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On February 23rd 1936, a boy-child (“Kn”) died in an asylum near Munich after years of severe congenital dis-ease, which had profoundly impaired his development leading to inability to walk, talk and see as well as to severe epilepsy. While a diagnosis of “Little’s disease” was made during life, his postmortem brain investiga-tion at Munich neuropathology (“Deutsche Forschungsanstalt für Psychiatrie”) revealed the diagnosis of “amaurotic idiocy” (AI). AI, as exemplified by Tay-Sachs-Disease (TSD), back then was not yet understood as a specific inborn error of metabolism encompassing several disease entities. Many neuropathological studies were performed on AI, but the underlying processes could only be revealed by new scientific techniques such as biochemical analysis of nervous tissue, deciphering AI as nervous system lipid storage diseases, e.g. GM2-gangliosidosis. In 1963, Sandhoff & Jatzkewitz published an article on a “biochemically special form of AI” reporting striking differences when comparing their biochemical observations of hallmark features of TSD to tissue composition in a single case: the boy Kn. This was the first description of “GM1-Gangliosidosis”, later understood as resulting from genetically determined deficiency in beta-galactosidase. Here we present illus-trative materials from this historic patient, including selected diagnostic slides from the case “Kn” in virtual microscopy, original records and other illustrative material available. Finally, we present results from genetic analysis performed on archived tissue proving beta-galactosidase-gene mutation, verifying the 1963 interpre-tation as correct. This synopsis shall give a first-hand impression of this milestone finding in neuropathology.

Epilepsy surgery is a viable therapy option for patients with pharmacoresistant focal epilepsies. A prerequisite for postoperative seizure freedom is the localization of the epileptogenic zone, e.g., using electro- and magnetoencephalography (EEG/MEG). Evidence shows that resting state MEG contains subtle alterations, which may add information to the workup of epilepsy surgery. Here, we investigate node degree (ND), a graph-theoretical parameter of functional connectivity, in relation to the seizure onset zone (SOZ) determined by invasive EEG (iEEG) in a consecutive series of 50 adult patients. Resting state data were subjected to whole brain, all-to-all connectivity analysis using the imaginary part of coherence. Graphs were described using parcellated ND. SOZ localization was investigated on a lobar and sublobar level. On a lobar level, all frequency bands except alpha showed significantly higher maximal ND (mND) values inside the SOZ compared to outside (ratios 1.11–1.20, alpha 1.02). Area-under-the-curve (AUC) was 0.67–0.78 for all expected alpha (0.44, ns). On a sublobar level, mND inside the SOZ was higher for all frequency bands (1.13–1.38, AUC 0.58–0.78) except gamma (1.02). MEG ND is significantly related to SOZ in delta, theta and beta bands. ND may provide new localization tools for presurgical evaluation of epilepsy surgery.

50 years ago back in 1971, David C. Taylor and colleagues from England reported on a small series of surgical epilepsy cases proposing a new type of tissue lesion as a cause of difficult-to-treat focal epilepsy: a localized malformation of cerebral cortex. The lesion is now known as focal cortical dysplasia (FCD) Type II or Taylor’s cortical dysplasia. FCD II is not rare, and today is a frequent finding in neurosurgical epilepsy specimens. Medical progress has been achieved in that the majority of FCD II is diagnosed non-invasively by magnetic resonance imaging today. Detailed studies on FCD revealed that the lesion belongs to a spectrum of mTOR-o-pathies, thereby confirming the authors´ initial hypothesis of a relationship to tuberous sclerosis. Here, selected original materials from Taylor´s series are presented as virtual slides, supplemented by original clinical records, in order to give a first-hand impression of this milestone finding in neuropathology of epilepsy.

Background: Epilepsy surgery for focal cortical dysplasia type II (FCD II) offers good chances for seizure freedom, but remains a challenge with respect to lesion detection, defining the epileptogenic zone and the optimal resection strategy. Integrating results from magnetic source imaging from magnetoencephalography (MEG) with magnetic resonance imaging (MRI) including MRI postprocessing may be useful for optimizing these goals. Methods: We here present data from 21 adult FCD II patients, investigated during a 10 year period and evaluated including magnetic source imaging. 16 patients had epilepsy surgery, i.e. histopathologically verified FCD II, and a long follow up. We present our analysis of epileptogenic zones including MEG in relation to structural data according to MRI data and relate these results to surgical outcomes. Results: FCD II in our cohort was characterized by high MEG yield and localization accuracy and MEG showed impact on surgical success-rates. MEG source localizations were detected in 95.2% of patients and were as close as 12.3 ± 8,1 mm to the MRI-lesion. After a mean follow up of >3 years, we saw >80% Engel I outcomes, with more favourable outcomes when the MEG source was completely resected (Fishers exact test 0,033). Conclusion: We argue for a high value of conducting a combined MEG-MRI approach in the presurgical workup and the resection strategy in patients with FCD II related epilepsy. Keywords: Focal cortical dysplasia, Magnetic source imaging, epilepsy surgery

Abstract Grasspea (Lathyrus sativus L.) is an underutilised but promising legume crop with tolerance to a wide range of abiotic and biotic stress factors, and potential for climate-resilient agriculture. Despite a long history and wide geographical distribution of cultivation, only limited breeding resources are available. This paper reports a 5.96 Gbp genome assembly of grasspea genotype LS007, of which 5.03 Gbp is scaffolded into 7 pseudo-chromosomes. The assembly has a BUSCO completeness score of 99.1% and is annotated with 31719 gene models and repeat elements. This represents the most contiguous and accurate assembly of the grasspea genome to date.

The objective of the current study was to optimize the postprocessing pipeline of 7 T chemical exchange saturation transfer (CEST) imaging for reproducibility and to prove this optimization for the detection of age differences and differences between patients with Parkinson's disease versus normal subjects. The following 7 T CEST MRI experiments were analyzed: repeated measurements of a healthy subject, subjects of two age cohorts (14 older, seven younger subjects), and measurements of 12 patients with Parkinson's disease. A slab‐selective, B1+‐homogeneous parallel transmit protocol was used. The postprocessing, consisting of motion correction, smoothing, B0‐correction, normalization, denoising, B1+‐correction and Lorentzian fitting, was optimized regarding the intrasubject and intersubject coefficient of variation (CoV) of the amplitudes of the amide pool and the aliphatic relayed nuclear Overhauser effect (rNOE) pool within the brain. Seven "tricks" for postprocessing accomplished an improvement of the mean voxel CoV of the amide pool and the aliphatic rNOE pool amplitudes of less than 5% and 3%, respectively. These postprocessing steps are: motion correction with interpolation of the motion of low‐signal offsets (1) using the amide pool frequency offset image as reference (2), normalization of the Z‐spectrum using the outermost saturated measurements (3), B0 correction of the Z‐spectrum with moderate spline smoothing (4), denoising using principal component analysis preserving the 11 highest intensity components (5), B1+ correction using a linear fit (6) and Lorentzian fitting using the five‐pool fit model (7). With the optimized postprocessing pipeline, a significant age effect in the amide pool can be detected. Additionally, for the first time, an aliphatic rNOE contrast between subjects with Parkinson's disease and age‐matched healthy controls in the substantia nigra is detected. We propose an optimized postprocessing pipeline for CEST multipool evaluation. It is shown that by the use of these seven "tricks", the reproducibility and, thus, the statistical power of a CEST measurement, can be greatly improved and subtle changes can be detected. [ABSTRACT FROM AUTHOR]

Isolated evaluation of multiparametric in vivo chemical exchange saturation transfer (CEST) MRI often requires complex computational processing for both correction of B0 and B1 inhomogeneity and contrast generation. For that, sufficiently densely sampled Z‐spectra need to be acquired. The list of acquired frequency offsets largely determines the total CEST acquisition time, while potentially representing redundant information. In this work, a linear projection‐based multiparametric CEST evaluation method is introduced that offers fast B0 and B1 inhomogeneity correction, contrast generation and feature selection for CEST data, enabling reduction of the overall measurement time. To that end, CEST data acquired at 7 T in six healthy subjects and in one brain tumor patient were conventionally evaluated by interpolation‐based inhomogeneity correction and Lorentzian curve fitting. Linear regression was used to obtain coefficient vectors that directly map uncorrected data to corrected Lorentzian target parameters. L1‐regularization was applied to find subsets of the originally acquired CEST measurements that still allow for such a linear projection mapping. The linear projection method allows fast and interpretable mapping from acquired raw data to contrast parameters of interest, generalizing from healthy subject training data to unseen healthy test data and to the tumor patient dataset. The L1‐regularization method shows that a fraction of the acquired CEST measurements is sufficient to preserve tissue contrasts, offering up to a 2.8‐fold reduction of scan time. Similar observations as for the 7‐T data can be made for data from a clinical 3‐T scanner. Being a fast and interpretable computation step, the proposed method is complementary to neural networks that have recently been employed for similar purposes. The scan time acceleration offered by the L1‐regularization ("CEST‐LASSO") constitutes a step towards better applicability of multiparametric CEST protocols in a clinical context. [ABSTRACT FROM AUTHOR]

Abstract Background CRISPR Cas9 and Cas12a are the two most frequently used programmable nucleases reported in plant systems. There is now a wide range of component parts for both which likely have varying degrees of effectiveness and potentially applicability to different species. Our aim was to develop and optimise Cas9 and Cas12a based systems for highly efficient genome editing in the monocotyledons barley and wheat and produce a user-friendly toolbox facilitating simplex and multiplex editing in the cereal community. Results We identified a Zea mays codon optimised Cas9 with 13 introns in conjunction with arrayed guides driven by U6 and U3 promoters as the best performer in barley where 100% of T0 plants were simultaneously edited in all three target genes. When this system was used in wheat > 90% of T0 plants were edited in all three subgenome targets. For Cas12a, an Arabidopsis codon optimised sequence with 8 introns gave the best editing efficiency in barley when combined with a tRNA based multiguide array, resulting in 90% mutant alleles in three simultaneously targeted genes. When we applied this Cas12a system in wheat 86% & 93% of T0 plants were mutated in two genes simultaneously targeted. We show that not all introns contribute equally to enhanced mutagenesis when inserted into a Cas12a coding sequence and that there is rationale for including multiple introns. We also show that the combined effect of two features which boost Cas12a mutagenesis efficiency (D156R mutation and introns) is more than the sum of the features applied separately. Conclusion Based on the results of our testing, we describe and provide a GoldenGate modular cloning system for Cas9 and Cas12a use in barley and wheat. Proven Cas nuclease and guide expression cassette options found in the toolkit will facilitate highly efficient simplex and multiplex mutagenesis in both species. We incorporate GRF-GIF transformation boosting cassettes in wheat options to maximise workflow efficiency.

Abstract Disorders of gallbladder motility can lead to serious pathology. Bitter tastants acting upon bitter taste receptors (TAS2R family) have been proposed as a novel class of smooth muscle relaxants to combat excessive contraction in the airways and other organs. To explore whether this might also emerge as an option for gallbladder diseases, we here tested bitter tastants for relaxant properties and profiled Tas2r expression in the mouse gallbladder. In organ bath experiments, the bitter tastants denatonium, quinine, dextromethorphan, and noscapine, dose-dependently relaxed the pre-contracted gallbladder. Utilizing gene-deficient mouse strains, neither transient receptor potential family member 5 (TRPM5), nor the Tas2r143/Tas2r135/Tas2r126 gene cluster, nor tuft cells proved to be required for this relaxation, indicating direct action upon smooth muscle cells (SMC). Accordingly, denatonium, quinine and dextromethorphan increased intracellular calcium concentration preferentially in isolated gallbladder SMC and, again, this effect was independent of TRPM5. RT-PCR revealed transcripts of Tas2r108, Tas2r126, Tas2r135, Tas2r137, and Tas2r143, and analysis of gallbladders from mice lacking tuft cells revealed preferential expression of Tas2r108 and Tas2r137 in tuft cells. A TAS2R143-mCherry reporter mouse labeled tuft cells in the gallbladder epithelium. An in silico analysis of a scRNA sequencing data set revealed Tas2r expression in only few cells of different identity, and from in situ hybridization histochemistry, which did not label distinct cells. Our findings demonstrate profound tuft cell- and TRPM5-independent relaxing effects of bitter tastants on gallbladder smooth muscle, but do not support the concept that these effects are mediated by bitter receptors.

Abstract In this work, we report on the concurrent emergence of the directional Kondo behavior and incommensurate magnetic ordering in a layered material. We employ temperature- and magnetic field-dependent resistivity measurements, susceptibility measurements, and high resolution wavelength X-ray diffraction spectroscopy to study the electronic properties of AgCrSe2. Impurity Kondo behavior with a characteristic temperature of T K = 32 K is identified through quantitative analysis of the in-plane resistivity, substantiated by magneto-transport measurements. The excellent agreement between our experimental data and the Schlottmann’s scaling theory allows us to determine the impurity spin as S = 3/2. Furthermore, we discuss the origin of the Kondo behavior and its relation to the material’s antiferromagnetic transition. Our study uncovers a rare phenomenon—the equivalence of the Néel temperature and the Kondo temperature—paving the way for further investigations into the intricate interplay between impurity physics and magnetic phenomena in quantum materials, with potential applications in advanced electronic and magnetic devices.

ABSTRACT In spring 2022, an increase in metallo-β-lactamase-producing Pseudomonas aeruginosa (MBL-Pa) infections was detected in a hospital in Upper Austria. To identify the source of infection and to stop further transmissions, an epidemiological outbreak investigation including whole-genome sequencing (WGS)-based typing was conducted. The final case definition included cases admitted to the hospital between 2020 and 2023 with an MBL-Pa in one of the three genomic clusters identified. In addition, the investigation was extended to include historical cases from 2017. Core genome multilocus sequence typing was performed to assess the genetic relatedness between the isolates. Fifty-four clinical P. aeruginosa isolates and eight P. aeruginosa isolates from the hospital environment were obtained. All but nine isolates grouped into one of three genomic clusters (ST235/blaVIM-1, ST111/blaVIM-2, or ST621/blaIMP-13), which were considered to be distinct, prolonged outbreaks involving 47 out of 52 cases. The most likely source of infection for cluster 1 (ST111/blaVIM-2) and cluster 2 (ST235/blaVIM-1) was sinks in the intensive care unit (ICU) washroom. Cluster 3 clone (ST621/blaIMP-13) could have originated in the urology ward in 2020 and then spread to the ICU years later. However, the nosocomial origin of this clone could not be proven. In March 2023, following the implementation of control measures (gowning, patient isolation, screening, and daily disinfection), no further MLB-Pa was detected, and the outbreaks were considered to be over. As ICUs play an important role in the transmission of P. aeruginosa, emphasis should be placed on genomic surveillance, infection prevention, and control in such wards.IMPORTANCEThe significance of our work lies in the successful resolution of three prolonged outbreaks of MBL-Pa infections in a hospital in Upper Austria. Through a comprehensive epidemiological investigation coupled with WGS-based typing of P. aeruginosa isolates, the study identified three distinct genomic clusters responsible for prolonged outbreaks involving 47 cases. The investigation pinpointed sinks in the ICU washroom as the likely source of infection for two of the clusters. The study demonstrates the effectiveness of control measures such as hand hygiene, gowning, patient isolation, screening, and disinfection in stopping further transmission and bringing the outbreaks to a close. This underscores the critical role of genomic surveillance and control measures, particularly in high-risk settings like ICUs, in reducing nosocomial transmission of MBL-Pa infections.

Federated Learning (FL) has emerged as a promising approach to address privacy concerns inherent in Machine Learning (ML) practices. However, conventional FL methods, particularly those following the Centralized FL (CFL) paradigm, utilize a central server for global aggregation, which exhibits limitations such as bottleneck and single point of failure. To address these issues, the Decentralized FL (DFL) paradigm has been proposed, which removes the client–server boundary and enables all participants to engage in model training and aggregation tasks. Nevertheless, as CFL, DFL remains vulnerable to adversarial attacks, notably poisoning attacks that undermine model performance. While existing research on model robustness has predominantly focused on CFL, there is a noteworthy gap in understanding the model robustness of the DFL paradigm. In this paper, a thorough review of poisoning attacks targeting the model robustness in DFL systems, as well as their corresponding countermeasures, are presented. Additionally, a solution called DART is proposed to evaluate the robustness of DFL models, which is implemented and integrated into a DFL platform. Through extensive experiments, this paper compares the behavior of CFL and DFL under diverse poisoning attacks, pinpointing key factors affecting attack spread and effectiveness within the DFL. It also evaluates the performance of different defense mechanisms and investigates whether defense mechanisms designed for CFL are compatible with DFL. The empirical results provide insights into research challenges and suggest ways to improve the robustness of DFL models for future research.