Genome-Nuclear Lamina Interactions Regulate Cardiac Stem Cell Lineage Restriction.

Progenitor cells differentiate into specialized cell types through coordinated expression of lineage-specific genes and modification of complex chromatin configurations. We demonstrate that a histone deacetylase (Hdac3) organizes heterochromatin at the nuclear lamina during cardiac progenitor lineage restriction. Specification of cardiomyocytes is associated with reorganization of peripheral heterochromatin, and independent of deacetylase activity, Hdac3 tethers peripheral heterochromatin containing lineage-relevant genes to the nuclear lamina. Deletion of Hdac3 in cardiac progenitor cells releases genomic regions from the nuclear periphery, leading to precocious cardiac gene expression and differentiation into cardiomyocytes; in contrast, restricting Hdac3 to the nuclear periphery rescues myogenesis in progenitors otherwise lacking Hdac3. Our results suggest that availability of genomic regions for activation by lineage-specific factors is regulated in part through dynamic chromatin-nuclear lamina interactions and that competence of a progenitor cell to respond to differentiation signals may depend upon coordinated movement of responding gene loci away from the nuclear periphery.

Circadian enhancers coordinate multiple phases of rhythmic gene transcription in vivo.

Mammalian transcriptomes display complex circadian rhythms with multiple phases of gene expression that cannot be accounted for by current models of the molecular clock. We have determined the underlying mechanisms by measuring nascent RNA transcription around the clock in mouse liver. Unbiased examination of enhancer RNAs (eRNAs) that cluster in specific circadian phases identified functional enhancers driven by distinct transcription factors (TFs). We further identify on a global scale the components of the TF cistromes that function to orchestrate circadian gene expression. Integrated genomic analyses also revealed mechanisms by which a single circadian factor controls opposing transcriptional phases. These findings shed light on the diversity and specificity of TF function in the generation of multiple phases of circadian gene transcription in a mammalian organ.

REV-ERB in GABAergic neurons controls diurnal hepatic insulin sensitivity.

Systemic insulin sensitivity shows a diurnal rhythm with a peak upon waking1,2. The molecular mechanism that underlies this temporal pattern is unclear. Here we show that the nuclear receptors REV-ERB-α and REV-ERB-ß (referred to here as 'REV-ERB') in the GABAergic (γ-aminobutyric acid-producing) neurons in the suprachiasmatic nucleus (SCN) (SCNGABA neurons) control the diurnal rhythm of insulin-mediated suppression of hepatic glucose production in mice, without affecting diurnal eating or locomotor behaviours during regular light-dark cycles. REV-ERB regulates the rhythmic expression of genes that are involved in neurotransmission in the SCN, and modulates the oscillatory firing activity of SCNGABA neurons. Chemogenetic stimulation of SCNGABA neurons at waking leads to glucose intolerance, whereas restoration of the temporal pattern of either SCNGABA neuron firing or REV-ERB expression rescues the time-dependent glucose metabolic phenotype caused by REV-ERB depletion. In individuals with diabetes, an increased level of blood glucose after waking is a defining feature of the 'extended dawn phenomenon'3,4. Patients with type 2 diabetes with the extended dawn phenomenon exhibit a differential temporal pattern of expression of REV-ERB genes compared to patients with type 2 diabetes who do not have the extended dawn phenomenon. These findings provide mechanistic insights into how the central circadian clock regulates the diurnal rhythm of hepatic insulin sensitivity, with implications for our understanding of the extended dawn phenomenon in type 2 diabetes.

Toxicity of overexpressed MeCP2 is independent of HDAC3 activity.

Duplication of the X-linked MECP2 gene causes a severe neurological syndrome whose molecular basis is poorly understood. To determine the contribution of known functional domains to overexpression toxicity, we engineered a mouse model that expresses wild-type or mutated MeCP2 from the Mapt (Tau) locus in addition to the endogenous protein. Animals that expressed approximately four times the wild-type level of MeCP2 failed to survive to weaning. Strikingly, a single amino acid substitution that prevents MeCP2 from binding to the TBL1X(R1) subunit of nuclear receptor corepressor 1/2 (NCoR1/2) complexes, when expressed at equivalent high levels, was phenotypically indistinguishable from wild type, suggesting that excessive corepressor recruitment underlies toxicity. In contrast, mutations affecting the DNA-binding domain were toxic when overexpressed. As the NCoR1/2 corepressors are thought to act through histone deacetylation by histone deacetylase 3 (HDAC3), we asked whether mutations in NCoR1 and NCoR2 that drastically reduced their ability to activate this enzyme would relieve the MeCP2 overexpression phenotype. Surprisingly, severity was unaffected, indicating that the catalytic activity of HDAC3 is not the mediator of toxicity. Our findings shed light on the molecular mechanisms underlying MECP2 duplication syndrome and call for a re-evaluation of the precise biological role played by corepressor recruitment.

A Light-Responsive Neural Circuit Suppresses Feeding.

Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHb→5-HTDRN circuit in mice blunts darkness-induced hyperphagia, while inhibition of the circuit prevents light-induced anorexia. Together, we discovered a light-responsive neural circuit that relays the environmental light signals to regulate feeding behavior in mice.

HDAC3 promotes Sertoli cell maturation and maintains the blood-testis barrier dynamics.

Germ cell development depends on the capacity of somatic Sertoli cells to undergo differentiation into a mature state and establish a germ cell-specific blood-testis barrier (BTB). The BTB structure confers an immunological barrier for meiotic and postmeiotic germ cells, and its dynamic permeability facilitates a transient movement of preleptotene spermatocytes through BTB to enter meiosis. However, the regulatory factors involved in Sertoli cell maturation and how BTB dynamics coordinate germ cell development remain unclear. Here, we found a histone deacetylase HDAC3 abundantly expresses in Sertoli cells and localizes in both cytoplasm and nucleus. Sertoli cell-specific Hdac3 knockout in mice causes infertility with compromised integrity of blood-testis barrier, leading to germ cells unable to traverse through BTB and an accumulation of preleptotene spermatocytes in juvenile testis. Mechanistically, nuclear HDAC3 regulates the expression program of Sertoli cell maturation genes, and cytoplasmic HDAC3 forms a complex with the gap junction protein Connexin 43 to modulate the BTB integrity and dynamics through regulating the distribution of tight junction proteins. Our findings identify HDAC3 as a critical regulator in promoting Sertoli cell maturation and maintaining the homeostasis of the blood-testis barrier.

The hepatic circadian clock fine-tunes the lipogenic response to feeding through RORα/γ.

Liver lipid metabolism is under intricate temporal control by both the circadian clock and feeding. The interplay between these two mechanisms is not clear. Here we show that liver-specific depletion of nuclear receptors RORα and RORγ, key components of the molecular circadian clock, up-regulate expression of lipogenic genes only under fed conditions at Zeitgeber time 22 (ZT22) but not under fasting conditions at ZT22 or ad libitum conditions at ZT10. RORα/γ controls circadian expression of Insig2, which keeps feeding-induced SREBP1c activation under check. Loss of RORα/γ causes overactivation of the SREBP-dependent lipogenic response to feeding, exacerbating diet-induced hepatic steatosis. These findings thus establish ROR/INSIG2/SREBP as a molecular pathway by which circadian clock components anticipatorily regulate lipogenic responses to feeding. This highlights the importance of time of day as a consideration in the treatment of liver metabolic disorders.

DcWRKY33 promotes petal senescence in carnation (Dianthus caryophyllus L.) by activating genes involved in the biosynthesis of ethylene and abscisic acid and accumulation of reactive oxygen species.

Carnation (Dianthus caryophyllus L.) is one of the most famous and ethylene-sensitive cut flowers worldwide, but how ethylene interacts with other plant hormones and factors to regulate petal senescence in carnation is largely unknown. Here we found that a gene encoding WRKY family transcription factor, DcWRKY33, was significantly upregulated upon ethylene treatment. Silencing and overexpression of DcWRKY33 could delay and accelerate the senescence of carnation petals, respectively. Abscisic acid (ABA) and H2 O2 treatments could also accelerate the senescence of carnation petals by inducing the expression of DcWRKY33. Further, DcWRKY33 can bind directly to the promoters of ethylene biosynthesis genes (DcACS1 and DcACO1), ABA biosynthesis genes (DcNCED2 and DcNCED5), and the reactive oxygen species (ROS) generation gene DcRBOHB to activate their expression. Lastly, relationships are existed between ethylene, ABA and ROS. This study elucidated that DcWRKY33 promotes petal senescence by activating genes involved in the biosynthesis of ethylene and ABA and accumulation of ROS in carnation, supporting the development of new strategies to prolong the vase life of cut carnation.

The mutual regulation between DcEBF1/2 and DcEIL3-1 is involved in ethylene induced petal senescence in carnation (Dianthus caryophyllus L.).

Carnation (Dianthus caryophyllus L.) is a respiratory climacteric flower, comprising one of the most important cut flowers that is extremely sensitive to plant hormone ethylene. Ethylene signaling core transcription factor DcEIL3-1 plays a key role in ethylene induced petal senescence in carnation. However, how the dose of DcEIL3-1 is regulated in the carnation petal senescence process is still not clear. Here, we screened out two EBF (EIN3 Binding F-box) genes, DcEBF1 and DcEBF2, which showed quick elevation by ethylene treatment according to the ethylene induced carnation petal senescence transcriptome. Silencing of DcEBF1 and DcEBF2 accelerated, whereas overexpression of DcEBF1 and DcEBF2 delayed, ethylene induced petal senescence in carnation by influencing DcEIL3-1 downstream target genes but not DcEIL3-1 itself. Furthermore, DcEBF1 and DcEBF2 interact with DcEIL3-1 to degrade DcEIL3-1 via an ubiquitination pathway in vitro and in vivo. Finally, DcEIL3-1 binds to the promoter regions of DcEBF1 and DcEBF2 to activate their expression. In conclusion, the present study reveals the mutual regulation between DcEBF1/2 and DcEIL3-1 during ethylene induced petal senescence in carnation, which not only expands our understanding about ethylene signal regulation network in the carnation petal senescence process, but also provides potential targets with respect to breeding a cultivar of long-lived cut carnation.

Chemical Framework to Design Linear-like Relaxors toward Capacitive Energy Storage.

ABO3-type perovskite relaxor ferroelectrics (RFEs) have emerged as the preferred option for dielectric capacitive energy storage. However, the compositional design of RFEs with high energy density and efficiency poses significant challenges owing to the vast compositional space and the absence of general rules. Here, we present an atomic-level chemical framework that captures inherent characteristics in terms of radius and ferroelectric activity of ions. By categorizing A/B-site ions as host framework, rattling, ferroelectrically active, and blocking ions and assembling these four types of ions with specific criteria, linear-like relaxors with weak locally correlated and highly extendable unit-cell polarization vectors can be constructed. As example, we demonstrate two new compositions of Bi0.5K0.5TiO3-based and BaTiO3-based relaxors, showing extremely high recoverable energy densities of 17.3 and 12.1 J cm-3, respectively, both with a high efficiency of about 90%. Further, the role of different types of ions in forming heterogeneous polar structures is identified through element-specific local structure analysis using neutron total scattering combined with reverse Monte Carlo modeling. Our work not only opens up new avenues toward rational compositional design of high energy storage performance lead-free RFEs but also sheds light on atomic-level manipulation of functional properties in compositionally complex ferroelectrics.

Strong Local Polarization Fluctuations Enabled High Electrostatic Energy Storage in Pb-Free Relaxors.

Electrostatic energy-storage ceramic capacitors are essential components of modern electrified power systems. However, improving their energy-storage density while maintaining high efficiency to facilitate cutting-edge miniaturized and integrated applications remains an ongoing challenge. Herein, we report a record-high energy-storage density of 20.3 J cm-3 together with a high efficiency of 89.3% achieved by constructing a relaxor ferroelectric state with strongly enhanced local polarization fluctuations. This is realized by incorporating highly polarizable, heterovalent, and large-sized Zn and Nb ions into a Bi0.5Na0.5TiO3-BaTiO3 ferroelectric matrix with very strong tetragonal distortion. Element-specific local structure analysis revealed that the foreign ions strengthen the magnitude of the unit-cell polarization vectors while simultaneously reducing their orientation anisotropy and forming strong fluctuations in both magnitude and orientation within 1-3 nm polar clusters. This leads to a particularly high polarization variation (ΔP) of 72 µC cm-2, low hysteresis, and a high effective polarization coefficient at a high breakdown strength of 80 kV mm-1. This work has surpassed the current energy density limit of 20 J cm-3 in bulk Pb-free ceramics and has demonstrated that controlling the local structure via the chemical composition design can open up new possibilities for exploring relaxors with high energy-storage performance.

Outstanding Energy-Storage Density Together with Efficiency of above 90% via Local Structure Design.

Dielectric ceramic capacitors with high recoverable energy density (Wrec) and efficiency (η) are of great significance in advanced electronic devices. However, it remains a challenge to achieve high Wrec and η parameters simultaneously. Herein, based on density functional theory calculations and local structure analysis, the feasibility of developing the aforementioned capacitors is demonstrated by considering Bi0.25Na0.25Ba0.5TiO3 (BNT-50BT) as a matrix material with large local polarization and structural distortion. Remarkable Wrec and η of 16.21 J/cm3 and 90.5% have been achieved in Bi0.25Na0.25Ba0.5Ti0.92Hf0.08O3 via simple chemical modification, which is the highest Wrec value among reported bulk ceramics with η greater than 90%. The examination results of local structures at lattice and atomic scales indicate that the disorderly polarization distribution and small nanoregion (∼3 nm) lead to low hysteresis and high efficiency. In turn, the drastic increase in local polarization activated via the ultrahigh electric field (80 kV/mm) leads to large polarization and superior energy storage density. Therefore, this study emphasizes that chemical design should be established on a clear understanding of the performance-related local structure to enable a targeted regulation of high-performance systems.

Melatonin in cancer biology: pathways, derivatives, and the promise of targeted delivery.

Melatonin, historically recognized for its primary role in regulating circadian rhythms, has expanded its influence particularly due to its wide range of biological activities. It has firmly established itself in cancer research. To highlight its versatility, we delved into how melatonin interacts with key signaling pathways, such as the Wnt/ß-Catenin, PI3K, and NF-κB pathways, which play foundational roles in tumor development and progression. Notably, melatonin can intricately modulate these pathways, potentially affecting various cellular functions such as apoptosis, metastasis, and immunity. Additionally, a comprehensive review of current clinical studies provides a dual perspective. These studies confirm melatonin's potential in cancer management but also underscore its inherent limitations, particularly its limited bioavailability, which often relegates it to a supplementary role in treatments. Despite this limitation, there is an ongoing quest for innovative solutions and current advancements include the development of melatonin derivatives and cutting-edge delivery systems. By synthesizing the past, present, and future, this review provides a detailed overview of melatonin's evolving role in oncology, positioning it as a potential cornerstone in future cancer therapeutics.

Knowledge-Augmented Deep Learning for Segmenting and Detecting Cerebral Aneurysms With CT Angiography: A Multicenter Study.

Background Deep learning (DL) could improve the labor-intensive, challenging processes of diagnosing cerebral aneurysms but requires large multicenter data sets. Purpose To construct a DL model using a multicenter data set for accurate cerebral aneurysm segmentation and detection on CT angiography (CTA) images and to compare its performance with radiology reports. Materials and Methods Consecutive head or head and neck CTA images of suspected unruptured cerebral aneurysms were gathered retrospectively from eight hospitals between February 2018 and October 2021 for model development. An external test set with reference standard digital subtraction angiography (DSA) scans was obtained retrospectively from one of the eight hospitals between February 2022 and February 2023. Radiologists (reference standard) assessed aneurysm segmentation, while model performance was evaluated using the Dice similarity coefficient (DSC). The model's aneurysm detection performance was assessed by sensitivity and comparing areas under the receiver operating characteristic curves (AUCs) between the model and radiology reports in the DSA data set with use of the DeLong test. Results Images from 6060 patients (mean age, 56 years ± 12 [SD]; 3375 [55.7%] female) were included for model development (training: 4342; validation: 1086; and internal test set: 632). Another 118 patients (mean age, 59 years ± 14; 79 [66.9%] female) were included in an external test set to evaluate performance based on DSA. The model achieved a DSC of 0.87 for aneurysm segmentation performance in the internal test set. Using DSA, the model achieved 85.7% (108 of 126 aneurysms [95% CI: 78.1, 90.1]) sensitivity in detecting aneurysms on per-vessel analysis, with no evidence of a difference versus radiology reports (AUC, 0.93 [95% CI: 0.90, 0.95] vs 0.91 [95% CI: 0.87, 0.94]; P = .67). Model processing time from reconstruction to detection was 1.76 minutes ± 0.32 per scan. Conclusion The proposed DL model could accurately segment and detect cerebral aneurysms at CTA with no evidence of a significant difference in diagnostic performance compared with radiology reports. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Payabvash in this issue.

Challenges in benchmarking metagenomic profilers.

Accurate microbial identification and abundance estimation are crucial for metagenomics analysis. Various methods for classification of metagenomic data and estimation of taxonomic profiles, broadly referred to as metagenomic profilers, have been developed. Nevertheless, benchmarking of metagenomic profilers remains challenging because some tools are designed to report relative sequence abundance while others report relative taxonomic abundance. Here we show how misleading conclusions can be drawn by neglecting this distinction between relative abundance types when benchmarking metagenomic profilers. Moreover, we show compelling evidence that interchanging sequence abundance and taxonomic abundance will influence both per-sample summary statistics and cross-sample comparisons. We suggest that the microbiome research community pay attention to potentially misleading biological conclusions arising from this issue when benchmarking metagenomic profilers, by carefully considering the type of abundance data that were analyzed and interpreted and clearly stating the strategy used for metagenomic profiling.

DNA methylation remodeled amino acids biosynthesis regulates flower senescence in carnation (Dianthus caryophyllus).

Dynamic DNA methylation regulatory networks are involved in many biological processes. However, how DNA methylation patterns change during flower senescence and their relevance with gene expression and related molecular mechanism remain largely unknown. Here, we used whole genome bisulfite sequencing to reveal a significant increase of DNA methylation in the promoter region of genes during natural and ethylene-induced flower senescence in carnation (Dianthus caryophyllus L.), which was correlated with decreased expression of DNA demethylase gene DcROS1. Silencing of DcROS1 accelerated while overexpression of DcROS1 delayed carnation flower senescence. Moreover, among the hypermethylated differentially expressed genes during flower senescence, we identified two amino acid biosynthesis genes, DcCARA and DcDHAD, with increased DNA methylation and reduced expression in DcROS1 silenced petals, and decreased DNA methylation and increased expression in DcROS1 overexpression petals, accompanied by decreased or increased amino acids content. Silencing of DcCARA and DcDHAD accelerates carnation flower senescence. We further showed that adding corresponding amino acids could largely rescue the senescence phenotype of DcROS1, DcCARA and DcDHAD silenced plants. Our study not only demonstrates an essential role of DcROS1-mediated remodeling of DNA methylation in flower senescence but also unravels a novel epigenetic regulatory mechanism underlying DNA methylation and amino acid biosynthesis during flower senescence.

Associations of MRI-Derived Glymphatic System Impairment With Global White Matter Damage and Cognitive Impairment in Mild Traumatic Brain Injury: A DTI-ALPS Study.

BACKGROUND: Assessing the glymphatic function using diffusion tensor image analysis along the perivascular space (DTI-ALPS) may be helpful for mild traumatic brain injury (mTBI) management. PURPOSE: To assess glymphatic function using DTI-ALPS and its associations with global white matter damage and cognitive impairment in mTBI. STUDY TYPE: Prospective. POPULATION: Thirty-four controls (44.1% female, mean age 49.2 years) and 58 mTBI subjects (43.1% female, mean age 48.7 years), including uncomplicated mTBI (N = 32) and complicated mTBI (N = 26). FIELD STRENGTH/SEQUENCE: 3-T, single-shot echo-planar imaging sequence. ASSESSMENT: Magnetic resonance imaging (MRI) was done within 1 month since injury. DTI-ALPS was performed to assess glymphatic function, and peak width of skeletonized mean diffusivity (PSMD) was used to assess global white matter damage. Cognitive tests included Auditory Verbal Learning Test and Digit Span Test (forward and backward). STATISTICAL TESTS: Neuroimaging findings comparisons were done between mTBI and control groups. Partial correlation and multivariable linear regression assessed the associations between DTI-ALPS, PSMD, and cognitive impairment. Mediation effects of PSMD on the relationship between DTI-ALPS and cognitive impairment were explored. P-value <0.05 was considered statistically significant, except for cognitive correlational analyses with a Bonferroni-corrected P-value set at 0.05/3 ≈ 0.017. RESULTS: mTBI showed lower DTI-ALPS and higher PSMD, especially in complicated mTBI. DTI-ALPS was significantly correlated with verbal memory (r = 0.566), attention abilities (r = 0.792), executive function (r = 0.618), and PSMD (r = -0.533). DTI-ALPS was associated with verbal memory (ß = 8.77, 95% confidence interval [CI] 5.00, 12.54), attention abilities (ß = 5.67, 95% CI 4.56, 6.97), executive function (ß = 2.34, 95% CI 1.49, 3.20), and PSMD (ß = -0.79, 95% CI -1.15, -0.43). PSMD mediated 46.29%, 20.46%, and 24.36% of the effects for the relationship between DTI-ALPS and verbal memory, attention abilities, and executive function. DATA CONCLUSION: Glymphatic function may be impaired in mTBI reflected by DTI-ALPS. Glymphatic dysfunction may cause cognitive impairment related to global white matter damage after mTBI. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Clot-based time attenuation curve as a novel imaging predictor of mechanical thrombectomy functional outcome in acute ischemia stroke.

OBJECTIVES: To investigate whether a novel assessment of thrombus permeability obtained from perfusion computed tomography (CTP) can act as a more accurate predictor of clinical response to mechanical thrombectomy (MT) in acute ischemic stroke (AIS). MATERIALS AND METHODS: We performed a study including two cohorts of AIS patients who underwent MT admitted to a single-center between April 2018 and February 2022: a retrospective development cohort (n = 71) and a prospective independent validation cohort (n = 96). Thrombus permeability was determined in terms of entire thrombus time-attenuation curve (TAC) on CTP. Association between thrombus TAC distributions and histopathological results was analyzed in the development cohort. Logistic regression was used to assess the performance of the TAC for predicting 90-day modified Rankin Scale (mRS) score, and good outcome was defined as a mRS score of ≤ 2. Basic clinical characteristics was used to build a routine clinical model. A combined model gathered TAC and basic clinical characteristics was also developed. The performance of the three models is compared on the independent validation set. RESULTS: Two TAC distributions were observed-unimodal (uTAC) and linear (lTAC). TAC distributions achieved strong correlations (|r|= 0.627, p < 0.001) with histopathological results, in which uTAC associated with fibrin- and platelet-rich clot while lTAC associated with red blood cell-rich clot. The uTAC was independently associated with poor outcome (odds ratio, 0.08 [95% confidence interval (CI), 0.02-0.31]; p < 0.001). TAC distributions yielded an AUC of 0.78 (95% CI, 0.70-0.87) for predicting clinical outcome. When combined clinical characteristics, the performance was significantly improved (AUC, 0.85 [95% CI, 0.76-0.93]; p < 0.001) and higher than routine clinical model (AUC, 0.69 [95% CI, 0.59-0.83]; p < 0.001). CONCLUSIONS: Thrombus TAC on CTP were found to be a promising new imaging biomarker to predict the outcomes of MT in AIS. CLINICAL RELEVANCE STATEMENT: This study revealed that clot-based time attenuation curve based on admission perfusion CT could reflect the permeability and composition of thrombus and, also, provide valuable information to predict the clinical outcomes of mechanical thrombectomy in patients with acute ischemia stroke. KEY POINTS: • Two time-attenuation curves distributions achieved strong correlations (|r|= 0.627, p < 0.001) with histopathological results. • The unimodal time-attenuation curve was independently associated with poor outcome (odds ratio, 0.08 [0.02-0.31]; p < 0.001). • The time-attenuation curve distributions yielded a higher performance for detecting clinical outcome than routine clinical model (AUC, 0.78 [0.70-0.87] vs 0.69 [0.59-0.83]; p < 0.001).

Deep learning-based automatic ASPECTS calculation can improve diagnosis efficiency in patients with acute ischemic stroke: a multicenter study.

OBJECTIVES: The Alberta Stroke Program Early CT Score (ASPECTS), a systematic method for assessing ischemic changes in acute ischemic stroke using non-contrast computed tomography (NCCT), is often interpreted relying on expert experience and can vary between readers. This study aimed to develop a clinically applicable automatic ASPECTS system employing deep learning (DL). METHODS: This study enrolled 1987 NCCT scans that were retrospectively collected from four centers between January 2017 and October 2021. A DL-based system for automated ASPECTS assessment was trained on a development cohort (N = 1767) and validated on an independent test cohort (N = 220). The consensus of experienced physicians was regarded as a reference standard. The validity and reliability of the proposed system were assessed against physicians' readings. A real-world prospective application study with 13,399 patients was used for system validation in clinical contexts. RESULTS: The DL-based system achieved an area under the receiver operating characteristic curve (AUC) of 84.97% and an intraclass correlation coefficient (ICC) of 0.84 for overall-level analysis on the test cohort. The system's diagnostic sensitivity was 94.61% for patients with dichotomized ASPECTS at a threshold of ≥ 6, with substantial agreement (ICC = 0.65) with expert ratings. Combining the system with physicians improved AUC from 67.43 to 89.76%, reducing diagnosis time from 130.6 ± 66.3 s to 33.3 ± 8.3 s (p < 0.001). During the application in clinical contexts, 94.0% (12,591) of scans successfully processed by the system were utilized by clinicians, and 96% of physicians acknowledged significant improvement in work efficiency. CONCLUSION: The proposed DL-based system could accurately and rapidly determine ASPECTS, which might facilitate clinical workflow for early intervention. CLINICAL RELEVANCE STATEMENT: The deep learning-based automated ASPECTS evaluation system can accurately and rapidly determine ASPECTS for early intervention in clinical workflows, reducing processing time for physicians by 74.8%, but still requires validation by physicians when in clinical applications. KEY POINTS: The deep learning-based system for ASPECTS quantification has been shown to be non-inferior to expert-rated ASPECTS. This system improved the consistency of ASPECTS evaluation and reduced processing time to 33.3 seconds per scan. 94.0% of scans successfully processed by the system were utilized by clinicians during the prospective clinical application.

Single-Electron Reduction of "Push-Pull" C-C Single Bond and Decyanation Using Tertiary Amines as the Organic Electron Donor.

Using commercially available tertiary amines as an organic electron donor (OED), the reduction of "push-pull" C-C single bond and reductive decyanation of tetrahydroisoquinolines were realized. These reactions exhibited higher reaction efficiency and better functional group tolerance compared with those of metallic reductants, and the mechanistic study indicated that a radical intermediate was involved in the reduction of the C-C single bond, which provides a new way to the OED-enabled mild reduction.