Search

The search for long-lived quantum memories, which can be efficiently interfaced with flying qubits, is longstanding. One possible solution is to use the electron spin of a color center in diamond to mediate interaction between a long-lived nuclear spin and a photon. Realizing this in a nanodiamond furthermore facilitates the integration into photonic devices and enables the realization of hybrid quantum systems with access to quantum memories. Here, we investigated the spin environment of negatively charged silicon-vacancy centers in a nanodiamond and demonstrate strong coupling of its electron spin, while the electron spin’s decoherence rate remained below 1 MHz. We furthermore demonstrate multi-spin coupling with the potential to establish registers of quantum memories in nanodiamonds.

Low-intensity focused ultrasound provides the means to noninvasively stimulate or release drugs in specified deep brain targets. However, successful clinical translations require hardware that maximizes acoustic transmission through the skull, enables flexible electronic steering, and provides accurate and reproducible targeting while minimizing the use of MRI. We have developed a device that addresses these practical requirements. The device delivers ultrasound through the temporal and parietal skull windows, which minimize the attenuation and distortions of the ultrasound by the skull. The device consists of 252 independently controlled elements, which provides the ability to modulate multiple deep brain targets at a high spatiotemporal resolution, without the need to move the device or the subject. And finally, the device uses a mechanical registration method that enables accurate deep brain targeting both inside and outside of the MRI. Using this method, a single MRI scan is necessary for accurate targeting; repeated subsequent treatments can be performed reproducibly in an MRI-free manner. We validated these functions by transiently modulating specific deep brain regions in two patients with treatment-resistant depression.

The structural determination of natural products (NPs) can be arduous because of sample heterogeneity. This often demands iterative purification processes and characterization of complex molecules that may be available only in miniscule quantities. Microcrystal electron diffraction (microED) has recently shown promise as a method to solve crystal structures of NPs from nanogram quantities of analyte. However, its implementation in NP discovery remains hampered by sample throughput and purity requirements, akin to traditional NP-discovery workflows. In the methods described herein, we leverage the resolving power of transmission electron microscopy (TEM) and the miniaturization capabilities of deoxyribonucleic acid (DNA) microarray technology to address these challenges through the establishment of an NP screening platform, array electron diffraction (ArrayED). In this workflow, an array of high-performance liquid chromatography (HPLC) fractions taken from crude extracts was deposited onto TEM grids in picoliter-sized droplets. This multiplexing of analytes on TEM grids enables 1200 or more unique samples to be simultaneously inserted into a TEM instrument equipped with an autoloader. Selected area electron diffraction analysis of these microarrayed grids allows for the rapid identification of crystalline metabolites. In this study, ArrayED enabled structural characterization of 14 natural products, including four novel crystal structures and two novel polymorphs, from 20 crude extracts. Moreover, we identify several chemical species that would not be detected by standard mass spectrometry (MS) or ultraviolet–visible (UV/vis) spectroscopy and crystal forms that would not be characterized using traditional methods.

We demonstrate an important step toward on-chip integration of single-photon sources at room temperature. Excellent photon directionality is achieved with a hybrid metal–dielectric bullseye antenna, while back-excitation is permitted by placement of the emitter in a subwavelength hole positioned at its center. The unique design enables a direct back-excitation and very efficient front coupling of emission either to a low numerical aperture (NA) optics or directly to an optical fiber. To show the versatility of the concept, we fabricate devices containing either a colloidal quantum dot or a nanodiamond containing silicon-vacancy centers, which are accurately positioned using two different nanopositioning methods. Both of these back-excited devices display front collection efficiencies of ∼70% at NAs as low as 0.5. The combination of back-excitation with forward directionality enables direct coupling of the emitted photons into a proximal optical fiber without any coupling optics, thereby facilitating and simplifying future integration.

The generation of indistinguishable photons is a key requirement for solid-state quantum emitters as a viable source for applications in quantum technologies. Restricting the dimensions of the solid-state host to a size well below the wavelength of light emitted by a defect-center enables efficient external optical coupling, for example, for hybrid integration into photonic devices. However, stringent restrictions on the host dimensions result in severe limitations on the spectral properties reducing the indistinguishability of emitted photons. Here, we demonstrate two-photon interference from two negatively charged silicon-vacancy centers located in remote nanodiamonds. The Hong–Ou–Mandel interference efficiency reaches 61 % with a coalescence time window of 0.35 ns. We furthermore show a high yield of pairs of silicon-vacancy centers with indistinguishable optical transitions. Therefore, our work opens new paths in hybrid quantum technology based on indistinguishable single-photon emitters in nanodiamonds.

Tuberculosis (TB) is a dreadful infectious disease and a leading cause of mortality and morbidity worldwide, second in 2020 only to severe acute respiratory syndrome 2 (SARS-Cov-2). With limited therapeutic options available and a rise in multidrug-resistant tuberculosis cases, it is critical to develop antibiotic drugs that display novel mechanisms of action. Bioactivity-guided fractionation employing an Alamar blue assay for Mycobacterium tuberculosisstrain H37Rv led to the isolation of duryne (13) from a marine sponge Petrosiasp. sampled in the Solomon Islands. Additionally, five new strongylophorine meroditerpene analogues (1–5) along with six known strongylophorines (6–12) were isolated from the bioactive fraction and characterized using MS and NMR spectroscopy, although only 13exhibited antitubercular activity.

This paper introduces a new technique to optimally design the fractional-order Butterworth low-pass filter in the complex F-plane. Design stability is assured by incorporating the critical phase angle as an inequality constraint. The poles of the proposed approximants reside on the unit circle in the stable region of the F-plane. The improved accuracy of the suggested scheme as compared to the recently published literature is demonstrated. A mixed-integer genetic algorithm which considers the parallel combinations of resistors and capacitors for the Valsa network is used to optimize the frequency responses of the fractional-order capacitor emulators as part of the experimental verification using the Sallen–Key filter topology. The total harmonic distortion and spurious-free dynamic range of the practical 1.5th-order Butterwoth filter are measured as 0.13% and 62.18 dBc, respectively; the maximum and mean absolute relative magnitude errors are 0.03929 and 0.02051, respectively.

Early detection of predators is critical to the survival of all living organisms. For phytoplankton, recognition and response to chemical cues from predators, as evidence of predation risk, are particularly crucial. The phytoplankton Alexandrium minutumupregulates its toxicity when exposed to copepodamides, a suite of compounds released by copepod predators. However, how A. minutumperceives these predatory cues and what metabolic pathways are involved in initiating toxin induction remains unknown. In this study, liquid chromatography‐mass spectrometry and NMR‐based metabolomics uncovered subtle physiological responses of A. minutumto copepodamides, including altered regulation of branched‐chain amino acid biosynthesis and potential enhancement of butanoate metabolism and arginine biosynthesis. While we have yet to identify a chemoreceptor directly activated by copepod cues, based on the results of inhibition experiments, detection of copepodamides appears to disrupt the activity of serine/threonine phosphatases leading to increased jasmonic acid biosynthesis and signaling, which leads to amplified gonyautoxin biosynthesis in A. minutum. This study is an important step toward a better understanding of chemosensory ecology of predator–prey interactions in phytoplankton.

Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy.

The formula of the all-pole low-pass frequency filter transfer function of the fractional order (N+ α) designated for implementation by non-cascade multiple-feedback analogue structures is presented. The aim is to determine the coefficients of this transfer function and its possible variants depending on the filter order and the distribution of the fractional-order terms in the transfer function. Optimization algorithm is used to approximate the target Butterworth low-pass magnitude response, whereas the approximation errors are evaluated. The interpolated equations for computing the transfer function coefficients are provided. An example of the transformation of the fractional-order low-pass to the high-pass filter is also presented. The results are verified by simulation of multiple-feedback filter with operational transconductance amplifiers and fractional-order element.

The formula of the all-pole low-pass frequency filter transfer function of the fractional order (N+ α) designated for implementation by non-cascade multiple-feedback analogue structures is presented. The aim is to determine the coefficients of this transfer function and its possible variants depending on the filter order and the distribution of the fractional-order terms in the transfer function. Optimization algorithm is used to approximate the target Butterworth low-pass magnitude response, whereas the approximation errors are evaluated. The interpolated equations for computing the transfer function coefficients are provided. An example of the transformation of the fractional-order low-pass to the high-pass filter is also presented. The results are verified by simulation of multiple-feedback filter with operational transconductance amplifiers and fractional-order element.

Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1-mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TLs) by quantitative reverse-transcription polymerase chain reaction and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TLs and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase 3 AMLSG 09-09 trial. A total of 3733 bone marrow (BM) samples and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥ 3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after 2 treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity was consistently revealed to be a poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TLs were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly greater proportion of patients achieving MRD negativity at EOT (56% vs 41%; P = .01). The better reduction in NPM1mut TLs after 2 treatment cycles in MRD positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR, 29.3% vs 45.7%, P = .009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction in NPM1mut TLs across all treatment cycles, leading to a significantly lower relapse rate.

Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1-mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1muttranscript levels (TLs) by quantitative reverse-transcription polymerase chain reaction and evaluated the prognostic impact of NPM1mutMRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mutTLs and the cumulative incidence of relapse (CIR) in patients with NPM1mutAML enrolled in the randomized phase 3 AMLSG 09-09 trial. A total of 3733 bone marrow (BM) samples and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mutTL log10reduction ≥ 3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after 2 treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity was consistently revealed to be a poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mutTLs were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly greater proportion of patients achieving MRD negativity at EOT (56% vs 41%; P= .01). The better reduction in NPM1mutTLs after 2 treatment cycles in MRD positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR, 29.3% vs 45.7%, P= .009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mutAML resulted in a significantly better reduction in NPM1mutTLs across all treatment cycles, leading to a significantly lower relapse rate.

Organisms are under selection pressure to recognize predators and assess predation risk to avoid becoming prey. In some cases, the presence of injured competitors alerts individuals to the likelihood that predators are nearby. Previous studies have shown that the marine dinoflagellate Alexandrium minutumresponds to chemical cues from copepods by dramatically upregulating sodium channel‐blocking toxins that appear to function as defenses against copepod grazing. However, it is unknown whether A. minutumuses other cues, such as damaged phytoplankton, some of which are its competitors, to assess predation risk and subsequently increase its resistance to predators. To investigate the role of dead phytoplankton cues in chemical defense plasticity, A. minutumwas exposed for 3 days to chemical cues from six different phytoplankton. Chemical cues from dead, unrelated, historically co‐occurring phytoplankton species induced toxin production in A. minutumcoincident with a decrease in growth. In contrast, exposure to chemical cues from more closely related dead phytoplankton, either conspecific or congeneric, suppressed toxin production in A. minutumrelative to their absence. This was coupled with a modest, yet significant, increase in growth. The consistent inverse relationship between toxin production and growth suggests that A. minutumexperiences a trade‐off. Together, these results reveal that relatedness of dead phytoplankton is important in how A. minutumutilizes resources for growth and defense.

Hybrid quantum photonics combines classical photonics with quantum emitters in a postprocessing step. It facilitates to link ideal quantum light sources to optimized photonic platforms. Optical cavities enable to harness the Purcell-effect boosting the device efficiency. Here, we postprocess a free-standing, crossed-waveguide photonic crystal cavity based on Si3N4with SiV−center in nanodiamonds. We develop a routine that optimizes the overlap with the cavity electric field utilizing atomic force microscope (AFM) nanomanipulation to attain control of spatial and dipole alignment. Temperature tuning further gives access to the spectral emitter-cavity overlap. After a few optimization cycles, we resolve the fine-structure of individual SiV−centers and achieve a Purcell enhancement of more than 4 on individual optical transitions, meaning that four out of five spontaneously emitted photons are channeled into the photonic device. Our work opens up new avenues to construct efficient quantum photonic devices.

Being abundant primary producers, single‐celled eukaryotic diatoms and dinoflagellates dominate marine food webs and significantly impact the ecology of the oceans. These organisms face competition and predation which have contributed to the evolution of chemical defenses and their ability to sense chemical cues. Elucidating how these chemical cues are perceived by organisms requires identification of proteins involved in relaying chemical information to cells. The functions of G protein‐coupled receptor (GPCR) signaling diversified over evolutionary time in multicellular organisms, but the role that GPCR signaling plays in unicellular eukaryotes remains largely unknown. Using comparative transcriptomic analysis, we identified repertoires of GPCR signaling proteins from 81 diatom and 36 dinoflagellate transcriptomes. Diatoms and dinoflagellates express putative GPCRs that are highly diverged from known metazoan GPCRs along with well‐conserved core components of GPCR signaling pathways. Unlike other eukaryotes that express multiple classes of GPCRs, diatoms and dinoflagellates were each found to express a single, major class of putative GPCRs with greatest similarity to class C and rhodopsin‐like GPCRs, respectively. Furthermore, only 4.2% of the GPCR‐like transcripts from dinoflagellates were predicted to be true GPCRs compared to 48% in diatoms. These results suggest that further expansion of GPCRs did not take place within each of these two major phytoplankton groups, and that dinoflagellate GPCRs are more divergent from known GPCRs than are diatom GPCRs. Our results provide additional evidence for the global existence of relatively ancestral GPCR signaling machinery in marine phytoplankton.

Striving for nanometer-sized solid-state single-photon sources, we investigate atom-like quantum emitters based on single germanium-vacancy (GeV) centers isolated in crystalline nanodiamonds (NDs). Cryogenic characterization indicated symmetry-protected and bright (>106counts/s with off-resonance excitation) zero-phonon optical transitions with up to 6-fold enhancement in energy splitting of their ground states as compared to that found for GeV centers in bulk diamonds (i.e. up to 870 GHz in highly strained NDs vs. 150 GHz in bulk). Utilizing lithographic alignment techniques, we demonstrate an integrated nanophotonic platform for deterministic interfacing plasmonic waveguides with isolated GeV centers in NDs, which enables 10-fold enhancement of single-photon decay rates along with the emission direction control by judiciously designing and positioning a Bragg reflector. This approach allows one to realize the unidirectional emission from single-photon dipolar sources, thereby opening new perspectives for the realization of quantum optical integrated circuits.

Transcranial ultrasound neuromodulation (TUSN) is a noninvasive and spatially specific therapy that promises to deliver treatments tailored to the specific needs of individuals. To fulfill this promise, each treatment must be modified to adequately correct for variation across individual skulls and neural anatomy. This study examines the use of ultrasound-induced voltage potentials (measured with electroencephalography [EEG]) to guide TUSN therapies.

Sensory perception of chemical threats coming from an organism's environment relies on the coordination of numerous receptors and cell types. In many cases, the physiological processes responsible for driving behavioral responses to chemical cues are poorly understood. Here, we investigated the physiological response of fish to an unpalatable compound, formoside, which is employed as a chemical defense by marine sponges. Construction of fluorescent probe derivatives of formoside allowed visualization of this chemical defense molecule in vivo, interacting with the cells and tissues of the early larvae of a model predator, the zebrafish (Danio rerio). This revealed the precise chemosensory structures targeted by formoside to be in the taste buds and olfactory epithelium of developing zebrafish. Mechanosensory neuromasts were also targeted. This study supports the involvement of a previously identified co-receptor in detection of the chemical defense and provides a springboard for the long-term goal of identification of the cellular receptor of formoside. Extension of this approach to other predators and chemical defenses may provide insight into common mechanisms of chemoreception by predators as well as common strategies of chemical defense employed by prey.

Two sulfated diterpene glycosides featuring a highly substituted and sterically encumbered cyclopropane ring have been isolated from the marine red alga Peyssonneliasp. Combination of a wide array of 2D NMR spectroscopic experiments, in a systematic structure elucidation workflow, revealed that peyssonnosides A–B (1–2) represent a new class of diterpene glycosides with a tetracyclo [7.5.0.01,10.05,9] tetradecane architecture. A salient feature of this workflow is the unique application of quantitative interproton distances obtained from the rotating frame Overhauser effect spectroscopy (ROESY) NMR experiment, wherein the β-d-glucose moiety of 1was used as an internal probe to unequivocally determine the absolute configuration, which was also supported by optical rotatory dispersion (ORD). Peyssonnoside A (1) exhibited promising activity against liver stage Plasmodium bergheiand moderate antimethicillin-resistant Staphylococcus aureus(MRSA) activity, with no cytotoxicity against human keratinocytes. Additionally, 1showed strong growth inhibition of the marine fungus Dendryphiella salinaindicating an antifungal ecological role in its natural environment. The high natural abundance and novel carbon skeleton of 1suggests a rare terpene cyclase machinery, exemplifying the chemical diversity in this phylogenetically distinct marine red alga.

Integrated nanophotonics is an emerging field with high potential for quantum technology applications such as quantum sensing or quantum networks. A desired photonics platform is Si3N4due to low-photon loss and well-established fabrication techniques. However, quantum optics applications are not yet established. Here, we investigate an approach toward Si3N4-based quantum photonics utilizing a crossed waveguide, pump–probe design. The platform enables efficient, on-chip excitation, strong background suppression, and at the same time, efficient coupling to the mode of a high-Qphotonic crystal cavity. The freestanding photonic crystal cavities reach high Q-factors up to 47 × 103. To test our platform, we positioned an ensemble of negatively charged nitrogen vacancy centers located in a nanodiamond within the interaction zone of the photonic crystal cavity. We quantify the efficiency of the coupling with the βλ-factor reaching values as large as 0.71. We further demonstrate on-chip excitation of the quantum emitter with strong suppression (∼20 dB) of the background fluorescence. Our results unfold the potential to utilize negatively charged nitrogen vacancy centers in nanodiamonds and Si3N4platforms as an efficient, on-chip spin-photon interface in quantum photonics experiments.

A series of oligomeric phenols including the known natural product 3,4,3′,4′-tetrahydroxy-1,1′-biphenyl (3), the previously synthesized 2,3,8,9-tetrahydroxybenzo[c]chromen-6-one (4), and eight new related natural products, cladophorols B–I (5–12), were isolated from the Fijian green alga Cladophora socialisand identified by a combination of NMR spectroscopy, mass spectrometric analysis, and computational modeling using DFT calculations. J-resolved spectroscopy and line width reduction by picric acid addition aided in resolving the heavily overlapped aromatic signals. A panel of Gram-positive and Gram-negative pathogens used to evaluate pharmacological potential led to the determination that cladophorol C (6) exhibits potent antibiotic activity selective toward methicillin-resistant Staphylococcus aureus(MRSA) with an MIC of 1.4 μg/mL. Cladophorols B (5) and D–H (7–11) had more modest but also selective antibiotic potency. Activities of cladophorols A–I (4–12) were also assessed against the asexual blood stages of Plasmodium falciparumand revealed cladophorols A (4) and B (5) to have modest activity with EC50values of 0.7 and 1.9 μg/mL, respectively.

•Fake, misleading and over-interpreted health news in social media is the potential threat for public health.•Top links related to common diseases in 40% cases contained misinformation and were shared 451 272 times in the period 2012–2017.•Analyzing social media could contribute to identification and take action on leading web pages polluting medical information.

Assessing eruption volumes is one of the major challenges in volcano research but provides valuable insights into the dynamics of an eruption and the associated hazard. One way to estimate this important parameter is the generation and differencing of digital elevation models (DEMs) acquired before, during, and after an eruption. The satellite mission TanDEM‐X enables generation of time series of DEMs using synthetic aperture radar satellite imagery. We use these data to study the 2012–2013 eruption of Tolbachik in Kamchatka. We developed a processing scheme for generation of 18 DEMs from TanDEM‐X imagery that relies on the generation of a preeruption DEM which is used to process the syneruption and posteruption data pairs. Differencing each DEM with the preeruption DEM enables mapping the lava flows and measuring lava flow volume over time and to estimate lava extrusion rates. We find a final lava flow volume of 0.53 km3covering an area of 36 km2by the end of the eruption. An uncertainty analysis is performed while analyzing the DEM differences in areas where no topographic change is expected, leading to an error of ±0.01 km3for the final lava flow volume. The lava effusion was with 247.92 m3/s very high in the first days of the eruption and rapidly decayed toward its end. While many basaltic eruptions follow an exponentially decaying flow model, the extrusion rates at Tolbachik are more compatible with a 1/tmodel. This special characteristic might be useful to gain further insight into the eruption process at Tolbachik. TanDEM‐X time series reveals topographic changes due to basaltic lava flow emplacementLava flow mapping and volume and effusion rate estimates for the 2012–2013 Tolbachik fissure eruptionUncertainty estimation for a time series of TanDEM‐X DEMs and derived volcanological results

The need to determine the mechanical properties of materials of machine parts working in operating conditions without shutdown of the entire unit and disintegration machine parts in the past led to the development of miniaturized specimens associated with the generation of special test procedures and methods. During many years the developed methods have been refining, the results are compared with conventional testing methods, the shape and dimensions of specimens are modified. The enormous development of information technologies in the last decades enabled the emergence of a new field of science - mechatronics - a multidisciplinary field of engineering that includes a combination of systems engineering, mechanical engineering, electrical engineering, telecommunications engineering, control engineering and computer engineering. Progress in the field of mechatronic together with development of new materials, new CNC machining methods for metallic and non-metallic materials, miniaturization of sensors of physical quantities, fast, accurate data sampling and recording significantly influenced the development of the testing devices and allowed to construct machines which was not possible in the past.Content of this paper presents the latest design, features of a test device for determining the residual life of machine components working at elevated temperatures (SPUTT500®), equipment for tensile and fracture testing small samples under the normal and low temperatures (CRYOSET®) and the scoop sampling machine (ESTIM®) used not only for further research but also for development and evaluation of small samples testing technology. The final part of this article comprises the proposal for improvement the Code of practise for small punch testing (CEN Workshop Agreement 15627).

Introduction:Recent-onset dilated cardiomyopathy (RODCM) is a disease of heterogeneous etiology and diverse clinical outcomes.Hypothesis:We hypothesized that the genotype of RODCM might correlate with left ventricular reverse remodeling (LVRR) and long-term clinical outcomes.Methods:A total of 386 RODCM patients (pts) [age 44±12 years, 277 males (72%), familial in 98 pts (25%)] with a history of symptoms less than six months underwent whole-exome sequencing (WES) where likely-pathogenic and pathogenic (class 4-5) disease-causing variants were identified. LVRR was defined as an improvement in left ventricular ejection fraction to >50% or ≥10% absolute increase, with left ventricular end-diastolic diameter ≤33 mm/m2 or ≥10% relative decrease. In this prospective study, the primary outcome was the first event of all-cause death, heart transplantation or ventricular assist device. The secondary outcome included sudden cardiac death, resuscitated cardiac arrest or treated ventricular tachyarrhythmias.Results:WES detected class 4-5 titin truncated variants (TTNtv) in 69 pts (19%), class 4-5 non-titin variants (non-TTN) (Figure)in 56 pts (14%), variants of unknown significance only in 103 pts (27%) and a negative result in 158 pts (40%). At 12 months, LVRR was assessed in 359 pts and was present in 171 pts (48%). Carriers of class 4-5 non-TTNvariants developed LVRR less frequently than subjects with other genetic testing results (28% vs. 51%, p˂0.01). During a median follow-up of 55 months, the primary and secondary outcomes occurred in 79 pts (20%) and 50 pts (13%), respectively. Carriers of class 4-5 non-TTNvariants had an increased risk of both primary [HR 2.36 (95% CI 1.32-4.20), p˂0.01] and secondary [HR 3.08 (95% CI 1.42-6.67), p˂0.01] outcomes as compared with genotype-negative pts. In multivariable models, genotype remained a strong predictor of both types of outcome.Conclusions:Among RODCM patients, carriers of class 4-5 non-TTNvariants have an increased risk of death and progressive heart failure, and a higher long-term burden of life-threatening ventricular arrhythmias compared to genotype-negative subjects.Funding:Supported by the research grant of the Ministry of Health, Czech Republic: [NV19-08-00122] and IPO 00023001.

Evidence regarding the use of bortezomib-containing schemes in primary treatment of antibody-mediated rejection in heart transplant recipients is scarce. This case report presents the clinical experience with upstream use of bortezomib in primary treatment of early antibody-mediated rejection in an adult heart transplant recipient. Two cycles of bortezomib together with methylprednisolone, immunoadsorption, rituximab, and supplementary doses of intravenous immunoglobulin G reversed signs of heart failure, production of donor-specific antibodies, and findings of antibody-mediated rejection in biopsy. This treatment regimen was tolerated with only mild hematologic toxicity and proved to be successful during a 12-month follow-up. Primary treatment with a bortezomib-containing regimen appears to be a new therapeutic option for severe antibody-mediated rejection in heart transplant recipients. However, the efficacy and safety of this treatment need to be tested in prospective trials.

Fulminant myocarditis (FM) is an inflammation of the myocardium characterized by progressive acute heart failure leading to cardiogenic shock that develops over several hours. In this article, we present a case of a female patient with acute fulminant lymphocytic myocarditis who was successfully treated with biventricular MCS.

Hypertrophic cardiomyopathy with severe left ventricular diastolic dysfunction has been associated with marked exercise intolerance and poor prognosis. However, molecular pathogenesis of this phenotype remains unexplained in a large proportion of cases.

Cytomegalovirus (CMV) is a major cause of infection in the early period after heart transplantation (HTx). There are limited data comparing universal prophylaxis with preemptive treatment of CMV infection in HTx recipients. Therefore, the goal of this study was to evaluate efficacy and safety of both strategies.

Tydemania expeditionisWeber–van Bosse (Udoteaceae) is a weakly calcified green alga. In the present paper, liquid chromatography coupled with photodiode array detection and electrospray mass spectrometry was developed to identify the fingerprint components. A total of four triterpenoid sulfates and three hydroxy fatty acids in the ethyl acetate fraction of the crude extract were structurally characterized on the basis of retention time, online UV spectrum, and mass fragmentation pattern. Furthermore, a detailed liquid chromatography–mass spectrometry analysis revealed two new hydroxy fatty acids, which were then prepared and characterized by extensive nuclear magnetic resonance (NMR) analyses. The proposed method provides a scientific and technical platform for the rapid identification of triterpenoid sulfates and hydroxy fatty acids in similar marine algae and terrestrial plants. Copyright © 2011 John Wiley & Sons, Ltd.

Whereas up to 10% (median: 0.046-0.1%) of platelet concentrates are regarded to be bacterially contaminated, approximately only one out of 9 million transfused red blood cell (RBC) units bears the chance of death from sepsis due to contamination with psychrophilic bacteria, mainly Yersiniα enterocoliticα. We report the clinical course and the bacteriological examination of unavoidable fatal septic shock resulting from transfusion of a RBC unit contaminated with Y. enterocoliticα in a 47-year-old man who underwent cystectomy due to bladder cancer. The case is discussed in the light of different recommended measures during collecting and processing of blood donations that could be suitable to prevent bacterial contamination.

Mit pharmakologischen Dosen von Erythropoetin (EPO) kann, wenn Eisen und erythropoetische Vorläuferzellen verfügbar sind, ohne wesentliche Nebenwirkungen fast immer eine Erhöhung der Hämoglobinkonzentration erzielt werden. Ob sich dabei die Lebensqualität von multimorbiden Patienten mit chronischen Anämien, bei denen z.B. das Hämoglobin von 9 auf 11 g% erhöht wird, verbessert, ist in Studien zu hinterfragen. EPO ist für Indikationen, außer der renalen Anämie, bisher nicht zugelassen. EPO als Adjuvans für die autologe Blutentnahme ist bei ausreichender Eisensubstitution für gewisse Kollektive wie Frauen mit einer grenzwertig niedrigen Hämoglobinkonzentration eine mögliche Therapie, wenn auch noch eine sehr aufwendige. EPO in hoher Dosierung (300 U/kg Körpergewicht für 14 Tage) als perioperative Therapie bei ausreichender Eisensubstitution spart, wiederum unter großem finanziellem Aufwand, etwa 50% Fremdblut ein. Ein solches Verfahren ist für den Patienten, der sich einer elektiven Operation unterzieht, wenig aufwendiger als die autologe präoperative Blutentnahme, schließt aber die Anwendung von Fremdblut nicht in jedem Fall aus. Der Kosten-Nutzen-Quotient muß von uns, den behandelnden Ärzten, im Kontext einer machbaren erfolgreichen medizinischen Versorgung und der knapper werdenden Ressourcen beantwortet werden. Daher ist es notwendig, in Studien die Patienten zu identifizieren, die von einer EPO-Therapie profitieren, um letztendlich die «beste» durchführbare Therapie für den individuellen Patienten zu definieren.

Four new bromophycolides, R−U (1−4), were isolated from the Fijian red alga Callophycus serratusand were identified by 1D and 2D NMR and mass spectroscopic analyses. These compounds expand the known structural variety of diterpene-benzoate macrolides and exhibited modest cytotoxicity toward selected human cancer cell lines. Bromophycolide S (2) also showed submicromolar activity against the human malaria parasite Plasmodium falciparum.

Ziel:Die Infektionsrisiken durch Blutpräparate sollen aus aktuellen Daten abgeschätzt werden. Design:Die Häufigkeiten der Infektionsmarker HIV, HCV und HBV unter den Blutspenden wurden erfaβt. Rahmen und TeilnehmenDurch das Studiensekretariat konnten die Befunde bei alien Blutspenden im Jahr 1994 erstmals aus alien staatlichkommunalen und DRK-Blutspendediensten in Deutschland erfaβt und ausgewertet werden. Ergebnisse:Das Risiko einer Infektionsübertragung durch zelluläre Blutpräparate aus Mehrfachspenden ist einzuschätzen als 1 : 1 Million für HIV mit einem Streubereich von 1: 300000 bis 1 : 3 Millionen und für HBV 1: 50000. Für HCV ist das Risiko für den Gesamtbereich noch nicht endgültig festzustellen, liegt jedoch sicher unter 1 : 20 000. Aus Teildaten der Serokonversion von HCV bei Blutspendern aus ländlichen Bereichen errechnen sich sogar Zahlen von kleiner 1 : 200000. Schluβfolgerungen:Durch die effektive Spender-selektion, für HIV seit 1985, für HCV seit 1990, ist ein hohes Maβ an Sicherheit erreicht.

Ziel:Ziel der vorliegenden Untersuchung war es, durch eine Lookback-Studie 1. die Zahl der HIV-Infektionen durch Bluttransfusionen vor Beginn der routinemäßigen HIV-Testung abzuschätzen, 2. auf die Zahl der HIV-Übertragungen durch HIV-negativ getestete Blutspenden nach der Anti-HIV-Testung zu schließen, 3. den Infektionsmodus bei HIV-positiv gemeldeten Transfusionsempfängern durch Rück-verfolgung der Präparate zum Spender abzuklären. Design:Retrospektive («Lookback»-)Untersuchung. Rahmen: HIV-Studiengruppe der DRK-Blutspendedienste in Deutschland, die 80% der Gesamtblutversorgung leisten. Teilnehmer:Die Blutpräparate der Spenden von HIV-Antikörperpositiven Mehrfachspendern wurden, soweit möglich, zum Empfänger zurückverfolgt und diese auf ihren HIV-Antikörperstatus untersucht. In dem Untersuchungszeitraum von 1981 bis 1992 wurden etwa 25 Mio. Blutspenden auf HIV-Antikörper untersucht. Interventionen:Keine. Ergebnisse: Von 289 HIV-Western-blot-positiven Mehrfachspendern wurde versucht, Spenderserien zum Empfänger zurückzuverfolgen. Etwa 50% der Transfusionsempfänger waren an ihrer Grundkrankheit verstorben. Etwa 40% der Spenderserien konnten nicht vollständig abgeklärt werden, da entweder die Empfänger nicht zur Verfügung standen oder eine HIV-Testung verweigerten, oder die Blutpräparate nicht bis zum Empfänger verfolgt werden konnten. Aus den Lookback-Serien von 289 positiven Mehrfachspendern wurden 25 HIV-positive Empfänger vor Beginn der Testung (1982-1985) und 9 HIV-positive Empfänger von HIV-negativ getesteten Blutpräparaten nach Beginn der Testung (1985-1992) identifiziert. Beim empfänger-bezogenen Lookback wurden die transfundierten Blutpräparate von 135 HIV-positiv gemeldeten Transfusionsempfängern zum involvierten Spender zurückverfolgt. Bei mehr als 50% konnte keine Kausalität hergestellt werden, d.h., die benannten Blutpräparate waren nicht Ursache der Infektion, wobei 40% der Fälle nicht vollständig abgeklärt werden konnten. Schlußfolgerungen:Die Übertragung von HIV-Infektionen durch getestete Bluttransfusionen ist extrem selten (1:1 Mio.) und war auch vor der HIV-Testung in

Ziel: Das aktuelle Risiko transfusionsassoziierter Infektionen, besonders mit dem Human Immunodeficiency Virus (HIV) und dem Hepatitis-C-Virus (HCV), für Mitteleuropa zu definieren. Quellen: Relevante neueste englische und deutsche Veröffentlichungen und eigene Daten. Auswahlkriterien: Keine spezielle Literaturrecherche über die Zeit. Ergebnisse: Durch verstärkte Spenderselektion, zusätzliches und verbessertes Labor-Screening und eine sich ändernde Epidemiologie ist das Risiko eine dynamische Gröβe, deren gegenwärtiger Stand immer wieder neu bestimmt werden muβ. Das Risiko einer HIV-Übertragung wird auf 1:1 Million per transfundierte Blutkomponente geschätzt. Durch die seit 1990 durchgeführte Testung aller Blutspenden auf Anti-HCV wurde die Posttransfusionshepatitis-C-(PTH-C-)Übertragung um 80% reduziert und nach eigenen Daten auf 1 per 5000 transfundierte Blutpräparate geschätzt. Eine zu erwartende Verbesserung des HCV-Screenings wird das Risiko, HCV durch Blut zu übertragen, weiter reduzieren. Das Risiko, Hepatitis B zu übertragen, liegt in der Gröβenordnung von 1 per 50000 transfundierte Blutkomponenten. Schluβfolgerung: Dieses in den letzten Jahren deutlich verminderte, aber häufig überschätzte Infektionsrisiko muβ bei einer Nutzen/Risiko-Abschätzung für alternative Methoden zur homologen Bluttransfusion für den einzelnen Patienten in Betracht gezogen werden.

Since early 2020, disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global pandemic, causing millions of infections and deaths worldwide. Despite rapid deployment of effective vaccines, it is apparent that the global community lacks multipronged interventions to combat viral infection and disease. A major limitation is the paucity of antiviral drug options representing diverse molecular scaffolds and mechanisms of action. Here we report the antiviral activities of three distinct marine natural products─homofascaplysin A (1), (+)-aureol (2), and bromophycolide A (3)─evidenced by their ability to inhibit SARS-CoV-2 replication at concentrations that are nontoxic toward human airway epithelial cells. These compounds stand as promising candidates for further exploration toward the discovery of novel drug leads against SARS-CoV-2.

Introduction:Fabry disease (FD) is a rare X-linked genetic disorder caused by α-galactosidase A (AGALA) deficiency. While "classic" variant has multisystemic manifestation, the more recently described "later-onset" variant is characterized by predominant cardiac involvement that often mimics hypertrophic cardiomyopathy (HCM).Hypothesis:Routine screening in patients with hypertrophic cardiomyopathy may detect patients with Fabry disease who are not clinically characterized by a typical multi-organ disorder.Methods:Consecutive unrelated patients with HCM were screened for FD in 16 (out of 17) cardiac centers in the Czech Republic covering specialized cardiology care from June 2017 to December 2018. AGALA activity and globotriaosylsphingosine (lyso-Gb3) levels were measured in all subjects using the dry blood spot method. FD was suspected in male patients with AGALA activity <1.2μmol/h/L and in females with either low AGALA activity or lyso-Gb3>3.5ng/mL. Positive screening results were confirmed by genetic testing.Results:We evaluated 589 patients (390 males, 66%) with HCM (mean maximal myocardial thickness 19.1±4.3 mm). The average age was 58.4±14.7 years. In total, 17 patients (11 males, 6 females) had a positive screening results and subsequently six of them (4 males and 2 females) had a genetically confirmed pathogenic variant (total prevalence of 1.02 %). Five of these patients were carrying the p.N215S mutation known to cause a typical later-onset cardiac FD.Conclusions:We confirmed the prevalence of FD repeatedly reported in previous screening programs (approximately 1 % irrespective of gender) in a non-selected HCM population in Central Europe. Our findings advocate a routine screening for FD in all adult patients with HCM phenotype including both genders. The dry blood spot method used led to identification of clearly pathogenic variants.

Cytotoxicity-guided fractionation of the green macroalga Tydemania expeditionisled to isolation of four sulfate-conjugated triterpenoids including one new lanostane-type triterpenoid disulfate, lanosta-8-en-3,29-diol-23-oxo-3,29-disodium sulfate ( 1), and three known cycloartane-type triterpenoid disulfates, cycloartan-3,29-diol-23-one 3,29-disodium sulfate ( 2), cycloart-24-en-3,29-diol-23-one 3,29-disodium sulfate ( 3), and cycloartan-3,23,29-triol 3,29-disodium sulfate ( 4). Extensive 1D and 2D NMR analyses in combination with X-ray crystallography established the structure and absolute configuration of 1and allowed determination of the absolute configurations of 2− 4with a revision of previously assigned configuration at C-5. Each natural product was moderately cytotoxic in tumor cell and invertebrate toxicity assays. Of the natural products, only 4exhibited significant antifungal activity at whole-tissue natural concentrations against the marine pathogen Lindra thalassiae. Comparison of the biological activities of natural products with their desulfated derivatives indicated that sulfation does not appear to confer cytotoxicity or antifungal activity.

Bromophycolides C−I (1−7) were isolated from extracts of the Fijian red alga Callophycus serratus and identified by NMR and mass spectral techniques. These novel natural products share a carbon skeleton and biosynthetic origin with previously identified bromophycolides A (8) and B (9), which form a rare group of diterpene−benzoate macrolides. Bromophycolides C−I (1−7) displayed modest antineoplastic activity against a range of human tumor cell lines.