Controlled Size Characterization Process for In-Situ TiB2 Particles from Al Matrix Composites Using Nanoparticle Size Analysis.

The wide size range and high tendency to agglomerate of in-situ TiB2 particles in reinforced Al matrix composites introduce great difficulties in their size characterization. In order to use a nanoparticle size analyzer (NSA) to obtain the precise size distribution of TiB2 particles, a controlled size characterization process has been explored. First, the extraction and drying processes for TiB2 particles were optimized. In the extraction process, alternated applications of magnetic stirring and normal ultrasound treatments were proven to accelerate the dissolution of the Al matrix in HCl solution. Furthermore, freeze-drying was found to minimize the agglomeration tendency among TiB2 particles, facilitating the acquisition of pure powders. Such powders were quantitatively made into an initial TiB2 suspension. Second, the chemical and physical dispersion technologies involved in initial TiB2 suspension were put into focus. Chemically, adding PEI (M.W. 10000) at a ratio of mPEI/mTiB2 = 1/30 into the initial suspension can greatly improve the degree of TiB2 dispersion. Physically, the optimum duration for high-energy ultrasound application to achieve TiB2 dispersion was 10 min. Overall, the corresponding underlying dispersion mechanisms were discussed in detail. With the combination of these chemical and physical dispersion specifications for TiB2 suspension, the bimodal size distribution of TiB2 was able to be characterized by NSA for the first time, and its number-average diameter was 111 ± 6 nm, which was reduced by 59.8% over the initial suspension. Indeed, the small-sized and large-sized peaks of the TiB2 particles characterized by NSA mostly match the results obtained from transmission electron microscopy and scanning electron microscopy, respectively.

Attentional control influence habituation through modulation of connectivity patterns within the prefrontal cortex: Insights from stereo-EEG.

Attentional control, guided by top-down processes, enables selective focus on pertinent information, while habituation, influenced by bottom-up factors and prior experiences, shapes cognitive responses by emphasizing stimulus relevance. These two fundamental processes collaborate to regulate cognitive behavior, with the prefrontal cortex and its subregions playing a pivotal role. Nevertheless, the intricate neural mechanisms underlying the interaction between attentional control and habituation are still a subject of ongoing exploration. To our knowledge, there is a dearth of comprehensive studies on the functional connectivity between subsystems within the prefrontal cortex during attentional control processes in both primates and humans. Utilizing stereo-electroencephalogram (SEEG) recordings during the Stroop task, we observed top-down dominance effects and corresponding connectivity patterns among the orbitofrontal cortex (OFC), the middle frontal gyrus (MFG), and the inferior frontal gyrus (IFG) during heightened attentional control. These findings highlighting the involvement of OFC in habituation through top-down attention. Our study unveils unique connectivity profiles, shedding light on the neural interplay between top-down and bottom-up attentional control processes, shaping goal-directed attention.

Induction of Salmonella Enteritidis into a Viable but Nonculturable State by Cinnamaldehyde and Its Resuscitation.

Trans-cinnamaldehyde (TC), a typical plant-derived compound, has been widely used in the control of foodborne pathogen contamination. Nevertheless, the risk associated with the occurrence of viable but nonculturable (VBNC) bacteria induced by TC remains unclear. The results of this study showed that Salmonella Enteritidis (S. Enteritidis) entered the VBNC state after being induced by TC at a minimum inhibitory concentration of 312.5 µg/mL and survived for at least 22 days under TC treatment. Enhanced resistance was found against heat treatment (75°C, 30 s), antibiotics (i.e., ampicillin, ceftriaxone sodium, chloramphenicol), and hydrogen peroxide (3%) in VBNC S. Enteritidis. A synergistic effect against VBNC S. Enteritidis occurred when TC was combined with acid treatment, including lactic acid and acetic acid (pH = 3.5). VBNC and resuscitated S. Enteritidis by sodium pyruvate treatment (100 mM) were found to retain the infectious ability to Caco-2 cells. Relative expression levels of the stress-related genes relA, spoT, ppx, lon, katG, sodA, dnaK, and grpE were upregulated in VBNC S. Enteritidis. Accumulation of reactive oxygen species (ROS) and protein aggregates was observed in VBNC cells. Besides, the resuscitation of VBNC cells was accompanied with clearance of ROS and protein aggregates. In summary, this study presents a comprehensive characterization of stress tolerance and resuscitation of VBNC S. Enteritidis induced by cinnamaldehyde, and the results provide useful information for the development of effective control strategy against VBNC pathogenic bacteria in food production.

Noncoding RNA Terc-53 and hyaluronan receptor Hmmr regulate ageing in mice.

One of the basic questions in the ageing field is whether there is fundamental difference between the ageing of lower invertebrates and mammals. A major difference between the lower invertebrates and mammals is the abundancy of noncoding RNAs, most of which are not conserved. We have previously identified a noncoding RNA Terc-53 that is derived from the RNA component of telomerase Terc. To study its physiological functions, we generated two transgenic mouse models overexpressing the RNA in wild-type and early-ageing Terc-/- backgrounds. Terc-53 mice showed age-related cognition decline and shortened life span, even though no developmental defects or physiological abnormality at early age was observed, indicating its involvement in normal ageing of mammals. Subsequent mechanistic study identified hyaluronan-mediated motility receptor (Hmmr) as the main effector of Terc-53. Terc-53 mediates the degradation of Hmmr, leading to an increase of inflammation in the affected tissues, accelerating organismal ageing. AAV-delivered supplementation of Hmmr in the hippocampus reversed the cognition decline in Terc-53 transgenic mice. Neither Terc-53 nor Hmmr has homologs in C. elegans. Neither do arthropods express hyaluronan (Stern 2017). These findings demonstrate the complexity of ageing in mammals, and open new paths for exploring noncoding RNA and Hmmr as means of treating age-related physical debilities and improving healthspan.

Antibody-drug conjugates in urothelial carcinoma: scientometric analysis and clinical trials analysis.

In 2020, bladder cancer, which commonly presents as urothelial carcinoma, became the 10th most common malignancy. For patients with metastatic urothelial carcinoma, the standard first-line treatment remains platinum-based chemotherapy, with immunotherapy serving as an alternative in cases of programmed death ligand 1 expression. However, treatment options become limited upon resistance to platinum and programmed death 1 or programmed death ligand 1 agents. Since the FDA's approval of Enfortumab Vedotin and Sacituzumab Govitecan, the therapeutic landscape has expanded, heralding a shift towards antibody-drug conjugates as potential first-line therapies. Our review employed a robust scientometric approach to assess 475 publications on antibody-drug conjugates in urothelial carcinoma, revealing a surge in related studies since 2018, predominantly led by U.S. institutions. Moreover, 89 clinical trials were examined, with 36 in Phase II and 13 in Phase III, exploring antibody-drug conjugates as both monotherapies and in combination with other agents. Promisingly, novel targets like HER-2 and EpCAM exhibit substantial therapeutic potential. These findings affirm the increasing significance of antibody-drug conjugates in urothelial carcinoma treatment, transitioning them from posterior-line to frontline therapies. Future research is poised to focus on new therapeutic targets, combination therapy optimization, treatment personalization, exploration of double antibody-coupled drugs, and strategies to overcome drug resistance.

Contextual facilitation: Separable roles of contextual guidance and context suppression in visual search.

Visual search is facilitated when targets are repeatedly encountered at a fixed position relative to an invariant distractor layout, compared to random distractor arrangements. However, standard investigations of this contextual-facilitation effect employ fixed distractor layouts that predict a constant target location, which does not always reflect real-world situations where the target location may vary relative to an invariant distractor arrangement. To explore the mechanisms involved in contextual learning, we employed a training-test procedure, introducing not only the standard full-repeated displays with fixed target-distractor locations but also distractor-repeated displays in which the distractor arrangement remained unchanged but the target locations varied. During the training phase, participants encountered three types of display: full-repeated, distractor-repeated, and random arrangements. The results revealed full-repeated displays to engender larger performance gains than distractor-repeated displays, relative to the random-display baseline. In the test phase, the gains were substantially reduced when full-repeated displays changed into distractor-repeated displays, while the transition from distractor-repeated to full-repeated displays failed to yield additional gains. We take this pattern to indicate that contextual learning can improve performance with both predictive and non-predictive (repeated) contexts, employing distinct mechanisms: contextual guidance and context suppression, respectively. We consider how these mechanisms might be implemented (neuro-)computationally.

Comparative and functional analysis unveils the contribution of photoperiod to DNA methylation, sRNA accumulation, and gene expression variations in short-day and long-day grasses.

Photoperiod employs complicated networks to regulate various developmental processes in plants, including flowering transition. However, the specific mechanisms by which photoperiod affects epigenetic modifications and gene expression variations in plants remain elusive. In this study, we conducted a comprehensive analysis of DNA methylation, small RNA (sRNA) accumulation, and gene expressions under different daylengths in facultative long-day (LD) grass Brachypodium distachyon and short-day (SD) grass rice. Our results showed that while overall DNA methylation levels were minimally affected by different photoperiods, CHH methylation levels were repressed under their favorable light conditions, particularly in rice. We identified numerous differentially methylated regions (DMRs) that were influenced by photoperiod in both plant species. Apart from differential sRNA clusters, we observed alterations in the expression of key components of the RNA-directed DNA methylation pathway, DNA methyltransferases, and demethylases, which may contribute to the identified photoperiod-influenced CHH DMRs. Furthermore, we identified many differentially expressed genes in response to different daylengths, some of which were associated with the DMRs. Notably, we discovered a photoperiod-responsive gene MYB11 in the transcriptome of B. distachyon, and further demonstrated its role as a flowering inhibitor by repressing FT1 transcription. Together, our comparative and functional analysis sheds light on the effects of daylength on DNA methylation, sRNA accumulation, and gene expression variations in LD and SD plants, thereby facilitating better designing breeding programs aimed at developing high-yield crops that can adapt to local growing seasons.

ERPs and alpha oscillations track the encoding and maintenance of object-based representations in visual working memory.

When memorizing an integrated object such as a Kanizsa figure, the completion of parts into a coherent whole is attained by grouping processes which render a whole-object representation in visual working memory (VWM). The present study measured event-related potentials (ERPs) and oscillatory amplitudes to track these processes of encoding and representing multiple features of an object in VWM. To this end, a change detection task was performed, which required observers to memorize both the orientations and colors of six "pacman" items while inducing configurations of the pacmen that systematically varied in terms of their grouping strength. The results revealed an effect of object configuration in VWM despite physically constant visual input: change detection for both orientation and color features was more accurate with increased grouping strength. At the electrophysiological level, the lateralized ERPs and alpha activity mirrored this behavioral pattern. Perception of the orientation features gave rise to the encoding of a grouped object as reflected by the amplitudes of the Ppc. The grouped object structure, in turn, modulated attention to both orientation and color features as indicated by the enhanced N1pc and N2pc. Finally, during item retention, the representation of individual objects and the concurrent allocation of attention to these memorized objects were modulated by grouping, as reflected by variations in the CDA amplitude and a concurrent lateralized alpha suppression, respectively. These results indicate that memorizing multiple features of grouped, to-be-integrated objects involves multiple, sequential stages of processing, providing support for a hierarchical model of object representations in VWM.

Knee osteoarthritis: A review of animal models and intervention of traditional Chinese medicine.

BACKGROUND: Knee osteoarthritis (KOA) characterized by degeneration of knee cartilage and subsequent bone hyperplasia is a prevalent joint condition primarily affecting aging adults. The pathophysiology of KOA remains poorly understood, as it involves complex mechanisms that result in the same outcome. Consequently, researchers are interested in studying KOA and require appropriate animal models for basic research. Chinese herbal compounds, which consist of multiple herbs with diverse pharmacological properties, possess characteristics such as multicomponent, multipathway, and multitarget effects. The potential benefits in the treatment of KOA continue to attract attention. PURPOSE: This study aims to provide a comprehensive overview of the advantages, limitations, and specific considerations in selecting different species and methods for KOA animal models. This will help researchers make informed decisions when choosing an animal model. METHODS: Online academic databases (e.g., PubMed, Google Scholar, Web of Science, and CNKI) were searched using the search terms "knee osteoarthritis," "animal models," "traditional Chinese medicine," and their combinations, primarily including KOA studies published from 2010 to 2023. RESULTS: Based on literature retrieval, this review provides a comprehensive overview of the methods of establishing KOA animal models; introduces the current status of advantages and disadvantages of various animal models, including mice, rats, rabbits, dogs, and sheep/goats; and presents the current status of methods used to establish KOA animal models. CONCLUSION: This study provides a review of the animal models used in recent KOA research, discusses the common modeling methods, and emphasizes the role of traditional Chinese medicine compounds in the treatment of KOA.

Targeting Senescent Alveolar Epithelial Cells Using Engineered Mesenchymal Stem Cell-Derived Extracellular Vesicles To Treat Pulmonary Fibrosis.

Type 2 alveolar epithelial cell (AEC2) senescence is crucial to the pathogenesis of pulmonary fibrosis (PF). The nicotinamide adenine dinucleotide (NAD+)-consuming enzyme cluster of differentiation 38 (CD38) is a marker of senescent cells and is highly expressed in AEC2s of patients with PF, thus rendering it a potential treatment target. Umbilical cord mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) have emerged as a cell-free treatment with clinical application prospects in antiaging and antifibrosis treatments. Herein, we constructed CD38 antigen receptor membrane-modified MSC-EVs (CD38-ARM-MSC-EVs) by transfecting MSCs with a lentivirus loaded with a CD38 antigen receptor-CD8 transmembrane fragment fusion plasmid to target AEC2s and alleviate PF. Compared with MSC-EVs, the CD38-ARM-MSC-EVs engineered in this study showed a higher expression of the CD38 antigen receptor and antifibrotic miRNAs and targeted senescent AEC2s cells highly expressing CD38 in vitro and in naturally aged mouse models after intraperitoneal administration. CD38-ARM-MSC-EVs effectively restored the NAD+ levels, reversed the epithelial-mesenchymal transition phenotype, and rejuvenated senescent A549 cells in vitro, thereby mitigating multiple age-associated phenotypes and alleviating PF in aged mice. Thus, this study provides a technology to engineer MSC-EVs and support our CD38-ARM-MSC-EVs to be developed as promising agents with high clinical potential against PF.

[Zuogui Pills improve testicular development of offspring rats exposed to prenatal stress via Cx43].

This study aims to reveal the mechanism of prenatal stress in affecting the testicular development of offspring rats and the intervention effects of Zuogui Pills via connexin 43(Cx43). Forty pregnant SD rats were randomized into a blank control group, a mo-del group, a high-dose(18.9 g·kg~(-1)) Zuogui Pills group, a low-dose(9.45 g·kg~(-1)) Zuogui Pills group, and a vitamin E(1.44 mg·kg~(-1)) group. The other groups except the blank control group was subjected to chronic unpredictable mild stress for the modeling of prenatal stress. The model was evaluated by sucrose preference test, open field test, and enzyme-linked immunosorbent assay(ELISA) of the glucocorticoid level. ELISA was employed to measure the thyroxine 4(T4), testosterone(T), and follicle-stimulating hormone(FSH) levels to assess kidney deficiency. Hematoxylin-eosin(HE) staining was employed to evaluate the status of testicular germ cells. An automatic sperm analyzer was used to measure the sperm quality. Immunofluorescence double staining was employed to detect the expression of Cx43 and follicle-stimulating hormone receptor(FSHR) in the testes of offspring rats. The mRNA and protein levels of Cx43, FSHR, phosphatidylinositol 3-kinase(PI3K), and protein kinase B(Akt) were determined by real-time fluorescence quantitative polymerase chain reaction and Western blot, respectively. Prenatal stress induced testicular development disorders in offspring rats. The HE staining results showed that on the day of birth, the model group had reduced seminiferous tubules in the testes, elevated FSH level in the serum, and lowered Cx43 level in the testicular tissue. Male offspring rats of 60 days old had reduced testicular spermatogenic function, decreased sperm quality, elevated FSH level and lowered T level in the serum, and down-regulated protein and mRNA levels of Cx43, FSHR, PI3K, and Akt in the testicular tissue. Zuogui Pills alleviated the abnormal development and dysfunction of testicles in the offspring rats caused by prenatal stress. In summary, Zuogui Pills may weaken the effects of prenatal stress on testicular development and spermatogenic function of offspring rats by activating the PI3K/Akt pathway to regulate Cx43 expression in the testicular tissue.

A rapid immunomagnetic beads-based sELISA method for the detection of bovine αs1-casein based on specific epitopes.

Although αs1-casein poses significant health risks to individuals with milk allergies, the availability of quantification methods for this allergen remains limited. In this study, we developed an immunomagnetic beads-based immunoassay (IMBs-ELISA) for the precise quantitative detection of bovine αs1-CN, specifically targeting epitope AA173-194. No cross-reactivity was observed with the other 7 food allergens including milk allergen. The linear detection range of the established IMBs-ELISA method was 0.125 µg/mL-2.000 µg/mL, with a limit of detection of 0.099 µg/mL. The accuracy of this method was 1.048 %, and the intra-plate and inter-plate precision achieved 4.100 % and 6.777 %, respectively. Notably, the entire IMBs-ELISA process could be completed within 75 min, representing a substantial time-saving advantage over traditional ELISA methods. These results proved the reliability and rapidity of the IMBs-ELISA method for detecting αs1-CN in real food.

Machine learning based biomarker discovery for chronic kidney disease-mineral and bone disorder (CKD-MBD).

INTRODUCTION: Chronic kidney disease-mineral and bone disorder (CKD-MBD) is characterized by bone abnormalities, vascular calcification, and some other complications. Although there are diagnostic criteria for CKD-MBD, in situations when conducting target feature examining are unavailable, there is a need to investigate and discover alternative biochemical criteria that are easy to obtain. Moreover, studying the correlations between the newly discovered biomarkers and the existing ones may provide insights into the underlying molecular mechanisms of CKD-MBD. METHODS: We collected a cohort of 116 individuals, consisting of three subtypes of CKD-MBD: calcium abnormality, phosphorus abnormality, and PTH abnormality. To identify the best biomarker panel for discrimination, we conducted six machine learning prediction methods and employed a sequential forward feature selection approach for each subtype. Additionally, we collected a separate prospective cohort of 114 samples to validate the discriminative power of the trained prediction models. RESULTS: Using machine learning under cross validation setting, the feature selection method selected a concise biomarker panel for each CKD-MBD subtype as well as for the general one. Using the consensus of these features, best area under ROC curve reached up to 0.95 for the training dataset and 0.74 for the perspective dataset, respectively. DISCUSSION/CONCLUSION: For the first time, we utilized machine learning methods to analyze biochemical criteria associated with CKD-MBD. Our aim was to identify alternative biomarkers that could serve not only as early detection indicators for CKD-MBD, but also as potential candidates for studying the underlying molecular mechanisms of the condition.

Substrate-directed divergent annulations of sulfur ylides: synthesis of functionalized bispirocyclopentane and bispirocyclopropane derivatives.

Herein, an efficient, substrate-directed divergent [2 + 3]/[2 + 1] annulation of tetra-substituted oxa-dienes and allylic sulfur ylides has been successfully developed. Under precise annulation regulation, a series of functionalized bispirocyclopentane and bispirocyclopropane derivatives were synthesized in a highly stereoselective and economical manner (up to 95% yield, >20 : 1 dr or >20 : 1 E/Z). This protocol offers the advantages of mild conditions, high chemo-, regio- and diastereoselectivity and broad substrate compatibility. In addition, the synthetic practicality of this protocol was evaluated through a scale-up preparation and a series of three-component reactions utilizing in situ generated sulfur ylides.

A comparative study of two aldehyde dehydrogenases from Sphingobium sp.: the substrate spectrum and catalytic mechanism.

Biocatalytic oxidation is one of the most important and indispensable organic reactions for the development of green and sustainable biomanufacturing processes. NAD(P)+-dependent aldehyde dehydrogenase (ALDH) catalyzes the oxidation of aldehydes to carboxylic acids. Here, two ALDHs, SpALDH1 and SpALDH2, were identified from Sphingobium sp. SYK-6. They belong to different ALDH families and share only 32.30% amino acid identity. Interestingly, SpALDH1 and SpALDH2 exhibit significantly different enzymatic properties and substrate profiles. SpALDH2 has better thermostability than SpALDH1. SpALDH1 is a metalloenzyme and is activated by potassium ions, while SpALDH2 is not metallic-dependent. Compared with SpALDH1, SpALDH2 has a relatively broad substrate spectrum toward aromatic aldehydes. Based on homology modeling and molecular docking analysis, mechanisms underlying the substrate specificity of ALDHs were elucidated. For both ALDHs, hydrophobicity of substrate binding pockets is important for the catalytic properties, especially substrate specificity. Notably, optimization of the flexible loop 444-457 reforms a hydrogen bond between pyridine substrates and SpALDH1, contributing to the high catalytic activity. Finally, a coupling reaction catalyzed by ALDHs and NOX was constructed for efficient production of aromatic carboxylic acids.

Pathogenomics model for personalized medicine in cervical cancer: Cross-talk of gene expressions and pathological images related to oxidative stress.

An increasing number of studies have shown that oxidative stress plays an important role in the development and progression of cancer. Cervical cancer (CC) is a disease of unique complexity that tends to exhibit high heterogeneity in molecular phenotypes. We aim here to characterize molecular features of cervical cancer by developing a classification system based on oxidative stress-related gene expression profiles. In this study, we obtained gene expression profiling data for cervical cancer from the TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) (GSE44001) databases. Oxidative stress-related genes used for clustering were obtained from GeneCards. Patients with cervical cancer were divided into two subtypes (C1 and C2) by non-negative matrix factorization (NMF) classification. By performing Kaplan-Meier survival analysis, differential expression analysis, and gene set enrichment analysis (GSEA) between the two subtypes, we found that subtype C2 had a worse prognosis and was highly enriched for immune-related pathways as well as epithelial-mesenchymal transition (EMT) pathways. Subsequently, we performed metabolic pathway analysis, gene mutation landscape analysis, immune microenvironment analysis, immunotherapy response analysis, and drug sensitivity analysis of the two isoforms. The results showed that the isoforms were significantly different between metabolic pathway enrichment and the immune microenvironment, and the chromosomes of subtype C1 were more unstable. In addition, we found that subtype C2 tends to respond to treatment with anti-CTLA4 agents, a conclusion that coincides with high chromosomal variation in C1, as well as C2 enrichment of immune-related pathways. Then, we screened 10 agents that were significantly susceptible to C2 subtype. Finally, we constructed pathogenomics models based on pathological features and linked them to molecular subtypes. This study establishes a novel CC classification based on gene expression profiles of oxidative stress-related genes and elucidates differences between immune microenvironments between CC subtypes, contributing to subtype-specific immunotherapy and drug therapy.

What Do Higher Alanine Aminotransferase Levels Mean in Premature Ovarian Insufficiency?

The objective of this study was to investigate the relationship between alanine aminotransferase and related biochemical parameters and potential risk factors in women with premature ovarian insufficiency (POI). This is a retrospective cohort study with 126 POI patients (including subclinical POI, n= 27) and 130 healthy controls who visited our clinic between April 2021 to November 2022. Associations were investigated by multiple linear regression, Person correlation analysis, the Kruskal-Wallis test, Mann-Whitney U test, and the independent t-test. When compared to controls, analysis of POI patients showed that body mass index (BMI), uric acid (UA) and urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), monocyte/lymphocyte ratio, monocyte count (MONO), neutrophil count (NEUT), follicle-stimulating hormone (FSH), luteinizing hormone, and neutrophil/lymphocyte ratio (NLR) were significantly higher, while estradiol (E2), the lymphocyte count and the AST/ALT ratio were lower (P < 0.05). According to linear correlation, it was clear that BMI, FSH, white blood cell count (WBC), NEUT, MONO, UA, AST, and NLR were positively associated with ALT (r = 0.215, 0.388, 0.195, 0.187, 0.184, 0.605, 0.819, and 0.189, respectively, all P < 0.05) while E2 was negatively associated with ALT (r = -0.278, P < 0.05). In addition, multiple linear regression revealed a significant, independent, and positive correlation between AST, FSH, and ALT (B =1.403 and 0.069, respectively, P < 0.05). Analysis revealed that the levels of ALT were significantly higher in POI patients. In addition, BMI, FSH, UA, AST, MONO, NLR, NEUT, and WBC were positively associated with ALT in POI patients. E2 was negatively associated with ALT. Multiple linear regression revealed an independent and positive correlation between AST, FSH, and ALT. In addition, there was also a risk of liver function damage in women with POI and subclinical POI. If patients were diagnosed with POI, early examination and corresponding intervention will be required to effectively prevent the further development of liver disease.

Noninvasive identification of HER2-low-positive status by MRI-based deep learning radiomics predicts the disease-free survival of patients with breast cancer.

OBJECTIVE: This study aimed to establish a MRI-based deep learning radiomics (DLR) signature to predict the human epidermal growth factor receptor 2 (HER2)-low-positive status and further verified the difference in prognosis by the DLR model. METHODS: A total of 481 patients with breast cancer who underwent preoperative MRI were retrospectively recruited from two institutions. Traditional radiomics features and deep semantic segmentation feature-based radiomics (DSFR) features were extracted from segmented tumors to construct models separately. Then, the DLR model was constructed to assess the HER2 status by averaging the output probabilities of the two models. Finally, a Kaplan‒Meier survival analysis was conducted to explore the disease-free survival (DFS) in patients with HER2-low-positive status. The multivariate Cox proportional hazard model was constructed to further determine the factors associated with DFS. RESULTS: First, the DLR model distinguished between HER2-negative and HER2-overexpressing patients with AUCs of 0.868 and 0.763 in the training and validation cohorts, respectively. Furthermore, the DLR model distinguished between HER2-low-positive and HER2-zero patients with AUCs of 0.855 and 0.750, respectively. Cox regression analysis showed that the prediction score obtained using the DLR model (HR, 0.175; p = 0.024) and lesion size (HR, 1.043; p = 0.009) were significant, independent predictors of DFS. CONCLUSIONS: We successfully constructed a DLR model based on MRI to noninvasively evaluate the HER2 status and further revealed prospects for predicting the DFS of patients with HER2-low-positive status. CLINICAL RELEVANCE STATEMENT: The MRI-based DLR model could noninvasively identify HER2-low-positive status, which is considered a novel prognostic predictor and therapeutic target. KEY POINTS: • The DLR model effectively distinguished the HER2 status of breast cancer patients, especially the HER2-low-positive status. • The DLR model was better than the traditional radiomics model or DSFR model in distinguishing HER2 expression. • The prediction score obtained using the model and lesion size were significant independent predictors of DFS.

Targeting cytohesin-1 suppresses acute myeloid leukemia progression and overcomes resistance to ABT-199.

Adhesion molecules play essential roles in the homeostatic regulation and malignant transformation of hematopoietic cells. The dysregulated expression of adhesion molecules in leukemic cells accelerates disease progression and the development of drug resistance. Thus, targeting adhesion molecules represents an attractive anti-leukemic therapeutic strategy. In this study, we investigated the prognostic role and functional significance of cytohesin-1 (CYTH1) in acute myeloid leukemia (AML). Analysis of AML patient data from the GEPIA and BloodSpot databases revealed that CYTH1 was significantly overexpressed in AML and independently correlated with prognosis. Functional assays using AML cell lines and an AML xenograft mouse model confirmed that CYTH1 depletion significantly inhibited the adhesion, migration, homing, and engraftment of leukemic cells, delaying disease progression and prolonging animal survival. The CYTH1 inhibitor SecinH3 exerted in vitro and in vivo anti-leukemic effects by disrupting leukemic adhesion and survival programs. In line with the CYTH1 knockdown results, targeting CYTH1 by SecinH3 suppressed integrin-associated adhesion signaling by reducing ITGB2 expression. SecinH3 treatment efficiently induced the apoptosis and inhibited the growth of a panel of AML cell lines (MOLM-13, MV4-11 and THP-1) with mixed-lineage leukemia gene rearrangement, partly by reducing the expression of the anti-apoptotic protein MCL1. Moreover, we showed that SecinH3 synergized with the BCL2-selective inhibitor ABT-199 (venetoclax) to inhibit the proliferation and promote the apoptosis of ABT-199-resistant leukemic cells. Taken together, our results not only shed light on the role of CYTH1 in cell-adhesion-mediated leukemogenesis but also propose a novel combination treatment strategy for AML.

Effect of RpoS on the survival, induction, resuscitation, morphology, and gene expression of viable but non-culturable Salmonella Enteritidis in powdered infant formula.

Involvement of the transcriptional regulator RpoS in the persistence of viable but non-culturable (VBNC) state has been demonstrated in several species of bacteria. This study investigated the role of the RpoS in the formation and resuscitation of VBNC state in Salmonella enterica serovar Enteritidis CICC 21482 by measuring bacterial survival, morphology, physiological characteristics, and gene expression in wild-type (WT) and rpoS-deletion (ΔrpoS) strains during long-term storage in powdered infant formula (PIF). The ΔrpoS strain was produced by allelic exchange using a suicide plasmid. Bacteria were inoculated into PIF for 635-day storage. Survival, morphology, intracellular reactive oxygen species (ROS) levels and intercellular quorum sensing autoinducer-2 (AI-2) contents were regularly measured. Resuscitation assays were conducted after obtaining VBNC cells. Gene expression was measured using real-time quantitative polymerase chain reaction (qPCR). The results showed that RpoS and low temperature conditions were associated with enhanced culturability and recoverability of Salmonella Enteritidis after desiccation storage in low water activity (aw) PIF. In addition, the synthesis of intracellular ROS and intercellular quorum sensing AI-2 was regulated by RpoS, inducing the formation and resuscitation of VBNC cells. Gene expression of soxS, katG and relA was found strongly associated with RpoS. Due to the lack of RpoS factor, the ΔrpoS strain could not normally synthesize SoxS, catalase and (p)ppGpp, resulting in its early shift to the VBNC state. This study elucidates the role of rpoS in desiccation stress and the formation and resuscitation mechanism of VBNC cells under desiccation stress. It serves as the basis for preventing and controlling the recovery of pathogenic bacteria in VBNC state in low aw foods.