal population of the 2 P 1/2 and 2 states at 870 K, the temperature of the In pick-up cell. Applying femtosecond pump-probe spectroscopy, we found the same dynamical response of the helium solvation shell after the photoexcitation of the two bands. He-density functional theory simulations of the excitation spectra are in agreement with the bimodal structure. Our findings show that the population of SO levels of hot dopants is conserved after pick-up inside the superfluid droplet. Implications for the interpretation of experiments on molecular aggregates are discussed.3/2 states at 870 K, the temperature of the In pick-up cell. Applying femtosecond pump-probe spectroscopy, we found the same dynamical response of the helium solvation shell after the photoexcitation of the two bands. He-density functional theory simulations of the excitation spectra are in agreement with the bimodal structure. Our findings show that the population of SO levels of hot dopants is conserved after pick-up inside the superfluid droplet. Implications for the interpretation of experiments on molecular aggregates are discussed.