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1.
J Pharm Anal ; 14(3): 389-400, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38618248

RESUMO

Antibody-drug conjugates (ADCs) are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells, thereby attracting considerable attention in precise oncology therapy. Cetuximab (Cet) is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma (cSCC); however, its anti-tumor activity is limited to a single use. Cisplatin (CisPt) shows good curative effects; however, its adverse effects and non-tumor-targeting ability are major drawbacks. In this study, we designed and developed a new ADC based on a new cytotoxic platinum (IV) prodrug (C8Pt(IV)) and Cet. The so-called antibody-platinum (IV) prodrugs conjugates, named Cet-C8Pt(IV), showed excellent tumor targeting in cSCC. Specifically, it accurately delivered C8Pt(IV) into tumor cells to exert the combined anti-tumor effect of Cet and CisPt. Herein, metabolomic analysis showed that Cet-C8Pt(IV) promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells, thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum (IV) prodrugs conjugates.

2.
Glob Med Genet ; 11(2): 150-158, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38628662

RESUMO

Background NFE2L2 (nuclear factor erythroid-2-related factor-2) encodes a basic leucine zipper (bZIP) transcription factor and exhibits variations in various tumor types, including lung cancer. In this study, we comprehensively investigated the impact of simultaneous mutations on the survival of NFE2L2 -mutant lung cancer patients within specific subgroups. Methods A cohort of 1,103 lung cancer patients was analyzed using hybridization capture-based next-generation sequencing. Results The NFE2L2 gene had alterations in 3.0% (33/1,103) of lung cancer samples, including 1.5% (15/992) in adenocarcinoma and 16.2% (18/111) in squamous cell carcinoma. Thirty-four variations were found, mainly in exons 2 (27/34). New variations in exon 2 (p.D21H, p.V36_E45del, p.F37_E45del, p.R42P, p.E67Q, and p.L76_E78delinsQ) were identified. Some patients had copy number amplifications. Co-occurrence with TP53 (84.8%), CDKN2A (33.3%), KMT2B (33.3%), LRP1B (33.3%), and PIK3CA (27.3%) mutations was common. Variations of NFE2L2 displayed the tightest co-occurrence with IRF2 , TERC , ATR , ZMAT3 , and SOX2 ( p < 0.001). In The Cancer Genome Atlas Pulmonary Squamous Carcinoma project, patients with NFE2L2 variations and 3q26 amplification had longer median survival (63.59 vs. 32.04 months, p = 0.0459) and better overall survival. Conclusions NFE2L2 mutations display notable heterogeneity in lung cancer. The coexistence of NFE2L2 mutations and 3q26 amplification warrants in-depth exploration of their potential clinical implications and treatment approaches for affected patients.

3.
J Am Chem Soc ; 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38605649

RESUMO

Chemigenetic fusion of synthetic dyes with genetically encoded protein tags presents a promising avenue for in vivo imaging. However, its full potential has been hindered by the lack of bright and fluorogenic dyes operating in the "tissue transparency" near-infrared window (NIR, 700-1700 nm). Here, we report 2X-rhodamine (2XR), a novel bright scaffold that allows for the development of live-cell-compatible, NIR-excited variants with strong fluorogenicity beyond 1000 nm. 2XR utilizes a rigidified π-skeleton featuring dual atomic bridges and functions via a spiro-based fluorogenic mechanism. This design affords longer wavelengths, higher quantum yield (ΦF = 0.11), and enhanced fluorogenicity in water when compared to the phosphine oxide-cored, or sulfone-cored rhodamine, the NIR fluorogenic benchmarks currently used. We showcase their bright performance in video-rate dynamic imaging and targeted deep-tissue molecular imaging in vivo. Notably, we develop a 2XR variant, 2XR715-HTL, an NIR fluorogenic ligand for the HaloTag protein, enabling NIR genetically encoded calcium sensing and the first demonstration of in vivo chemigenetic labeling beyond 1000 nm. Our work expands the library of NIR fluorogenic tools, paving the way for in vivo imaging and sensing with the chemigenetic approach.

4.
Med Image Anal ; 95: 103165, 2024 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-38608510

RESUMO

Diffusion magnetic resonance imaging (dMRI) tractography is a critical technique to map the brain's structural connectivity. Accurate segmentation of white matter, particularly the superficial white matter (SWM), is essential for neuroscience and clinical research. However, it is challenging to segment SWM due to the short adjacent gyri connection in a U-shaped pattern. In this work, we propose an Anatomically-guided Superficial Fiber Segmentation (Anat-SFSeg) framework to improve the performance on SWM segmentation. The framework consists of a unique fiber anatomical descriptor (named FiberAnatMap) and a deep learning network based on point-cloud data. The spatial coordinates of fibers represented as point clouds, as well as the anatomical features at both the individual and group levels, are fed into a neural network. The network is trained on Human Connectome Project (HCP) datasets and tested on the subjects with a range of cognitive impairment levels. One new metric named fiber anatomical region proportion (FARP), quantifies the ratio of fibers in the defined brain regions and enables the comparison with other methods. Another metric named anatomical region fiber count (ARFC), represents the average fiber number in each cluster for the assessment of inter-subject differences. The experimental results demonstrate that Anat-SFSeg achieves the highest accuracy on HCP datasets and exhibits great generalization on clinical datasets. Diffusion tensor metrics and ARFC show disorder severity associated alterations in patients with Alzheimer's disease (AD) and mild cognitive impairments (MCI). Correlations with cognitive grades show that these metrics are potential neuroimaging biomarkers for AD. Furthermore, Anat-SFSeg could be utilized to explore other neurodegenerative, neurodevelopmental or psychiatric disorders.

5.
Acta Pharmacol Sin ; 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38609561

RESUMO

Proteolysis targeting chimeras (PROTACs) have emerged as revolutionary anticancer therapeutics that degrade disease-causing proteins. However, the anticancer performance of PROTACs is often impaired by their insufficient bioavailability, unsatisfactory tumor specificity and ability to induce acquired drug resistance. Herein, we propose a polymer-conjugated PROTAC prodrug platform for the tumor-targeted delivery of the most prevalent von Hippel-Lindau (VHL)- and cereblon (CRBN)-based PROTACs, as well as for the precise codelivery of a degrader and conventional small-molecule drugs. The self-assembling PROTAC prodrug nanoparticles (NPs) can specifically target and be activated inside tumor cells to release the free PROTAC for precise protein degradation. The PROTAC prodrug NPs caused more efficient regression of MDA-MB-231 breast tumors in a mouse model by degrading bromodomain-containing protein 4 (BRD4) or cyclin-dependent kinase 9 (CDK9) with decreased systemic toxicity. In addition, we demonstrated that the PROTAC prodrug NPs can serve as a versatile platform for the codelivery of a PROTAC and chemotherapeutics for enhanced anticancer efficiency and combination benefits. This study paves the way for utilizing tumor-targeted protein degradation for precise anticancer therapy and the effective combination treatment of complex diseases.

6.
Int J Mol Sci ; 25(7)2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38612586

RESUMO

BAHD acyltransferases are involved in catalyzing and regulating the secondary metabolism in plants. Despite this, the members of BAHD family and their functions have not been reported in the Taxus species. In this study, a total of 123 TwBAHD acyltransferases from Taxus wallichiana var. mairei genome were identified and divided into six clades based on phylogenetic analysis, of which Clade VI contained a Taxus-specific branch of 52 members potentially involved in taxol biosynthesis. Most TwBAHDs from the same clade shared similar conserved motifs and gene structures. Besides the typical conserved motifs within the BAHD family, the YPLAGR motif was also conserved in multiple clades of T. mairei. Moreover, only one pair of tandem duplicate genes was found on chromosome 1, with a Ka/Ks ratio < 1, indicating that the function of duplicate genes did not differentiate significantly. RNA-seq analysis revealed different expression patterns of TwBAHDs in MeJA induction and tissue-specific expression experiments. Several TwBAHD genes in the Taxus-specific branch were highly expressed in different tissues of T. mairei, suggesting an important role in the taxol pathway. This study provides comprehensive information for the TwBAHD gene family and sets up a basis for its potential functions.


Assuntos
Taxus , Humanos , Filogenia , Taxus/genética , Aciltransferases , Cromossomos Humanos Par 1 , Paclitaxel
7.
Nutrients ; 16(7)2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38613006

RESUMO

BACKGROUND: Water intake and hydration status may potentially influence maternal and child health. However, there is little research regarding this topic. OBJECTIVES: This study aimed to investigate pregnant women's total fluid intake (TFI) levels, hydration status, and body composition and further explore their relationship with infant birth weight. METHODS: A 7-day, 24 h fluid intake recorded was applied to determine participants' TFI levels. Morning urine samples were collected and tested to evaluate their hydration status. Maternal body compositions in their third trimester and infant birth weights were measured. RESULTS: A total of 380 participants completed the study. The TFI was insufficient for pregnant women during their third trimester (median = 1574 mL), with only 12.1% of participants meeting the recommended adequate fluid intake level for pregnant women living in China (1.7 L per day). With the increasing TFI values, the urine osmolality decreased, which showed statistical significance among the four groups (χ2 = 22.637, p < 0.05). The participants displayed a poor hydration status. Meanwhile, the percentage of participants who were in dehydrated status decreased (χ2 = 67.618, p < 0.05), while body water content and basal metabolic rate increased with the increase in TFI levels (χ2 = 20.784, p < 0.05; χ2 = 14.026, p < 0.05). There were positive linear relationships between plain water intake, the basal metabolic rate of pregnant women and their infant birth weight (SE = 0.153, p < 0.05; SE = 0.076, p < 0.05). CONCLUSIONS: Water intake was insufficient, and poor hydration status was common among pregnant women in China. There may be potential relationships between plain water intake, basal metabolic rate, and infant birth weight.


Assuntos
Ingestão de Líquidos , Gestantes , Gravidez , Criança , Lactente , Humanos , Feminino , Peso ao Nascer , Terceiro Trimestre da Gravidez , Estudos Prospectivos , Composição Corporal , China
8.
Mol Phylogenet Evol ; : 108072, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38615706

RESUMO

While the diversity of species formation is broadly acknowledged, significant debate exists regarding the universal nature of hybrid species formation. Through an 18-year comprehensive study of all Populus species on the Qinghai-Tibet Plateau, 23 previously recorded species and 8 new species were identified. Based on morphological characteristics, these can be classified into three groups: species in section Leucoides, species with large leaves, and species with small leaves in section Tacamahaca. By conducting whole-genome re-sequencing of 150 genotypes from these 31 species, 2.28 million single nucleotide polymorphisms (SNPs) were identified. Phylogenetic analysis utilizing these SNPs not only revealed a highly intricate evolutionary network within the large-leaf species of section Tacamahaca but also confirmed that a new species, P. curviserrata, naturally hybridized with P. cathayana, P. szechuanica, and P. ciliata, resulting in 11 hybrid species. These findings indicate the widespread occurrence of hybrid species formation within this genus, with hybridization serving as a key evolutionary mechanism for Populus on the plateau. A novel hypothesis, "Hybrid Species Exterminating Their Ancestral Species (HSEAS)," is introduced to explain the mechanisms of hybrid species formation at three different scales: the entire plateau, the southeastern mountain region, and individual river valleys.

9.
Chem Commun (Camb) ; 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38629394

RESUMO

A calix[3]carbazole-based cavitand was conveniently synthesized. It was found that the cavitand with adjustable conformation could show excellent complexation with fullerenes C60 and C70 in both solution and the solid state. Moreover, the crystal structures of the host-guest complexes show that the cavitand can stack into channel-like architectures, in which fullerenes are orderly arranged inside.

10.
Cancer Metab ; 12(1): 12, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38610045

RESUMO

INTRODUCTION: Metformin and statins are considered as potential agents for prevention of breast cancer, however, existing evidence does not uniformly substantiate this claim, and the data is scarce concerning their interaction in relation to breast cancer risk. This study aims to investigate whether the effect of metformin on breast cancer incidence varied by statin use among women with type 2 diabetes mellitus (T2DM). METHODS: This study included women with T2DM, without a history of cancers, and followed up for more than one year from the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) for the period 1998-2014. The dataset was structured using a person-time approach, where the cumulative medication usage was annually updated for each person. The extended Cox proportional hazards models were employed, reporting adjusted hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: During a median follow-up of 5 years, 515 of 29,498 women received a breast cancer diagnosis. Each additional year of metformin or statins use corresponded to a decrease in breast cancer incidence, while the magnitude attenuated over time. Noteworthily, statin use modified the effect of metformin on breast cancer incidence. For instance, after 5 years of follow-up, one-year increase of metformin use among women who used statins for 3 years was linked to a substantially reduced breast cancer risk (HR, 95% CI: 0.88, 0.84-0.93), however, there was no significant decrease in risk for those non-statins users (HR, 95% CI: 0.96, 0.89-1.04). CONCLUSIONS: Extending metformin or statin usage by one year conferred breast cancer protection in women with T2DM. Enhanced protective effect of metformin was observed among those who also use statins. These results suggest the potential of combined metformin and statin therapy as promising breast cancer prevention strategies.

11.
Comput Biol Med ; 173: 108375, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38569232

RESUMO

Atrial fibrillation (AF) is a common cardiac arrhythmia, with stroke being its most detrimental comorbidity. The exact mechanism of AF related stroke (AFS) still needs to be explored. In this study, we integrated proteomics and metabolomics platform to explore disordered plasma proteins and metabolites between AF patients and AFS patients. There were 22 up-regulated and 31 down-regulated differentially expressed proteins (DEPs) in AFS plasma samples. Moreover, 63 up-regulated and 51 down-regulated differentially expressed metabolites (DEMs) were discovered in AFS plasma samples. We integrated proteomics and metabolomics based on the topological interactions of DEPs and DEMs, which yielded revealed several related pathways such as arachidonic acid metabolism, serotonergic synapse, purine metabolism, tyrosine metabolism and steroid hormone biosynthesis. We then performed a machine learning model to identify potential biomarkers of stroke in AF. Finally, we selected 6 proteins and 6 metabolites as candidate biomarkers for predicting stroke in AF by random forest, the area under the curve being 0.976. In conclusion, this study provides new perspectives for understanding the progressive mechanisms of AF related stroke and discovering innovative biomarkers for determining the prognosis of stroke in AF.


Assuntos
Fibrilação Atrial , Acidente Vascular Cerebral , Humanos , Proteômica , Biomarcadores , Aprendizado de Máquina
12.
Medicine (Baltimore) ; 103(15): e37722, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38608101

RESUMO

RATIONALE: Due to the lack of specificity symptoms and site of onset of castleman disease (CD), it is difficult to diagnose and poses unique challenges for both patients and clinicians, leading to confusion in diagnosis and delays in treatment. To enhance understanding, we present 3 cases of CD treated at our hospital, including a single-center, multicenter, and mixed-type CD. PATIENT CONCERNS: Case 1: A 53-year-old female patient was admitted with a chief complaint of "abdominal pain and fever for 10 days." Marked enlargement of inguinal lymph nodes on both sides was observed. Case 2: A 58-year-old female patient was admitted with the main complaint of "discovering a left lower abdominal mass during a routine checkup for the past 10 days." Upon deep palpation, a palpable mass of approximately 5.0 * 3.0 cm was identified in the left lower abdomen. Case 3: A 40-year-old male patient was admitted with the main complaint of "progressive right upper abdominal and lumbar back pain for over 6 months." Computed tomography examination revealed multiple nodular soft tissue masses between the abdominal aorta and inferior vena cava, with the largest measuring 5.0 * 4.0 cm. DIAGNOSES: Based on the immunohistochemical results, the diagnoses for the 3 patients are as follows: Case 1: Multicentric Castleman's Disease (Mixed Type). Case 2: Pelvic Retroperitoneal Castleman Disease (Hyaline Vascular Type). Case 3: Castleman Disease Multicentric Type. INTERVENTION: Case 1: cyclophosphamide 0.6-1 g + vincristine 2 mg + methylprednisolone 50 mg/5 days. Cyclophosphamide 1 g + prednisone 30-50 mg/5 days. This alternating chemotherapy cycle is repeated every 6 months. Case 2: Laparoscopic pelvic mass excision surgery. Case 3: Surgical excision of the mass. OUTCOMES: Case 1: After a 43-month follow-up, the patient's general symptoms have improved compared to before, but regular chemotherapy is still necessary at present. Case 2: The patient did not take any medication postoperatively, and there has been no evidence of metastasis or recurrence during the 18-month follow-up. Case 3: The patient did not take any medication, and there has been no evidence of metastasis or recurrence during the 21-month follow-up. LESSONS SUBSECTIONS: The lack of specific signs on imaging studies and nonspecific blood tests increases the difficulty of diagnosis. However, tissue biopsy remains a feasible option. Therefore, we recommend conducting thorough examinations for suspected CD patients to reduce misdiagnosis and determine the CD type for effective targeted treatment.


Assuntos
Hiperplasia do Linfonodo Gigante , Feminino , Masculino , Humanos , Pessoa de Meia-Idade , Adulto , Hiperplasia do Linfonodo Gigante/diagnóstico , Dor Abdominal/etiologia , Aorta Abdominal , Biópsia , Ciclofosfamida , Estudos Multicêntricos como Assunto
13.
Bioresour Technol ; 400: 130690, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38614150

RESUMO

Microbial enhanced oil recovery (EOR) has become the focus of oilfield research due to its low cost, environmental friendliness and sustainability. The degradation and EOR capacity of A. borkumensis through the production of bio-enzyme and bio-surfactant were first investigated in this study. The total protein concentration, acetylcholinesterase, esterase, lipase, alkane hydroxylase activity, surface tension, and emulsification index (EI) were determined at different culture times. The bio-surfactant was identified as glycolipid compound, and the yield was 2.6 ± 0.2 g/L. The nC12 and nC13 of crude oil were completely degraded, and more than 40.0 % of nC14-nC24 was degraded by by A. borkumensis. The results of the microscopic etching model displacement and core flooding experiments showed that emulsification was the main mechanism of EOR. A. borkumensis enhanced the recovery rate by 20.2 %. This study offers novel insights for the development of environmentally friendly and efficient oil fields.

14.
Zhongguo Zhong Yao Za Zhi ; 49(4): 1073-1081, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38621914

RESUMO

The present study aimed to investigate the effect and mechanism of Bupleuri Radix-Paeoniae Radix Alba medicated plasma on HepG2 hepatoma cells by regulating the microRNA-1297(miR-1297)/phosphatase and tensin homologue deleted on chromosome 10(PTEN) signaling axis. Real-time quantitative PCR(RT-qPCR) was carried out to determine the mRNA levels of miR-1297 and PTEN in different hepatoma cell lines. The dual luciferase reporter assay was employed to verify the targeted interaction between miR-1297 and PTEN. The cell counting kit-8(CCK-8) was used to detect cell proliferation, and the optimal concentration and intervention time of the medicated plasma were determined. The cell invasion and migration were examined by Transwell assay and wound healing assay. Cell cycle distribution was detected by PI staining, and the apoptosis of cells was detected by Annexin V-FITC/PI double staining. The mRNA levels of miR-1297, PTEN, protein kinase B(Akt), and phosphatidylinositol 3-kinase(PI3K) were determined by RT-qPCR. Western blot was employed to determine the protein levels of PTEN, Akt, p-Akt, caspase-3, caspase-9, B-cell lymphoma-2(Bcl-2), and Bcl-2-associated X protein(Bax). The results showed that HepG2 cells were the best cell line for subsequent experiments. The dual luciferase reporter assay confirmed that miR-1297 could bind to the 3'-untranslated region(3'UTR) in the mRNA of PTEN. The medicated plasma inhibited the proliferation of HepG2 cells, and the optimal intervention concentration and time were 20% and 72 h. Compared with the blank plasma, the Bupleuri Radix-Paeoniae Radix Alba medicated plasma, miR-1297 inhibitor, miR-1297 inhibitor + medicated plasma all inhibited the proliferation, invasion, and migration of HepG2 cells, increased the proportion of cells in the G_0/G_1 phase, decreased the proportion of cells in the S phase, and increased the apoptosis rate. The medicated plasma down-regulated the mRNA levels of miR-1297, PI3K, and Akt and up-regulated the mRNA level of PTEN. In addition, it up-regulated the protein levels of PTEN, Bax, caspase-3, and caspsae-9 and down-regulated the protein levels of p-Akt, p-PI3K, and Bcl-2. In conclusion, Bupleuri Radix-Paeoniae Radix Alba medicated plasma can inhibit the expression of miR-1297 in HepG2 hepatoma cells, promote the expression of PTEN, and negatively regulate PI3K/Akt signaling pathway, thereby inhibiting the proliferation and inducing the apoptosis of HepG2 cells.


Assuntos
Carcinoma Hepatocelular , Medicamentos de Ervas Chinesas , Neoplasias Hepáticas , MicroRNAs , Paeonia , Extratos Vegetais , Humanos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Células Hep G2 , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Caspase 3/metabolismo , Proteína X Associada a bcl-2 , MicroRNAs/genética , MicroRNAs/metabolismo , Transdução de Sinais , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/genética , Apoptose , Proliferação de Células , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , RNA Mensageiro , Luciferases/metabolismo , Luciferases/farmacologia , Linhagem Celular Tumoral
15.
ACS Appl Mater Interfaces ; 16(15): 19442-19452, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38563482

RESUMO

Porous polymers have many industrial applications, but their pore structures (open or closed) are usually fixed during polymerization. In this study, polymers with reversible and controllable pore structures, namely, thermosensitive porous hydrogels with regulated volume phase transition temperature, were prepared using a Pickering high-internal-phase emulsion as the template. Upon heating, the hydrogels transformed not only in their wettability (between hydrophilicity and hydrophobicity with water contact angles of 21.8 and 100.9°) but also their pore structure (between open through-holes and closed holes with pore throat sizes of 15.58 and 0 µm, respectively) in a short time (<10 s). When the hydrogel was used as a separator in smart supercapacitors (SCs), this behavior effectively limited the path of electrolyte migration, reducing the chance of conflagration accidents. Moreover, by utilizing the highly reversible pore structures and wettability of the porous hydrogel, reversible charging and discharging were restored after the system cooled down. This work not only provides great guidance for preparing porous polymers with reversible pore structures but also paves the way for designing smart SCs with enhanced safety.

16.
Cell Res ; 2024 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-38575718

RESUMO

CRISPR-Cas systems and IS200/IS605 transposon-associated TnpBs have been utilized for the development of genome editing technologies. Using bioinformatics analysis and biochemical experiments, here we present a new family of RNA-guided DNA endonucleases. Our bioinformatics analysis initially identifies the stable co-occurrence of conserved RAGATH-18-derived RNAs (reRNAs) and their upstream IS607 TnpBs with an average length of 390 amino acids. IS607 TnpBs form programmable DNases through interaction with reRNAs. We discover the robust dsDNA interference activity of IS607 TnpB systems in bacteria and human cells. Further characterization of the Firmicutes bacteria IS607 TnpB system (ISFba1 TnpB) reveals that its dsDNA cleavage activity is remarkably sensitive to single mismatches between the guide and target sequences in human cells. Our findings demonstrate that a length of 20 nt in the guide sequence of reRNA achieves the highest DNA cleavage activity for ISFba1 TnpB. A cryo-EM structure of the ISFba1 TnpB effector protein bound by its cognate RAGATH-18 motif-containing reRNA and a dsDNA target reveals the mechanisms underlying reRNA recognition by ISFba1 TnpB, reRNA-guided dsDNA targeting, and the sensitivity of the ISFba1 TnpB system to base mismatches between the guide and target DNA. Collectively, this study identifies the IS607 TnpB family of compact and specific RNA-guided DNases with great potential for application in gene editing.

17.
J Ultrasound Med ; 2024 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-38577871

RESUMO

OBJECTIVES: This study aims to identify distinct ultrasound (US) characteristics for distinguishing follicular thyroid carcinoma (FTC) from follicular thyroid adenoma (FTA), and construct a user-friendly preoperative risk stratification model for thyroid follicular neoplasms. METHODS: In this retrospective study, patients diagnosed with pathologically confirmed FTA or FTC and undergoing US examinations between July 2017 and June 2021 were designated as the training cohort, and those from July 2021 to June 2023 were enrolled as the external validation set. We systematically assessed and compared the sonographic and clinical characteristics of FTC and FTA. Univariable and multivariable logistic regression analyses were used to assess the association of US features with FTC in the training set. A prediction nomogram model, incorporating US features independently associated with FTC, was developed and validated externally to assess its performance. RESULTS: A total of 645 patients (FTA/FTC = 530/115) were included in the training set, while 197 patients (FTA/FTC = 165/32) constituted the validation set. In the training set, solid composition, hypo-echogenicity, irregular margin, calcification, protrusion sign, trabecular formation, absent or thick halo, and mainly central hypervascularity were identified as independent factors associated with FTC. The prediction nomogram model constructed using these variables showed good performance in differentiating FTC from FTA with an area under the curve of 0.948 in the training set and 0.915 in the validation set. CONCLUSIONS: The preoperative nomogram model constructed based on US features serves as an effective tool for the risk stratification of thyroid follicular neoplasms.

18.
Opt Lett ; 49(7): 1848-1851, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38560880

RESUMO

In this Letter, a novel, to the best of our knowledge, channel modeling scheme based on cascading chromatic dispersion-nonlinearity feature decoupling modules is proposed with the center-oriented long short-term memory (Co-LSTM) network structure adopted for modeling nonlinearity of each optical fiber span. By tracking the amplified spontaneous emission (ASE) noise at the output of each fiber span, the Co-LSTM-based channel modeling scheme achieves high waveform accuracy for long-haul coherent optical transmission compared with the conventional split-step Fourier transform method (SSFM) while saving calculation time by almost one order of magnitude.

19.
Cereb Cortex ; 34(4)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38566507

RESUMO

Crohn's disease is an acknowledged "brain-gut" disorder with unclear physiopathology. This study aims to identify potential neuroimaging biomarkers of Crohn's disease. Gray matter volume, cortical thickness, amplitude of low-frequency fluctuations, and regional homogeneity were selected as indices of interest and subjected to analyses using both activation likelihood estimation and seed-based d mapping with permutation of subject images. In comparison to healthy controls, Crohn's disease patients in remission exhibited decreased gray matter volume in the medial frontal gyrus and concurrently increased regional homogeneity. Furthermore, gray matter volume reduction in the medial superior frontal gyrus and anterior cingulate/paracingulate gyri, decreased regional homogeneity in the median cingulate/paracingulate gyri, superior frontal gyrus, paracentral lobule, and insula were observed. The gray matter changes of medial frontal gyrus were confirmed through both methods: decreased gray matter volume of medial frontal gyrus and medial superior frontal gyrus were identified by activation likelihood estimation and seed-based d mapping with permutation of subject images, respectively. The meta-regression analyses showed a positive correlation between regional homogeneity alterations and patient age in the supplementary motor area and a negative correlation between gray matter volume changes and patients' anxiety scores in the medial superior frontal gyrus. These anomalies may be associated with clinical manifestations including abdominal pain, psychiatric disorders, and possibly reflective of compensatory mechanisms.


Assuntos
Encefalopatias , Doença de Crohn , Córtex Motor , Humanos , Doença de Crohn/complicações , Doença de Crohn/diagnóstico por imagem , Doença de Crohn/patologia , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Substância Cinzenta/patologia , Encefalopatias/patologia
20.
Endocrine ; 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38570388

RESUMO

PURPOSE: This study aims to develop a deep learning-based computer-aided diagnosis (CAD) system for the automatic detection and classification of lateral cervical lymph nodes (LNs) on original ultrasound images of papillary thyroid carcinoma (PTC) patients. METHODS: A retrospective data set of 1801 cervical LN ultrasound images from 1675 patients with PTC and a prospective test set including 185 images from 160 patients were collected. Four different deep leaning models were trained and validated in the retrospective data set. The best model was selected for CAD system development and compared with three sonographers in the retrospective and prospective test sets. RESULTS: The Deformable Detection Transformer (DETR) model showed the highest diagnostic efficacy, with a mean average precision score of 86.3% in the retrospective test set, and was therefore used in constructing the CAD system. The detection performance of the CAD system was superior to the junior sonographer and intermediate sonographer with accuracies of 86.3% and 92.4% in the retrospective and prospective test sets, respectively. The classification performance of the CAD system was better than all sonographers with the areas under the curve (AUCs) of 94.4% and 95.2% in the retrospective and prospective test sets, respectively. CONCLUSIONS: This study developed a Deformable DETR model-based CAD system for automatically detecting and classifying lateral cervical LNs on original ultrasound images, which showed excellent diagnostic efficacy and clinical utility. It can be an important tool for assisting sonographers in the diagnosis process.

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