A multifaceted crosstalk between brassinosteroid and gibberellin regulates the resistance of cucumber to Phytophthora melonis.

Cucumber plants are highly susceptible to the hemibiotroph oomycete Phytophthora melonis. However, the mechanism of resistance to cucumber blight remains poorly understood. Here, we demonstrated that cucumber plants with impairment in the biosynthesis of brassinosteroids (BRs) or gibberellins (GAs) were more susceptible to P. melonis. By contrast, increasing levels of endogenous BRs or exogenously application of 24-epibrassinolide enhanced the resistance of cucumber plants against P. melonis. Furthermore, we found that both knockout and overexpression of the BR biosynthesis gene CYP85A1 reduced the endogenous GA3 content compared with that of wild-type plants under the condition of inoculation with P. melonis, and the enhancement of disease resistance conferred by BR was inhibited in plants with silencing of the GA biosynthetic gene GA20ox1 or KAO. Together, these findings suggest that GA homeostasis is an essential factor mediating BRs-induced disease resistance. Moreover, BZR6, a key regulator of BR signaling, was found to physically interact with GA20ox1, thereby suppressing its transcription. Silencing of BZR6 promoted endogenous GA biosynthesis and compromised GA-mediated resistance. These findings reveal multifaceted crosstalk between BR and GA in response to pathogen infection, which can provide a new approach for genetically controlling P. melonis damage in cucumber production.

Mass spectrometry-based draft of the mouse proteome.

The laboratory mouse ranks among the most important experimental systems for biomedical research and molecular reference maps of such models are essential informational tools. Here, we present a quantitative draft of the mouse proteome and phosphoproteome constructed from 41 healthy tissues and several lines of analyses exemplify which insights can be gleaned from the data. For instance, tissue- and cell-type resolved profiles provide protein evidence for the expression of 17,000 genes, thousands of isoforms and 50,000 phosphorylation sites in vivo. Proteogenomic comparison of mouse, human and Arabidopsis reveal common and distinct mechanisms of gene expression regulation and, despite many similarities, numerous differentially abundant orthologs that likely serve species-specific functions. We leverage the mouse proteome by integrating phenotypic drug (n > 400) and radiation response data with the proteomes of 66 pancreatic ductal adenocarcinoma (PDAC) cell lines to reveal molecular markers for sensitivity and resistance. This unique atlas complements other molecular resources for the mouse and can be explored online via ProteomicsDB and PACiFIC.

Illuminating phenotypic drug responses of sarcoma cells to kinase inhibitors by phosphoproteomics.

Kinase inhibitors (KIs) are important cancer drugs but often feature polypharmacology that is molecularly not understood. This disconnect is particularly apparent in cancer entities such as sarcomas for which the oncogenic drivers are often not clear. To investigate more systematically how the cellular proteotypes of sarcoma cells shape their response to molecularly targeted drugs, we profiled the proteomes and phosphoproteomes of 17 sarcoma cell lines and screened the same against 150 cancer drugs. The resulting 2550 phenotypic profiles revealed distinct drug responses and the cellular activity landscapes derived from deep (phospho)proteomes (9-10,000 proteins and 10-27,000 phosphorylation sites per cell line) enabled several lines of analysis. For instance, connecting the (phospho)proteomic data with drug responses revealed known and novel mechanisms of action (MoAs) of KIs and identified markers of drug sensitivity or resistance. All data is publicly accessible via an interactive web application that enables exploration of this rich molecular resource for a better understanding of active signalling pathways in sarcoma cells, identifying treatment response predictors and revealing novel MoA of clinical KIs.

Transcription factor WRKY75 maintains auxin homeostasis to promote tomato defense against Pseudomonas syringae.

The hemibiotrophic bacterial pathogen Pseudomonas syringae infects a range of plant species and causes enormous economic losses. Auxin and WRKY transcription factors play crucial roles in plant responses to P. syringae, but their functional relationship in plant immunity remains unclear. Here, we characterized tomato (Solanum lycopersicum) SlWRKY75, which promotes defenses against P. syringae pv. tomato (Pst) DC3000 by regulating plant auxin homeostasis. Overexpressing SlWRKY75 resulted in low free indole-3-acetic acid (IAA) levels, leading to attenuated auxin signaling, decreased expansin transcript levels, upregulated expression of PATHOGENESIS-RELATED GENES (PRs) and NONEXPRESSOR OF PATHOGENESIS-RELATED GENE 1 (NPR1), and enhanced tomato defenses against Pst DC3000. RNA interference-mediated repression of SlWRKY75 increased tomato susceptibility to Pst DC3000. Yeast one-hybrid, electrophoretic mobility shift assays, and luciferase activity assays suggested that SlWRKY75 directly activates the expression of GRETCHEN HAGEN 3.3 (SlGH3.3), which encodes an IAA-amido synthetase. SlGH3.3 enhanced tomato defense against Pst DC3000 by converting free IAA to the aspartic acid (Asp)-conjugated form IAA-Asp. In addition, SlWRKY75 interacted with a tomato valine-glutamine (VQ) motif-containing protein 16 (SlVQ16) in vivo and in vitro. SlVQ16 enhanced SlWRKY75-mediated transcriptional activation of SlGH3.3 and promoted tomato defense responses to Pst DC3000. Our findings illuminate a mechanism in which the SlVQ16-SlWRKY75 complex participates in tomato pathogen defense by positively regulating SlGH3.3-mediated auxin homeostasis.

Unified Workflow for the Rapid and In-Depth Characterization of Bacterial Proteomes.

Bacteria are the most abundant and diverse organisms among the kingdoms of life. Due to this excessive variance, finding a unified, comprehensive, and safe workflow for quantitative bacterial proteomics is challenging. In this study, we have systematically evaluated and optimized sample preparation, mass spectrometric data acquisition, and data analysis strategies in bacterial proteomics. We investigated workflow performances on six representative species with highly different physiologic properties to mimic bacterial diversity. The best sample preparation strategy was a cell lysis protocol in 100% trifluoroacetic acid followed by an in-solution digest. Peptides were separated on a 30-min linear microflow liquid chromatography gradient and analyzed in data-independent acquisition mode. Data analysis was performed with DIA-NN using a predicted spectral library. Performance was evaluated according to the number of identified proteins, quantitative precision, throughput, costs, and biological safety. With this rapid workflow, over 40% of all encoded genes were detected per bacterial species. We demonstrated the general applicability of our workflow on a set of 23 taxonomically and physiologically diverse bacterial species. We could confidently identify over 45,000 proteins in the combined dataset, of which 30,000 have not been experimentally validated before. Our work thereby provides a valuable resource for the microbial scientific community. Finally, we grew Escherichia coli and Bacillus cereus in replicates under 12 different cultivation conditions to demonstrate the high-throughput suitability of the workflow. The proteomic workflow we present in this manuscript does not require any specialized equipment or commercial software and can be easily applied by other laboratories to support and accelerate the proteomic exploration of the bacterial kingdom.

Stabilization of Organic Cations in Lead Halide Perovskite Solar Cells Using Phosphine Oxides Derivatives.

Preventing ion migration in perovskite photovoltaics is key to achieving stable and efficient devices. The activation energy for ion migration is affected by the chemical environment surrounding the ions. Thus, the migration of organic cations in lead halide perovskites can be mitigated by engineering their local interactions, for example through hydrogen bonding. Ion migration also leads to ionic losses via interfacial reactions. Undesirable reactivities of the organic cations can be eliminated by introducing protecting groups. In this work, we report bis(2-oxo-3-oxazolidinyl) phosphinic chloride (BOP-Cl) as a perovskite ink additive with the following benefits: (1) The phosphoryl and two oxo groups form six-membered intermolecular hydrogen-bonded rings with the formamidinium cation (FA), mitigating ion migrations. (2) The hydrogen bonding reduces the electrophilicity of the ammonium protons by donating electron density, therefore reducing its reactivity with the surface oxygen on the metal oxide. Furthermore, the molecule can react to form a protecting group on the nucleophilic oxygen at the tin oxide transport layer surface through the elimination of chlorine. As a result, we achieve perovskite solar cells with an efficiency of 25.0% and improved MPP stability T93 = 1200 h at 40-45 °C compared to a control device (T86 = 550 h). In addition, we show a negative correlation between the strength of hydrogen bonding of different phosphine oxide derivatives to the organic cations and the degree of metastable behavior (e.g., initial burn-in) of the device.

DHA-containing phospholipids control membrane fusion and transcellular tunnel dynamics.

Metabolic studies and animal knockout models point to the critical role of polyunsaturated docosahexaenoic acid (22:6, DHA)-containing phospholipids (DHA-PLs) in physiology. Here, we investigated the impact of DHA-PLs on the dynamics of transendothelial cell macroapertures (TEMs) triggered by RhoA inhibition-associated cell spreading. Lipidomic analyses showed that human umbilical vein endothelial cells (HUVECs) subjected to a DHA diet undergo a 6-fold enrichment in DHA-PLs at the plasma membrane (PM) at the expense of monounsaturated oleic acid-containing PLs (OA-PLs). Consequently, DHA-PL enrichment at the PM induces a reduction in cell thickness and shifts cellular membranes towards a permissive mode of membrane fusion for transcellular tunnel initiation. We provide evidence that a global homeostatic control of membrane tension and cell cortex rigidity minimizes overall changes of TEM area through a decrease of TEM size and lifetime. Conversely, low DHA-PL levels at the PM lead to the opening of unstable and wider TEMs. Together, this provides evidence that variations of DHA-PL levels in membranes affect cell biomechanical properties.

Non-Steady-State Symmetry Breaking Growth of Multilayered SnSe2 Nanoplates.

The use of non-equilibrium growth modes with non-steady dynamics is extensively explored in bulk materials such as amorphous and polycrystalline materials. Yet, research into the non-steady-state (NSS) growth of two-dimensional (2D) materials is still in its infancy. In this study, multilayered tin selenide (SnSe2 ) nanoplates are grown by chemical vapor deposition under NSS conditions (modulating carrier gas flow and temperature). Given the facile diffusion and inherent instability of SnSe2 , it proves to be an apt candidate for nucleation and growth in NSS scenarios. This leads to the emergence of SnSe2 nanoplates with distinct features (self-growth twisting, symmetry transformation, interlayer decoupling, homojunction, and large-area 2D domain), exhibiting pronounced second harmonic generation. The authors' findings shed light on the growth dynamics of 2D materials, broadening their potential applications in various fields.

Systematic synthesis and identification of monolignol pathway metabolites.

Monolignol serves as the building blocks to constitute lignin, the second abundant polymer on Earth. Despite two decades of diligent efforts, complete identification of all metabolites in the currently proposed monolignol biosynthesis pathway has proven elusive. This limitation also hampers their potential application. One of the primary obstacles is the challenge of assembling a collection of all molecules, because many are commercially unavailable or prohibitively costly. In this study, we established systematic pipelines to synthesize all 24 molecules through the conversions between functional groups on a core structure followed by the application to other core structures. We successfully identified all of them in Populus trichocarpa and Eucalyptus grandis, two representative species respectively from malpighiales and myrtales in angiosperms. Knowledge about monolignol metabolite chemosynthesis and identification will form the foundation for future studies.

Untargeted metabolomics reveals PTI-associated metabolites.

Plants employ a multilayered immune system to combat pathogens. In one layer, recognition of Pathogen- or Microbe-Associated Molecular Patterns or elicitors, triggers a cascade that leads to defence against the pathogen and Pattern Triggered Immunity. Secondary or specialised metabolites (SMs) are expected to play a role, because they are potentially anti-fungal compounds. Tomato (Solanum lycopersicum) plants inoculated with Alternaria solani s.l. show symptoms of infection after inoculation. Plants inoculated with Alternaria alternata remain symptomless. We hypothesised that pattern-triggered induction of resistance related metabolites in tomato contributes to the resistance against A. alternata. We compared the metabolomic profile (metabolome) of tomato after treatments with A. alternata, A. solani and the fungal elicitor chitin, and identified SMs involved in early defence of tomato plants. We revealed differential metabolome fingerprints. The composition of A. alternata and chitin induced metabolomes show larger overlap with each other than with the A. solani induced metabolome. We identify 65 metabolites possibly associated with PTI in tomato plants, including NAD and trigonelline. We confirm that trigonelline inhibits fungal growth in vitro at physiological concentrations. Thus, a true pattern-triggered, chemical defence is mounted against A. alternata, which contains anti-fungal compounds that could be interesting for crop protection strategies.

Target deconvolution of HDAC pharmacopoeia reveals MBLAC2 as common off-target.

Drugs that target histone deacetylase (HDAC) entered the pharmacopoeia in the 2000s. However, some enigmatic phenotypes suggest off-target engagement. Here, we developed a quantitative chemical proteomics assay using immobilized HDAC inhibitors and mass spectrometry that we deployed to establish the target landscape of 53 drugs. The assay covers 9 of the 11 human zinc-dependent HDACs, questions the reported selectivity of some widely-used molecules (notably for HDAC6) and delineates how the composition of HDAC complexes influences drug potency. Unexpectedly, metallo-ß-lactamase domain-containing protein 2 (MBLAC2) featured as a frequent off-target of hydroxamate drugs. This poorly characterized palmitoyl-CoA hydrolase is inhibited by 24 HDAC inhibitors at low nanomolar potency. MBLAC2 enzymatic inhibition and knockdown led to the accumulation of extracellular vesicles. Given the importance of extracellular vesicle biology in neurological diseases and cancer, this HDAC-independent drug effect may qualify MBLAC2 as a target for drug discovery.

Plant characterization of insect-protected soybean.

Insect-protected soybean (SIP) that produces the Cry1A.105 and Cry2Ab2 insecticidal crystal proteins has been developed to provide protection from feeding damage caused by targeted lepidopteran insect pests. Typically, as part of environmental risk assessment (ERA), plant characterization is conducted, and the data submitted to regulatory agencies prior to commercialization of genetically modified (GM) crops. The objectives of this research were to: (a) compare soybean with and without the SIP trait in plant characterization field trials designed to fulfill requirements for submissions to global regulatory agencies and address China-specific considerations and (b) compare risk assessment conclusions across regions and the methodologies used in the field trials. The soybean with and without the SIP trait in temperate, tropical, and subtropical germplasm were planted in replicated multi-location trials in the USA (in 2012 and 2018) and Brazil (in 2013/2014 and 2017/2018). Agronomic, phenotypic, plant competitiveness, and survival characteristics were assessed for soybean entries with and without the SIP trait. Regardless of genetic background, growing region, season, or testing methodology, the risk assessment conclusions were the same: the evaluated insect-protected soybean did not differ from conventional soybean in evaluated agronomic, phenotypic, competitiveness, and survival characteristics indicating no change in plant pest/weed potential. These results reinforce the concept of data transportability across global regions, different seasons, germplasm, and methodologies that should be considered when assessing environmental risks of GM crops.

Gut microbiota influence frailty syndrome in older adults: mechanisms and therapeutic strategies.

Frailty syndrome denotes a decreased capacity of the body to maintain the homeostasis and stress of the internal environment, which simultaneously increases the risk of adverse health outcomes in older adults, including disability, hospitalization, falls, and death. To promote healthy aging, we should find strategies to cope with frailty. However, the pathogenesis of frailty syndrome is not yet clear. Recent studies have shown that the diversity, composition, and metabolites of gut microbiota significantly changed in older adults with frailty. In addition, several frailty symptoms were alleviated by adjusting gut microbiota with prebiotics, probiotics, and symbiosis. Therefore, we attempt to explore the pathogenesis of frailty syndrome in older people from gut microbiota and summarize the existing interventions for frailty syndrome targeting gut microbiota, with the aim of providing timely and necessary interventions and assistance for older adults with frailty.

Discovery of novel co-degradation CK1α and CDK7/9 PROTACs with p53 activation for treating acute myeloid leukemia.

Reactivating p53 activity to restore its anticancer function is an attractive cancer treatment strategy. In this study, we designed and synthesized a series of novel PROTACs to reactivate p53 via the co-degradation of CK1α and CDK7/9 proteins. Bioactivity studies showed that the selected PROTAC 13i exhibited potency antiproliferative activity in MV4-11 (IC50 = 0.096 ± 0.012 µM) and MOLM-13 (IC50 = 0.072 ± 0.014 µM) cells, and induced apoptosis of MV4-11 cells. Western-blot analysis showed that PROTAC 13i triple CK1α and CDK7/9 protein degradation resulted in the significantly increased expression of p53. At the same time, the transcriptional repression due to the degradation significantly reduced downstream gene expression of MYC, MDM2, BCL-2 and MCL-1, and reduced the inflammatory cytokine levels of TNF-α, IL-1ß and IL-6 in PMBCs. These results indicate the beneficial impact of simultaneous CK1α and CDK7/9 degradation for acute myeloid leukemia therapy.

Poly (ADP-ribose) polymerases 16 triggers pathological cardiac hypertrophy via activating IRE1α-sXBP1-GATA4 pathway.

BACKGROUND: Pressure overload-induced pathological cardiac hypertrophy is an independent predecessor of heart failure (HF), which remains the leading cause of worldwide mortality. However, current evidence on the molecular determinants of pathological cardiac hypertrophy is still inadequacy. This study aims to elucidate the role and mechanisms of Poly (ADP-ribose) polymerases 16 (PARP16) in the pathogenesis of pathological cardiac hypertrophy. METHODS: Gain and loss of function approaches were used to demonstrate the effects of genetic overexpression or deletion of PARP16 on cardiomyocyte hypertrophic growth in vitro. Ablation of PARP16 by transducing the myocardium with serotype 9 adeno-associated virus (AAV9)-encoding PARP16 shRNA were then subjected to transverse aortic construction (TAC) to investigate the effect of PARP16 on pathological cardiac hypertrophy in vivo. Co-immunoprecipitation (IP) and western blot assay were used to detect the mechanisms of PARP16 in regulating cardiac hypertrophic development. RESULTS: PARP16 deficiency rescued cardiac dysfunction and ameliorated TAC-induced cardiac hypertrophy and fibrosis in vivo, as well as phenylephrine (PE)-induced cardiomyocyte hypertrophic responses in vitro. Whereas overexpression of PARP16 exacerbated hypertrophic responses including the augmented cardiomyocyte surface area and upregulation of the fetal gene expressions. Mechanistically, PARP16 interacted with IRE1α and ADP-ribosylated IRE1α and then mediated the hypertrophic responses through activating the IRE1α-sXBP1-GATA4 pathway. CONCLUSIONS: Collectively, our results implicated that PARP16 is a contributor to pathological cardiac hypertrophy at least in part via activating the IRE1α-sXBP1-GATA4 pathway, and may be regarded as a new potential target for exploring effective therapeutic interventions of pathological cardiac hypertrophy and heart failure.

Transcriptome analysis reveals how cadmium promotes root development and accumulates in Apocynum venetum, a promising plant for greening cadmium-contaminated soil.

Cadmium (Cd) contamination poses a substantial threat the environment, necessitating effective remediation strategies. Phytoremediation emerges as a cost-efficient and eco-friendly approach for reducing Cd levels in the soil. In this study, the suitability of A. venetum for ameliorating Cd-contaminated soils was evaluated. Mild Cd stress promoted seedling and root growth, with the root being identified as the primary tissue for Cd accumulation. The Cd content of roots ranged from 0.35 to 0.55 mg/g under treatment with 10-50 µM CdCl2·2.5 H2O, and the bioaccumulation factor ranged from 28.78 to 84.43. Transcriptome sequencing revealed 20,292 unigenes, and 7507 nonredundant differentially expressed genes (DEGs) were identified across five comparison groups. DEGs belonging to the "MAPK signaling pathway-plant," "monoterpenoid biosynthesis," and "flavonoid biosynthesis pathway" exhibited higher expression levels in roots compared to stems and leaves. In addition, cytokinin-related DEGs, ROS scavenger genes, such as P450, glutathione-S-transferase (GST), and superoxide dismutase (SOD), and the cell wall biosynthesis-related genes, CSLG and D-GRL, were also upregulated in the root tissue, suggesting that Cd promotes root development. Conversely, certain ABC transporter genes, (e.g, NRAMP5), and some vacuolar iron transporters, predominantly expressed in the roots, displayed a strong correlation with Cd content, revealing the mechanism underlying the compartmentalized storage of Cd in the roots. KEGG enrichment analysis of DEGs showed that the pathways associated with the biosynthesis of flavonoids, lignin, and some terpenoids were significantly enriched in the roots under Cd stress, underscoring the pivotal role of these pathways in Cd detoxification. Our study suggests A. venetum as a potential Cd-contaminated phytoremediation plant and provides insights into the molecular-level mechanisms of root development promotion and accumulation mechanism in response to Cd stress.

Asymmetric C3-Allylation of Pyridines.

Asymmetric intermolecular C-H functionalization of pyridines at C3 is unprecedented. Herein, we report the first examples of such transformations: specifically, C3-allylation of pyridines via tandem borane and iridium catalysis. First, borane-catalyzed pyridine hydroboration generates nucleophilic dihydropyridines; then, the dihydropyridine undergoes enantioselective iridium-catalyzed allylation; and finally, oxidative aromatization with air as the oxidant gives the C3-allylated pyridine. This protocol provides direct access to C3-allylated pyridines with excellent enantioselectivity (up to >99% ee) and is suitable for late-stage functionalization of pyridine-containing drugs.

Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5.

BACKGROUND: Rare mutations in NADH:ubiquinone oxidoreductase complex assembly factor 5 (NDUFAF5) are linked to Leigh syndrome. OBJECTIVE: We aimed to describe clinical characteristics and functional findings in a patient cohort with NDUFAF5 mutations. METHODS: Patients with biallelic NDUFAF5 mutations were recruited from multi-centers in Taiwan. Clinical, laboratory, radiological, and follow-up features were recorded and mitochondrial assays were performed in patients' skin fibroblasts. RESULTS: Nine patients from seven unrelated pedigrees were enrolled, eight homozygous for c.836 T > G (p.Met279Arg) in NDUFAF5 and one compound heterozygous for p.Met279Arg. Onset age had a bimodal distribution. The early-onset group (age <3 years) presented with psychomotor delay, seizure, respiratory failure, and hyponatremia. The late-onset group (age ≥5 years) presented with normal development, but slowly progressive dystonia. Combing 25 previously described patients, the p.Met279Arg variant was exclusively identified in Chinese ancestry. Compared with other groups, patients with late-onset homozygous p.Met279Arg were older at onset (P = 0.008), had less developmental delay (P = 0.01), less hyponatremia (P = 0.01), and better prognosis with preserved ambulatory function into early adulthood (P = 0.01). Bilateral basal ganglia necrosis was a common radiological feature, but brainstem and spinal cord involvement was more common with early-onset patients (P = 0.02). A modifier gene analysis showed higher concomitant mutation burden in early-versus late-onset p.Met279Arg homozygous cases (P = 0.04), consistent with more impaired mitochondrial function in fibroblasts from an early-onset case than a late-onset patient. CONCLUSIONS: The p.Met279Arg variant is a common mutation in our population with phenotypic heterogeneity and divergent prognosis based on age at onset. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Automated unruptured cerebral aneurysms detection in TOF MR angiography images using dual-channel SE-3D UNet: a multi-center research.

OBJECTIVES: Time of flight magnetic resonance angiography (TOF-MRA) is the primary non-invasive screening method for cerebral aneurysms. We aimed to develop a computer-aided aneurysm detection method to improve the diagnostic efficiency and accuracy, especially decrease the false positive rate. METHODS: This is a retrospective multicenter study. The dataset contained 1160 TOF-MRA examinations composed of unruptured aneurysms (n = 1096) and normal controls (n = 166) from six hospitals. A total of 1037 examinations acquired from 2013 to 2019 were used as training set; 123 examinations acquired from 2020 to 2021 were used as external test set. We proposed an equalized augmentation strategy based on aneurysm location and constructed a detection model based on dual channel SE-3D UNet. The model was trained with a 5-fold cross-validation in the training set, then tested on the external test set. RESULTS: The proposed method achieved 82.46% sensitivity on patient-level, 73.85% sensitivity on lesion-level, and 0.88 false positives per case in the external test set. The performance did not show significant differences in subgroups according to the aneurysm site (except ACA), aneurysm size (except smaller than 3 mm), or MRI scanners. The performance preceded the basic SE-3D UNet by increasing 15.79% patient-level sensitivity and decreasing 4.19 FPs/case. CONCLUSIONS: The proposed automated aneurysm detection method achieved acceptable sensitivity while controlling fairly low false positives per case. It might provide a useful auxiliary tool of cerebral aneurysms MRA screening. KEY POINTS: • The need for automated cerebral aneurysms detecting is growing. • The strategy of equalized augmentation based on aneurysm location and dual-channel input could improve the model performance. • The retrospective multi-center study showed that the proposed automated cerebral aneurysms detection using dual-channel SE-3D UNet could achieve acceptable sensitivity while controlling a low false positive rate.

Blood neurofilament light chain as a surrogate marker for dystonia.

BACKGROUND AND PURPOSE: Dystonia is a heterogeneous movement disorder, and it remains unclear whether neurodegeneration is involved. Neurofilament light chain (NfL) is a biosignature of neurodegeneration. We aimed to investigate whether plasma NfL levels were elevated and associated with disease severity in patients with dystonia. METHOD: We enrolled 231 unrelated dystonia patients (isolated dystonia n = 203; combined dystonia n = 28) and 54 healthy controls from movement disorder clinics. Clinical severity was evaluated using the Fahn Marsden Dystonia Rating Scale, the Unified Dystonia Rating Scale, and the Global Dystonia Rating Scale. Blood NfL levels were measured by single-molecule array. RESULTS: Plasma NfL levels were significantly higher in those with generalized dystonia compared to those with focal dystonia (20.1 ± 8.8 vs. 11.7 ± 7.2 pg/mL; p = 0.01) or controls (p < 0.01), while the level was comparable between the focal dystonia group and controls (p = 0.08). Furthermore, the dystonia combined with parkinsonism group had higher NfL levels than the isolated dystonia group (17.4 ± 6.2 vs. 13.5 ± 7.5 pg/mL; p = 0.04). Notably, whole-exome sequencing was performed in 79 patients and two patients were identified as having likely pathogenic variants: one had a heterozygous c.122G>A (p.R41H) variant in THAP1 (DYT6) and the other carried a c.1825G>A (p.D609N) substitution in ATP1A3 (DYT12). No significant correlation was found between plasma NfL levels and dystonia rating scores. CONCLUSION: Plasma NfL levels are elevated in patients with generalized dystonia and dystonia combined with parkinsonism, suggesting that neurodegeneration is involved in the disease process of this subgroup of patients.