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1.
Nat Neurosci ; 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38347199

RESUMO

Fear-related disorders (for example, phobias and anxiety) cause a substantial public health problem. To date, studies of the neural basis of fear have mostly focused on the amygdala. Here we identify a molecularly defined amygdala-independent tetra-synaptic pathway for olfaction-evoked innate fear and anxiety in male mice. This pathway starts with inputs from the olfactory bulb mitral and tufted cells to pyramidal neurons in the dorsal peduncular cortex that in turn connect to cholecystokinin-expressing (Cck+) neurons in the superior part of lateral parabrachial nucleus, which project to tachykinin 1-expressing (Tac1+) neurons in the parasubthalamic nucleus. Notably, the identified pathway is specifically involved in odor-driven innate fear. Selective activation of this pathway induces innate fear, while its inhibition suppresses odor-driven innate fear. In addition, the pathway is both necessary and sufficient for stress-induced anxiety-like behaviors. These findings reveal a forebrain-to-hindbrain neural substrate for sensory-triggered fear and anxiety that bypasses the amygdala.

2.
Artigo em Inglês | MEDLINE | ID: mdl-38302198

RESUMO

BACKGROUND AND PURPOSE: DTI can be used to derive conventional diffusion measurements, which can measure WM abnormalities in multiple sclerosis. DTI can also be used to construct structural brain networks and derive network measurements. However, few studies have compared their sensitivity in detecting brain alterations, especially in longitudinal studies. Therefore, in this study, we aimed to determine which type of measurement is more sensitive in tracking the dynamic changes over time in MS. MATERIALS AND METHODS: Eighteen patients with MS were recruited at baseline and followed up at 6 and 12 months. All patients underwent MR imaging and clinical evaluation at 3 time points. Diffusion and network measurements were derived, and their brain changes were evaluated. RESULTS: None of the conventional DTI measurements displayed statistically significant changes during the follow-up period; however, the nodal degree, nodal efficiency, and nodal path length of the left middle frontal gyrus and bilateral inferior frontal gyrus, opercular part showed significant longitudinal changes between baseline and at 12 months, respectively. CONCLUSIONS: The nodal degree, nodal efficiency, and nodal path length of the left middle frontal gyrus and bilateral inferior frontal gyrus, opercular part may be used to monitor brain changes over time in MS.

3.
Mol Plant ; 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38327054

RESUMO

Tomato is an ideal model for studying how plants effectively coordinate specialized metabolites to adapt to environmental change. Among plant metabolites, phenolamides, which are conjugates of hydroxycinnamic acid derivatives and polyamines, play important roles in plant adaptation to abiotic and biotic stresses. However, the molecular mechanisms underlying phenolamides metabolism and regulation in tomato, as well as the effects of domestication in breeding on phenolamide diversity, have not been fully elucidated. Here, we performed a metabolite-based genome-wide association study (mGWAS) to identify two biosynthetic gene clusters containing twelve genes involved in phenolamide metabolism, including four biosynthesis genes (two 4CL genes, one C3H gene, and one CPA gene), seven decoration genes (five AT genes and two UGT genes), and one transport protein (DTX29). We also discovered that SlMYB13 positively regulates two gene clusters, thereby promoting phenolamide accumulation. Moreover, phenolamides accumulation induced the scavenging of reactive oxygen species (ROS) and the increase of abscisic acid (ABA) content to enhance drought tolerance in tomato, which was further validated through the exogenous application of Fer-Put. Finally, the combined "HapB" (i.e., SlAT1.1-CHapB, SlAT1.2-AHapB, SlAT1.3-CHapB, SlCV86-THapB, SlDH29-THapB, and SlMYB13-GHapB) were negatively selected during tomato domestication and improvement, leading to a reduction in phenolamide content, and consequently, a diminished drought tolerance. In this study, we systematically dissected the mechanism of phenolamide biosynthesis through a multi-omics approach, and revealed the effects of human domestication on plant metabolic diversity and environmental adaptation during tomato breeding.

4.
Gene ; 904: 148215, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38307218

RESUMO

BACKGROUND: A growing body of research indicates that colorectal cancer (CRC) is significantly influenced by the ubiquitin-proteasome system. Nevertheless, reliable immune landscapes and ubiquitin-associated prognostic markers are still scarce. METHODS: We systematically analyzed the RNA-seq data of 2,830 ubiquitin-related genes from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). A CRC prognostic risk model was developed based on ubiquitin-associated gene signatures. In-depth multi-dimensional analyses were performed on ubiquitin-related subgroups with high and low risk. Drug response sensitivity for high-risk CRC patients was also predicted. RESULTS: A total of 131 ubiquitin-related differentially expressed genes were retrieved, of which 9 prognostic genes for CRC were ultimately identified and further validated by our clinical CRC tumor and adjacent normal samples. The expression pattern of these 9 ubiquitin-associated genes was found to be strongly related to overall survival, immune cell fractions, and immune-related genes of CRC patients. CRC patients stratified by the ubiquitin prognostic model exhibited distinct clinicopathological characteristics and immune landscapes. A comprehensive framework for personalized medicine prediction identified regorafenib and sorafenib as the most promising therapeutic agents for high ubiquitin-related risk CRC patients, which was confirmed in cell viability assays. CONCLUSIONS: Ubiquitin characteristics can reflect CRC prognosis and help develop innovative biomarkers for precision treatment.


Assuntos
Neoplasias Colorretais , Imunoterapia , Humanos , Sobrevivência Celular , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Citoplasma , Ubiquitinas
5.
Artigo em Inglês | MEDLINE | ID: mdl-38364286

RESUMO

The identification of Chinese medicinal herbs occupies a crucial part in the development of the food and drug market. Although molecular identification based on real-time PCR offers good versatility and uniform digital standards compared with traditional methods, such as morphology, the dependence on large-scale equipment hinders spot detection and marketable applications. In this study, we developed a DNA nanoclaw for colorimetric detection and visible on-site identification of Chinese medicines. When specific miRNA is present, the DNAzyme is activated and cleaves the substrate strand, triggering the catalytic hairpin assembly (CHA) reaction and forming branched DNA junctions on AuNP-I. This can then capture AuNP-II through hybridization and facilitate their aggregation, resulting in a noticeable color change that is observable to the naked eye. By harnessing the dual amplification of DNAzyme and CHA, this highly sensitive nanoprobe successfully achieved specific identification of Chinese medicines. This offers a new perspective for on-site testing in the herbal market.

6.
IEEE Trans Med Imaging ; PP2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38373127

RESUMO

Medical image analysis techniques have been employed in diagnosing and screening clinical diseases. However, both poor medical image quality and illumination style inconsistency increase uncertainty in clinical decision-making, potentially resulting in clinician misdiagnosis. The majority of current image enhancement methods primarily concentrate on enhancing medical image quality by leveraging high-quality reference images, which are challenging to collect in clinical applications. In this study, we address image quality enhancement within a fully self-supervised learning setting, wherein neither high-quality images nor paired images are required. To achieve this goal, we investigate the potential of self-supervised learning combined with domain adaptation to enhance the quality of medical images without the guidance of high-quality medical images. We design a Domain Adaptation Self-supervised Quality Enhancement framework, called DASQE. More specifically, we establish multiple domains at the patch level through a designed rule-based quality assessment scheme and style clustering. To achieve image quality enhancement and maintain style consistency, we formulate the image quality enhancement as a collaborative self-supervised domain adaptation task for disentangling the low-quality factors, medical image content, and illumination style characteristics by exploring intrinsic supervision in the low-quality medical images. Finally, we perform extensive experiments on six benchmark datasets of medical images, and the experimental results demonstrate that DASQE attains state-of-the-art performance. Furthermore, we explore the impact of the proposed method on various clinical tasks, such as retinal fundus vessel/lesion segmentation, nerve fiber segmentation, polyp segmentation, skin lesion segmentation, and disease classification. The results demonstrate that DASQE is advantageous for diverse downstream image analysis tasks.

7.
Chin Herb Med ; 16(1): 3-12, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38375050

RESUMO

To promote the development of extracellular vesicles of herbal medicine especially the establishment of standardization, led by the National Expert Committee on Research and Application of Chinese Herbal Vesicles, research experts in the field of herbal medicine and extracellular vesicles were invited nationwide with the support of the Expert Committee on Research and Application of Chinese Herbal Vesicles, Professional Committee on Extracellular Vesicle Research and Application, Chinese Society of Research Hospitals and the Guangdong Engineering Research Center of Chinese Herbal Vesicles. Based on the collation of relevant literature, we have adopted the Delphi method, the consensus meeting method combined with the nominal group method to form a discussion draft of "Consensus statement on research and application of Chinese herbal medicine derived extracellular vesicles-like particles (2023)". The first draft was discussed in online and offline meetings on October 12, 14, November 2, 2022 and April and May 2023 on the current status of research, nomenclature, isolation methods, quality standards and research applications of extracellular vesicles of Chinese herbal medicines, and 13 consensus opinions were finally formed. At the Third Academic Conference on Research and Application of Chinese Herbal Vesicles, held on May 26, 2023, Kewei Zhao, convenor of the consensus, presented and read the consensus to the experts of the Expert Committee on Research and Application of Chinese Herbal Vesicles. The consensus highlights the characteristics and advantages of Chinese medicine, inherits the essence, and keeps the righteousness and innovation, aiming to provide a reference for colleagues engaged in research and application of Chinese herbal vesicles at home and abroad, decode the mystery behind Chinese herbal vesicles together, establish a safe, effective and controllable accurate Chinese herbal vesicle prevention and treatment system, and build a bridge for Chinese medicine to the world.

8.
Cell Commun Signal ; 22(1): 116, 2024 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-38347540

RESUMO

BACKGROUND: R140Q mutation in isocitrate dehydrogenase 2 (IDH2) promotes leukemogenesis. Targeting IDH2/R140Q yields encouraging therapeutic effects in the clinical setting. However, therapeutic resistance occurs in 12% of IDH2/R140Q inhibitor treated patients. The IDH2/R140Q mutant converted TF-1 cells to proliferate in a cytokine-independent manner. This study investigated the signaling pathways involved in TF-1(R140Q) cell proliferation conversion as alternative therapeutic strategies to improve outcomes in patients with acute myeloid leukemia (AML) harboring IDH2/R140Q. METHODS: The effects of IDH2/R140Q mutation on TF-1 cell survival induced by GM-CSF withdrawal were evaluated using flow cytometry assay. The expression levels of apoptosis-related proteins, total or phosphorylated STAT3/5, ERK, and AKT in wild-type TF-1(WT) or TF-1(R140Q) cells under different conditions were evaluated using western blot analysis. Cell viability was tested using MTT assay. The mRNA expression levels of GM-CSF, IL-3, IL-6, G-CSF, leukemia inhibitory factor (LIF), oncostatin M (OSM), and IL-11 in TF-1(WT) and TF-1(R140Q) cells were quantified via RT-PCR. The secretion levels of GM-CSF, OSM, and LIF were determined using ELISA. RESULTS: Our results showed that STAT3 and STAT5 exhibited aberrant constitutive phosphorylation in TF-1(R140Q) cells compared with TF-1(WT) cells. Inhibition of STAT3/5 phosphorylation suppressed the cytokine-independent proliferation of TF-1(R140Q) cells. Moreover, the autocrine GM-CSF, LIF and OSM levels increased, which is consistent with constitutive STAT5/3 activation in TF-1(R140Q) cells, as compared with TF-1(WT) cells. CONCLUSIONS: The autocrine cytokines, including GM-CSF, LIF, and OSM, contribute to constitutive STAT3/5 activation in TF-1(R140Q) cells, thereby modulating IDH2/R140Q-mediated malignant proliferation in TF-1 cells. Targeting STAT3/5 phosphorylation may be a novel strategy for the treatment of AML in patients harboring the IDH2/R140Q mutation. Video Abstract.


Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos , Leucemia Mieloide Aguda , Humanos , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Fator de Transcrição STAT5/metabolismo , Fosforilação , Leucemia Mieloide Aguda/genética , Mutação , Proliferação de Células , Fator de Transcrição STAT3/metabolismo
9.
Cell Rep ; 43(2): 113804, 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38368612

RESUMO

Neural mechanisms underlying amputation-related secondary pain are unclear. Using in vivo two-photon imaging, three-dimensional reconstruction, and fiber photometry recording, we show that a microglial activation cascade from the primary somatosensory cortex of forelimb (S1FL) to the primary somatosensory cortex of hindlimb (S1HL) mediates the disinhibition and subsequent hyperexcitation of glutamatergic neurons in the S1HL (S1HLGlu), which then drives secondary mechanical hypersensitivity development in ipsilateral hindpaws of mice with forepaw amputation. Forepaw amputation induces rapid S1FL microglial activation that further activates S1HL microglia via the CCL2-CCR2 signaling pathway. Increased engulfment of GABAergic presynapses by activated microglia stimulates S1HLGlu neuronal activity, ultimately leading to secondary mechanical hypersensitivity of hindpaws. It is widely believed direct neuronal projection drives interactions between distinct brain regions to prime specific behaviors. Our study reveals microglial interactions spanning different subregions of the somatosensory cortex to drive a maladaptive neuronal response underlying secondary mechanical hypersensitivity at non-injured sites.

10.
Adv Sci (Weinh) ; : e2308235, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38353384

RESUMO

Personalized cancer vaccines based on resected tumors from patients is promising to address tumor heterogeneity to inhibit tumor recurrence or metastasis. However, it remains challenge to elicit immune activation due to the weak immunogenicity of autologous tumor antigens. Here, a hybrid membrane cancer vaccine is successfully constructed by membrane fusion to enhance adaptive immune response and amplify personalized immunotherapy, which formed a codelivery system for autologous tumor antigens and immune adjuvants. Briefly, the functional hybrid vesicles (HM-NPs) are formed by hybridizing ginseng-derived extracellular vesicles-like particles (G-EVLPs) with the membrane originated from the resected autologous tumors. The introduction of G-EVLPs can enhance the phagocytosis of autologous tumor antigens by dendritic cells (DCs) and facilitate DCs maturation through TLR4, ultimately activating tumor-specific cytotoxic T lymphocytes (CTLs). HM-NPs can indeed strengthen specific immune responses to suppress tumors recurrence and metastasis including subcutaneous tumors and orthotopic tumors. Furthermore, a long-term immune protection can be obtained after vaccinating with HM-NPs, and prolonging the survival of animals. Overall, this personalized hybrid autologous tumor vaccine based on G-EVLPs provides the possibility of mitigating tumor recurrence and metastasis after surgery while maintaining good biocompatibility.

11.
Org Lett ; 26(6): 1224-1228, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38305744

RESUMO

The semipinacol rearrangement is a powerful and versatile method for constructing all-carbon quaternary stereocenters. The development of catalytic asymmetric semipinacol rearrangements using multifunctionalizable electrophiles remains highly sought-after in organic synthesis. In this study, a catalytic enantioselective allylic cation-induced semipinacol rearrangement reaction was presented that enables the simultaneous construction of two skipped chiral carbon centers. Chiral Ir(I)-(P,olefin) and Sc(OTf)3 catalysts cooperatively initiate the asymmetric allylic alkylation of alkenyl cyclobutanols with allylic alcohols, triggering ring expansion of the cyclobutanol moiety through a stereoselective 1,2-alkyl migration. The reaction afforded a range of cyclopentanones bearing an α-quaternary carbon that is adjacent to a chiral allyl scaffold. The products were applied to synthesize enantioenriched fused tricyclopentanoids bearing four stereogenic carbon centers.

12.
Int J Biol Macromol ; : 130307, 2024 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-38382784

RESUMO

N-acylethanolamine acid amidase (NAAA) is a nucleophilic lysosomal cysteine hydrolase, which primarily mediates the hydrolytic inactivation of endogenous palmitoylethanolamide (PEA), which further influences the inflammatory process by regulating peroxisome proliferator-activated receptor-α (PPARα). Herein, a novel lysosome (Lyso)-targeting fluorescent probe (i.e., PMBD) was designed and synthesized for detecting endogenous NAAA selectively and sensitively, allowing real-time visual monitoring of endogenous NAAA in living cells. Moreover, PMBD can target Lyso with a high colocalization in Lyso Tracker. Finally, a high-throughput assay method for NAAA inhibitor screening was established using PMBD, and the NAAA-inhibitory effects of 42 anti-inflammatory Traditional Chinese medicines were evaluated. A novel potent inhibitor of NAAA, ellagic acid, was isolated from Cornus officinalis, which can suppress LPS-induced iNOS upregulation and NO production in RAW264.7 cells that display anti-inflammatory activities. PMBD, a novel Lyso-targeting fluorescent probe for visually imaging NAAA, could serve as a useful molecular tool for exploring the physiological functions of NAAA and drug development based on NAAA-related diseases.

13.
Med Phys ; 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38386904

RESUMO

BACKGROUND: Time-resolved magnetic resonance fingerprinting (MRF), or 4D-MRF, has been demonstrated its feasibility in motion management in radiotherapy (RT). However, the prohibitive long acquisition time is one of challenges of the clinical implementation of 4D-MRF. The shortening of acquisition time causes data insufficiency in each respiratory phase, leading to poor accuracies and consistencies of the predicted tissues' properties of each phase. PURPOSE: To develop a technique for the reconstruction of multi-phase parametric maps in four-dimensional magnetic resonance fingerprinting (4D-MRF) through the optimization of local T1 and T2 sensitivities. METHODS: The proposed technique employed an iterative optimization to tailor the data arrangement of each phase by manipulation of inter-phase frames, such that the T1 and T2 sensitivities, which were quantified by the modified Minkowski distance, of the truncated signal evolution curve was maximized. The multi-phase signal evolution curves were modified by sliding window reconstruction and inter-phase frame sharing (SWIFS). Motion correction (MC) and dot product matching were sequentially performed on the modified signal evolution and dictionary to reconstruct the multi-parametric maps. The proposed technique was evaluated by numerical simulations using the extended cardiac-torso (XCAT) phantom with regular and irregular breathing patterns, and by in vivo MRF data of three health volunteers and six liver cancer patients acquired at a 3.0 T scanner. RESULTS: In simulation study, the proposed SWIFS approach achieved the overall mean absolute percentage error (MAPE) of 8.62% ± 1.59% and 16.2% ± 3.88% for the eight-phases T1 and T2 maps, respectively, in the sagittal view with irregular breathing patterns. In contrast, the overall MAPE of T1 and T2 maps generated by the conventional approach with multiple MRF repetitions were 22.1% ± 11.0% and 30.8% ± 14.9%, respectively. For in-vivo study, the predicted mean T1 and T2 of liver by the proposed SWIFS approach were 795 ms ± 38.9 ms and 58.3 ms ± 11.7 ms, respectively. CONCLUSIONS: Both simulation and in vivo results showed that the approach empowered by T1 and T2 sensitivities optimization and sliding window under the shortened acquisition of MRF had superior performance in the estimation of multi-phase T1 and T2 maps as compared to the conventional approach with oversampling of MRF data.

14.
Eur Spine J ; 2024 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-38190004

RESUMO

OBJECTIVE: To develop a deep neural network for the detection of inflammatory spine in short tau inversion recovery (STIR) sequence of magnetic resonance imaging (MRI) on patients with axial spondyloarthritis (axSpA). METHODS: A total 330 patients with axSpA were recruited. STIR MRI of the whole spine and clinical data were obtained. Regions of interests (ROIs) were drawn outlining the active inflammatory lesion consisting of bone marrow edema (BME). Spinal inflammation was defined by the presence of an active inflammatory lesion on the STIR sequence. The 'fake-color' images were constructed. Images from 270 and 60 patients were randomly separated into the training/validation and testing sets, respectively. Deep neural network was developed using attention UNet. The neural network performance was compared to the image interpretation by a radiologist blinded to the ground truth. RESULTS: Active inflammatory lesions were identified in 2891 MR images and were absent in 14,590 MR images. The sensitivity and specificity of the derived deep neural network were 0.80 ± 0.03 and 0.88 ± 0.02, respectively. The Dice coefficient of the true positive lesions was 0.55 ± 0.02. The area under the curve of the receiver operating characteristic (AUC-ROC) curve of the deep neural network was 0.87 ± 0.02. The performance of the developed deep neural network was comparable to the interpretation of a radiologist with similar sensitivity and specificity. CONCLUSION: The developed deep neural network showed similar sensitivity and specificity to a radiologist with four years of experience. The results indicated that the network can provide a reliable and straightforward way of interpreting spinal MRI. The use of this deep neural network has the potential to expand the use of spinal MRI in managing axSpA.

15.
Materials (Basel) ; 17(2)2024 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-38255519

RESUMO

This study aims to enhance the productivity of high-voltage transmission line insulators and their operational safety by investigating their failure mechanisms under ultimate load conditions. Destructive tests were conducted on a specific type of insulator under ultimate load conditions. A high-speed camera was used to document the insulator's failure process and collect strain data from designated points. A simulation model of the insulator was established to predict the effects of ultimate loads. The simulation results identified a maximum first principal stress of 94.549 MPa in the porcelain shell, with stress distribution characteristics resembling a cantilever beam subjected to bending. This implied that the insulator failure occurred when the stress reached the bending strength of the porcelain shell. To validate the simulation's accuracy, bending and tensile strength tests were conducted on the ceramic materials constituting the insulator. The bending strength of the porcelain shell was 100.52 MPa, showing a 5.6% variation from the simulation results, which indicated the reliability of the simulation model. Finally, optimization designs on the design parameters P1 and P2 of the insulator were conducted. The results indicated that setting P1 to 8° and P2 to 90.062 mm decreased the first principal stress of the porcelain shell by 47.6% and Von Mises stress by 31.6% under ultimate load conditions, significantly enhancing the load-bearing capacity. This research contributed to improving the production yield and safety performance of insulators.

16.
Comput Methods Programs Biomed ; 245: 108032, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38244339

RESUMO

BACKGROUND AND OBJECTIVE: Multi-label Chest X-ray (CXR) images often contain rich label relationship information, which is beneficial to improve classification performance. However, because of the intricate relationships among labels, most existing works fail to effectively learn and make full use of the label correlations, resulting in limited classification performance. In this study, we propose a multi-label learning framework that learns and leverages the label correlations to improve multi-label CXR image classification. METHODS: In this paper, we capture the global label correlations through the self-attention mechanism. Meanwhile, to better utilize label correlations for guiding feature learning, we decompose the image-level features into label-level features. Furthermore, we enhance label-level feature learning in an end-to-end manner by a consistency constraint between global and local label correlations, and a label correlation guided multi-label supervised contrastive loss. RESULTS: To demonstrate the superior performance of our proposed approach, we conduct three times 5-fold cross-validation experiments on the CheXpert dataset. Our approach obtains an average F1 score of 44.6% and an AUC of 76.5%, achieving a 7.7% and 1.3% improvement compared to the state-of-the-art results. CONCLUSION: More accurate label correlations and full utilization of the learned label correlations help learn more discriminative label-level features. Experimental results demonstrate that our approach achieves exceptionally competitive performance compared to the state-of-the-art algorithms.


Assuntos
Aprendizagem , Tórax , Tórax/diagnóstico por imagem , Algoritmos , Projetos de Pesquisa
17.
Nat Commun ; 15(1): 679, 2024 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-38263179

RESUMO

Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and analgesic effects. Here, we present a scalable asymmetric syntheses of Tetrodotoxin and 9-epiTetrodotoxin from the abundant chemical feedstock furfuryl alcohol. The optically pure cyclohexane skeleton is assembled via a stereoselective Diels-Alder reaction. The dense heteroatom substituents are established sequentially by a series of functional group interconversions on highly oxygenated cyclohexane frameworks, including a chemoselective cyclic anhydride opening, and a decarboxylative hydroxylation. An innovative SmI2-mediated concurrent fragmentation, an oxo-bridge ring opening and ester reduction followed by an Upjohn dihydroxylation deliver the highly oxidized skeleton. Ruthenium-catalyzed oxidative alkyne cleavage and formation of the hemiaminal and orthoester under acidic conditions enable the rapid assembly of Tetrodotoxin, anhydro-Tetrodotoxin, 9-epiTetrodotoxin, and 9-epi lactone-Tetrodotoxin.


Assuntos
Cicloexanos , Estresse Oxidativo , Tetrodotoxina , Hidroxilação , Compostos Radiofarmacêuticos
18.
Natl Sci Rev ; 11(1): nwad256, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38288368

RESUMO

Nausea and vomiting are important defensive responses to cope with pathogens and toxins that invade the body. The nucleus of the solitary tract (NTS) is important for initiating these responses. However, the molecular heterogeneities and cellular diversities of the NTS occlude a better understanding of these defensive responses. Here, we constructed the single-nucleus transcriptomic atlas of NTS cells and found multiple populations of NTS neurons that may be involved in these defensive responses. Among these, we identified Calbindin1-positive (Calb1+) NTS neurons that are molecularly distinct from Tac1+ neurons. These Calb1+ neurons are critical for nausea and retching induced by cereulide; an emetic toxin secreted by Bacillus Cereus. Strikingly, we found that cereulide can directly modulate vagal sensory neurons that innervate Calb1+ NTS neurons, a novel mechanism distinct from that for nausea and retching induced by Staphylococcal enterotoxin A. Together, our transcriptomic atlas of NTS neurons and the functional analyses revealed the neural mechanism for cereulide-induced retching-like behavior. These results demonstrate the molecular and cellular complexities in the brain that underlie defensive responses to the diversities of pathogens and toxins.

19.
Magn Reson Med ; 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38291598

RESUMO

PURPOSE: Recent work has shown MRI is able to measure and quantify signals of phospholipid membrane-bound protons associated with myelin in the human brain. This work seeks to develop an improved technique for characterizing this brain ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ component in vivo accounting for T 1 $$ {\mathrm{T}}_1 $$ weighting. METHODS: Data from ultrashort echo time scans from 16 healthy volunteers with variable flip angles (VFA) were collected and fitted into an advanced regression model to quantify signal fraction, relaxation time, and frequency shift of the ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ component. RESULTS: The fitted components show intra-subject differences of different white matter structures and significantly elevated ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ signal fraction in the corticospinal tracts measured at 0.09 versus 0.06 in other white matter structures and significantly elevated ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ frequency shift in the body of the corpus callosum at - $$ - $$ 1.5 versus - $$ - $$ 2.0 ppm in other white matter structures. CONCLUSION: The significantly different measured components and measured T 1 $$ {\mathrm{T}}_1 $$ relaxation time of the ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ component suggest that this method is picking up novel signals from phospholipid membrane-bound protons.

20.
Sensors (Basel) ; 24(2)2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38276332

RESUMO

Since the avalanche phenomenon was first found in bulk materials, avalanche photodiodes (APDs) have been exclusively investigated. Among the many devices that have been developed, silicon APDs stand out because of their low cost, performance stability, and compatibility with CMOS. However, the increasing industrial needs pose challenges for the fabrication cycle time and fabrication cost. In this work, we proposed an improved fabrication process for ultra-deep mesa-structured silicon APDs for photodetection in the visible and near-infrared wavelengths with improved performance and reduced costs. The improved process reduced the complexity through significantly reduced photolithography steps, e.g., half of the steps of the existing process. Additionally, single ion implantation was performed under low energy (lower than 30 keV) to further reduce the fabrication costs. Based on the improved ultra-concise process, a deep-mesa silicon APD with a 140 V breakdown voltage was obtained. The device exhibited a low capacitance of 500 fF, the measured rise time was 2.7 ns, and the reverse bias voltage was 55 V. Moreover, a high responsivity of 103 A/W@870 nm at 120 V was achieved, as well as a low dark current of 1 nA at punch-through voltage and a maximum gain exceeding 1000.

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