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Abstract The defining feature of Parkinson disease (PD) and Lewy body dementia (LBD) is the accumulation of alpha-synuclein (Asyn) fibrils in Lewy bodies and Lewy neurites. Here we develop and validate a method to amplify Asyn fibrils extracted from LBD postmortem tissue samples and use solid state nuclear magnetic resonance (SSNMR) studies to determine atomic resolution structure. Amplified LBD Asyn fibrils comprise a mixture of single protofilament and two protofilament fibrils with very low twist. The protofilament fold is highly similar to the fold determined by a recent cryo-electron microscopy study for a minority population of twisted single protofilament fibrils extracted from LBD tissue. These results expand the structural characterization of LBD Asyn fibrils and approaches for studying disease mechanisms, imaging agents and therapeutics targeting Asyn.

Abstract Introduction Neurosurgery is considered the mainstay of treatment for pediatric low‐grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long‐term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies. Patients and Methods Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1‐5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1‐status, sex, and age. Results The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p

Aging is one of the key steps in the preparation of highly active Cu/ZnO-based catalysts for use in the production of methanol. If certain pH and temperature specifications are met, an initially amorphous precipitate transforms into the crystalline precursor phase of zincian malachite, which is characterized by a periodic arrangement of Cu and Zn atoms and has proven advantageous for the quality of the final catalyst. However, aging generally takes between 30 min and multiple hours until the desired phase transformation is completed. With our study, we show that aging can be significantly accelerated by seeding the freshly precipitated suspension with already aged zincian malachite crystals: the necessary aging time was reduced by 41% for seeding mass fractions as low as 3 wt.% and from 83 min to less than 2 min for 30 wt.% seeds. No negative influence of seeding on the phase composition, specific surface area, molar metal ratios, or the morphology of the aged precursor could be identified. Consequently, the catalyst performance in the synthesis of methanol from CO2, as well as from a CO/CO2 mixture, was identical to a catalyst from an unseeded preparation and showed small advantages compared to a commercial sample. Thus, we conclude that seeding is a vital tool to accelerate the preparation of all Cu/Zn-based catalysts while maintaining product quality, presumably also on an industrial scale.

Inhibition of IL-4/IL-13 signaling has dramatically improved the treatment of atopic dermatitis (AD). However, in many patients, clinical responses are slow to develop and remain modest. Indeed, some symptoms of AD are dependent on IL-31, which is only partially reduced by IL-4/IL-13 inhibition. Thus, there is an unmet need for AD treatments that concomitantly block IL-4/IL-13 and IL-31 pathways. We engineered NM26-2198, a bispecific tetravalent antibody designed to accomplish this task. In reporter cell lines, NM26-2198 concomitantly inhibited IL-4/IL-13 and IL-31 signaling with a potency comparable with that of the combination of an anti–IL-4Rα antibody (dupilumab) and an anti–IL-31 antibody (BMS-981164). In human PBMCs, NM26-2198 inhibited IL-4–induced upregulation of CD23, demonstrating functional binding to FcγRII (CD32). NM26-2198 also inhibited the secretion of the AD biomarker thymus and activation-regulated chemokine (TARC) in blood samples from healthy human donors. In male cynomolgus monkeys, NM26-2198 exhibited favorable pharmacokinetics and significantly inhibited IL-31–induced scratching at a dose of 30 mg/kg. In a repeat-dose, good laboratory practice toxicology study in cynomolgus monkeys, no adverse effects of NM26-2198 were observed at a weekly dose of 125 mg/kg. Together, these results justify the clinical investigation of NM26-2198 as a treatment for moderate-to-severe AD.

Background: Radiotherapy (RT) involving craniospinal irradiation (CSI) is important in the initial treatment of medulloblastoma. At recurrence, the re-irradiation options are limited and associated with severe side-effects. Methods: For pre-irradiated patients, patients with re-irradiation (RT2) were matched by sex, histology, time to recurrence, disease status and treatment at recurrence to patients without RT2. Results: A total of 42 pre-irradiated patients with RT2 were matched to 42 pre-irradiated controls without RT2. RT2 improved the median PFS [21.0 (CI: 15.7–28.7) vs. 12.0 (CI: 8.1–21.0) months] and OS [31.5 (CI: 27.6–64.8) vs. 20.0 (CI: 14.0–36.7) months]. Concerning long-term survival after ten years, RT2 only lead to small improvements in OS [8% (CI: 1.4–45.3) vs. 0%]. RT2 improved survival most without (re)-resection [PFS: 17.5 (CI: 9.7–41.5) vs. 8.0 (CI: 6.6–12.2)/OS: 31.5 (CI: 27.6–NA) vs. 13.3 (CI: 8.1–20.1) months]. In the RT-naïve patients, CSI at recurrence improved their median PFS [25.0 (CI: 16.8–60.6) vs. 6.6 (CI: 1.5–NA) months] and OS [40.2 (CI: 18.7–NA) vs. 12.4 (CI: 4.4–NA) months]. Conclusions: RT2 could improve the median survival in a matched cohort but offered little benefit regarding long-term survival. In RT-naïve patients, CSI greatly improved their median and long-term survival.

Adoptive immunotherapy based on chimeric antigen receptor (CAR)-engineered T cells has exhibited impressive clinical efficacy in treating B-cell malignancies. However, the potency of CAR-T cells carriethe potential for significant on-target/off-tumor toxicities when target antigens are shared with healthy cells, necessitating the development of complementary safety measures. In this context, there is a need to selectively eliminate therapeutically administered CAR-T cells, especially to revert long-term CAR-T cell-related side effects. To address this, we have developed an effective cellular-based safety mechanism to specifically target and eliminate the transferred CAR-T cells. As proof-of-principle, we have designed a secondary CAR (anti-CAR CAR) capable of recognizing a short peptide sequence (Strep-tag II) incorporated into the hinge domain of an anti-CD19 CAR. In in vitro experiments, these anti-CAR CAR-T cells have demonstrated antigen-specific cytokine release and cytotoxicity when co-cultured with anti-CD19 CAR-T cells. Moreover, in both immunocompromised and immunocompetent mice, we observed the successful depletion of anti-CD19 CAR-T cells when administered concurrently with anti-CAR CAR-T cells. We have also demonstrated the efficacy of this safeguard mechanism in a clinically relevant animal model of B-cell aplasia induced by CD19 CAR treatment, where this side effect was reversed upon anti-CAR CAR-T cells infusion. Notably, efficient B-cell recovery occurred even in the absence of any pre-conditioning regimens prior anti-CAR CAR-T cells transfer, thus enhancing its practical applicability. In summary, we developed a robust cellular safeguard system for selective in vivo elimination of engineered T cells, offering a promising solution to address CAR-T cell-related on-target/off-tumor toxicities.

AIMS: Many cardiovascular events occur in seemingly healthy individuals.We set out to assess the predictive value of atherosclerosis imaging in combination with cardiovascular risk calculators in subjects aged 40–65 years. METHODS: We compared PROCAM (PROspective CArdiovascular Münster study), SCORE (Systematic COronary Risk Evaluation) and SCORE2 with carotid ultrasound (total plaque area, TPA) in subjects without cardiovascular disease. In this prospective cohort study, follow-up was obtained by phone or mail from patients; or from clinical records, if needed. RESULTS: In 2842 subjects (mean age 50±8 years; 38% women), cardiovascular events occurred in 154 (5.4%) of them over an mean follow-up period of 5.9 (range 1–12) years, specifically: 41 cases of AMI (myocardial infarction), 16 strokes, 21 CABG (coronary artery bypass grafting), 41 PTCA (percutaneous transluminal coronary angioplasty) and 35 CAD (coronary artery disease). Mean PROCAM risk was 5±6%, mean SCORE risk was 1.3±1.6% and mean SCORE2 risk was 5±3%. Both for the primary outcome (major adverse cardiovascular events, MACEs, i.e. AMI + strokes) and the secondary outcome (atherosclerotic cardiovascular disease, ASCVD, i.e. MACEs + CABG + CAD + PTCA), hazards increased significantly for TPA tertiles and SCORE2 post-test risk between 6.7 to 12.8 after adjustment for risk factors (age, smoke, sex, systolic blood pressure, lipids, medication) and after adjustment for results from PROCAM, SCORE and SCORE2. Model performance was statistically improved regarding model fit in all models using TPA. Net reclassification improvement for SCORE2 with TPA post-test risk increased significantly by 24% for MACEs (p = 0.01) and 39% for ASCVD (p

Aging is one of the key steps in the preparation of highly active Cu/ZnO-based catalysts for use in the production of methanol. If certain pH and temperature specifications are met, an initially amorphous precipitate transforms into the crystalline precursor phase of zincian malachite, which is characterized by a periodic arrangement of Cu and Zn atoms and has proven advantageous for the quality of the final catalyst. However, aging generally takes between 30 min and multiple hours until the desired phase transformation is completed. With our study, we show that aging can be significantly accelerated by seeding the freshly precipitated suspension with already aged zincian malachite crystals: the necessary aging time was reduced by 41% for seeding mass fractions as low as 3 wt.% and from 83 min to less than 2 min for 30 wt.% seeds. No negative influence of seeding on the phase composition, specific surface area, molar metal ratios, or the morphology of the aged precursor could be identified. Consequently, the catalyst performance in the synthesis of methanol from CO2, as well as from a CO/CO2 mixture, was identical to a catalyst from an unseeded preparation and showed small advantages compared to a commercial sample. Thus, we conclude that seeding is a vital tool to accelerate the preparation of all Cu/Zn-based catalysts while maintaining product quality, presumably also on an industrial scale. [ABSTRACT FROM AUTHOR]

Introduction: Neurosurgery is considered the mainstay of treatment for pediatric low‐grade glioma (LGG); the extent of resection determines subsequent stratification in current treatment protocols. Yet, surgical radicality must be balanced against the risks of complications that may affect long‐term quality of life. We investigated whether this consideration impacted surgical resection patterns over time for patients of the German LGG studies. Patients and Methods: Four thousand two hundred and seventy pediatric patients from three successive LGG studies (median age at diagnosis 7.6 years, neurofibromatosis (NF1) 14.7%) were grouped into 5 consecutive time intervals (TI1‐5) for date of diagnosis and analyzed for timing and extent of first surgery with respect to tumor site, histology, NF1‐status, sex, and age. Results: The fraction of radiological LGG diagnoses increased over time (TI1 12.6%; TI5 21.7%), while the extent of the first neurosurgical intervention (3440/4270) showed a reduced fraction of complete/subtotal and an increase of partial resections from TI1 to TI5. Binary logistic regression analysis for the first intervention within the first year following diagnosis confirmed the temporal trends (p < 0.001) and the link with tumor site for each extent of resection (p < 0.001). Higher age is related to more complete resections in the cerebellum and cerebral hemispheres. Conclusions: The declining extent of surgical resections over time was unrelated to patient characteristics. It paralleled the evolution of comprehensive treatment algorithms; thus, it may reflect alignment of surgical practice to recommendations in respect to age, tumor site, and NF1‐status integrated as such into current treatment guidelines. Further investigations are needed to understand how planning, performance, or tumor characteristics impact achieving surgical goals. [ABSTRACT FROM AUTHOR]

Context. Stellar flares cannot be spatially resolved, which complicates ascertaining the physical processes behind particular spectral signatures. Due to their proximity to Earth, solar flares can serve as a stepping stone for understanding their stellar counterparts, especially when using a Sun-as-a-star instrument and in combination with spatially resolved observations. Aims. We aim to understand the disk-integrated spectral behaviors of a confined X2.2 flare and its eruptive X9.3 successor, which had energies of 2.2 × 1031 erg and 9.3 × 1031 erg, respectively, as measured by Sun-as-a-star observations with the High Accuracy Radial velocity Planet Searcher for the Northern hemisphere (HARPS-N). Methods. The behavior of multiple photospheric (Na D1 & D2, Mg I at 5173 Å, Fe I at 6173 Å, and Mn I at 4031 Å) and chromospheric (Ca II H & K, Hα, Hβ, and He ID3) spectral lines were investigated by means of activity indices and contrast profiles. A number of different photospheric lines were also investigated by means of equivalent widths, and radial velocity measures, which were then related to physical processes directly observed in high-resolution observations made with the Swedish 1-m Solar Telescope (SST) and the Atmospheric Imaging Assembly (AIA) on board of the Solar Dynamics Observatory (SDO). Results. Our findings suggest a relationship between the evolving shapes of contrast profile time and the flare locations, which assists in constraining flare locations in disk-integrated observations. In addition, an upward bias was found in flare statistics based on activity indices derived from the Ca II H & K lines. In this case, much smaller flares cause a similar increase in the activity index as that produced by larger flares. Hα-based activity indices do not show this bias and are therefore less susceptible to activity jitter. Sodium line profiles show a strongly asymmetric response during flare activity, which is best captured with a newly defined asymmetrical sodium activity index. A strong flare response was detected in Mn I line profiles, which is unexpected and calls for further exploration. Intensity increases in Hα, Hβ, and certain spectral windows of AIA before the flare onset suggest their potential use as short-term flare predictors. [ABSTRACT FROM AUTHOR]

Adoptive immunotherapy based on chimeric antigen receptor (CAR)-engineered T cells has exhibited impressive clinical efficacy in treating B-cell malignancies. However, the potency of CAR-T cells carriethe potential for significant on-target/off-tumor toxicities when target antigens are shared with healthy cells, necessitating the development of complementary safetymeasures. In this context, there is a need to selectively eliminate therapeutically administered CAR-T cells, especially to revert long-term CAR-T cell-related side effects. To address this, we have developed an effective cellular-based safety mechanism to specifically target and eliminate the transferred CAR-T cells. As proof-of-principle, we have designed a secondary CAR (anti-CAR CAR) capable of recognizing a short peptide sequence (Strep-tag II) incorporated into the hinge domain of an anti-CD19 CAR. In in vitro experiments, these anti-CAR CAR-T cells have demonstrated antigen-specific cytokine release and cytotoxicity when co-cultured with anti-CD19 CAR-T cells. Moreover, in both immunocompromised and immunocompetent mice, we observed the successful depletion of anti-CD19 CAR-T cells when administered concurrently with anti-CAR CAR-T cells. We have also demonstrated the efficacy of this safeguardmechanism in a clinically relevant animal model of B-cell aplasia induced by CD19 CAR treatment, where this side effect was reversed upon anti-CAR CAR-T cells infusion. Notably, efficient B-cell recovery occurred even in the absence of any pre-conditioning regimens prior anti-CAR CAR-T cells transfer, thus enhancing its practical applicability. In summary, we developed a robust cellular safeguard system for selective in vivo elimination of engineered T cells, offering a promising solution to address CAR-T cell-related on-target/off-tumor toxicities. [ABSTRACT FROM AUTHOR]

Purpose: Depicting the stiffness of biological soft tissues, MR elastography (MRE) has a wide range of diagnostic applications. The purpose of this study was to improve the temporal resolution of 2D hepatic MRE in order to provide more rapid feedback on the quality of the wavefield and ensure better temporal sampling of respiration‐induced stiffness changes. Methods: We developed a rapid MRE sequence that uses 2D segmented gradient‐echo spiral readout to encode 40 Hz harmonic vibrations and generate stiffness maps within 625 ms. We demonstrate the use of this technique as a rapid test for shear wave amplitudes and overall MRE image quality and as a method for monitoring respiration‐induced stiffness changes in the liver in comparison to 3D MRE and ultrasound‐based time‐harmonic elastography. Results: Subsecond MRE allowed monitoring of increasing shear wave amplitudes in the liver with increasing levels of external stimulation within a single breath‐hold. Furthermore, the technique detected respiration‐induced changes in liver stiffness with peak values (1.83 ± 0.22 m/s) at end‐inspiration, followed by softer values during forced abdominal pressure (1.60 ± 0.22 m/s) and end‐expiration (1.49 ± 0.22 m/s). The effects of inspiration and expiration were confirmed by time‐harmonic elastography. Conclusion: Our results suggest that subsecond MRE of the liver is useful for checking MRE driver settings and monitoring breathing‐induced changes in liver stiffness in near real time. [ABSTRACT FROM AUTHOR]