Tissue-resident macrophages are essential to protect from pathogen invasion and maintain organ homeostasis. The ability of thymic macrophages to engulf apoptotic thymocytes is well appreciated, but ...little is known about their ontogeny, maintenance, and diversity. Here, we characterized the surface phenotype and transcriptional profile of these cells and defined their expression signature. Thymic macrophages were most closely related to spleen red pulp macrophages and Kupffer cells and shared the expression of the transcription factor (TF) SpiC with these cells. Single-cell RNA sequencing (scRNA-Seq) showed that the macrophages in the adult thymus are composed of two populations distinguished by the expression of
and
. Remarkably,
cells were located in the cortex, while
macrophages were restricted to the medulla and the cortico-medullary junction. Using shield chimeras, transplantation of embryonic thymuses, and genetic fate mapping, we found that the two populations have distinct origins.
thymic macrophages are of embryonic origin, while
macrophages are derived from adult hematopoietic stem cells. Aging has a profound effect on the macrophages in the thymus.
cells underwent gradual attrition, while
cells slowly accumulated with age and, in older mice, were the dominant macrophage population in the thymus. Altogether, our work defines the phenotype, origin, and diversity of thymic macrophages.
Primary aldosteronism (PA) is a common cause of secondary hypertension and is associated with worse cardiovascular outcomes. The elevated aldosterone in PA leads to left ventricular (LV) remodeling ...and dysfunction. In recent decades, clinical studies have demonstrated worse LV remodeling including increased LV mass and cardiac fibrosis in patients with PA compared to patients with essential hypertension. Several mechanisms may explain the process of aldosterone-induced LV remodeling, including directly profibrotic and hypertrophic effects of aldosterone on myocardium, increased reactive oxygen species and profibrotic molecules, dysregulation of extracellular matrix metabolism, endothelium dysfunction and circulatory macrophages activation. LV remodeling causes LV diastolic and systolic dysfunction, which may consequently lead to clinical complications such as heart failure, atrial fibrillation, ischemic heart disease, and other vascular events. Adequate treatment with adrenalectomy or medical therapy can improve LV remodeling and dysfunction in PA patients. In this review, we discuss the mechanisms of aldosterone-induced LV remodeling and provide an up-to-date review of clinical research about LV remodeling-related heart structural changes, cardiac dysfunction, and their clinical impacts on patients with PA.
Recognizing specific heart sound patterns is important for the diagnosis of structural heart diseases. However, the correct recognition of heart murmur depends largely on clinical experience. ...Accurately identifying abnormal heart sound patterns is challenging for young and inexperienced clinicians. This study is aimed at the development of a novel algorithm that can automatically recognize systolic murmurs in patients with ventricular septal defects (VSDs). Heart sounds from 51 subjects with VSDs and 25 subjects without a significant heart malformation were obtained in this study. Subsequently, the soundtracks were divided into different training and testing sets to establish the recognition system and evaluate the performance. The automatic murmur recognition system was based on a novel temporal attentive pooling-convolutional recurrent neural network (TAP-CRNN) model. On analyzing the performance using the test data that comprised 178 VSD heart sounds and 60 normal heart sounds, a sensitivity rate of 96.0% was obtained along with a specificity of 96.7%. When analyzing the heart sounds recorded in the second aortic and tricuspid areas, both the sensitivity and specificity were 100%. We demonstrated that the proposed TAP-CRNN system can accurately recognize the systolic murmurs of VSD patients, showing promising potential for the development of software for classifying the heart murmurs of several other structural heart diseases.
Lactobacillus plantarum
PS128 has been reported as a psychobiotic to improve mental health through the gut–brain axis in experimental animal models. To explore its mechanism of action in the gut, ...this study aimed to analyze the effects of
L. plantarum
PS128 ingestion on naïve and loperamide (Lop)-induced constipation mice. We found that, in the two mouse models, the weight, number, and water content of feces in the
L. plantarum
PS128 group were higher than those in the vehicle control group. Histological observation revealed that
L. plantarum
PS128 increased the level of colonic mucins including the major mucin MUC2. In addition, the charcoal meal test showed that
L. plantarum
PS128 significantly increased the small intestine transit in naïve mice, but not in the Lop-treated mice. Since intestinal serotonin has been found to modulate motility, we further analyzed the expression of genes related to serotonin signal transduction in the small intestine of naïve mice. The results showed that
L. plantarum
PS128 significantly altered the expression levels of
Tph1
,
Chga
,
Slc6a4
, and
Htr4
, but did not affect the expression levels of
Tph2
,
Htr3a
, and
Maoa
. Furthermore, immunohistochemistry revealed that
L. plantarum
PS128 significantly increased the number of serotonin-containing intestinal cells in mice. Taken together, our results suggest that
L. plantarum
PS128 could promote intestinal motility, mucin production, and serotonin signal transduction, leading to a laxative effect in mice.
Patients bitten by
who are treated with bivalent freeze-dried neurotoxic antivenom in Taiwan have an improved survival rate but develop necrotic wound changes. The World Health Organization (WHO) has ...suggested using the minimum necrotizing dose (MND) of venom as a method of evaluating the neutralization effect of antivenom. The aim of this study was to evaluate the effectiveness of antivenom for the prevention of necrosis based on the MND and clarify which component of the venom of
induces necrosis. The neurotoxins (NTXs) were removed from the crude venom (deNTXs), and different concentrations of deNTXs were injected intradermally into the dorsal skin of mice. After three days, the necrotic lesion diameter was found to be approximately 5 mm, and the MND was calculated. A reduction in the necrotic diameter of 50% was used to identify the MND
. Furthermore, both phospholipase A
(PLA
) and cytotoxins (CTXs) were separately removed from the deNTXs to identify the major necrosis-inducing factor, and the necrotic lesions were scored. All mice injected with deNTXs survived for three days and developed necrotic wounds. The MND of the deNTXs for mice was 0.494 ± 0.029 µg/g, that of the deNTXs-dePLA
(major component retained: CTXs) was 0.294 ± 0.05 µg/g, and that of the deNTX-deCTX (major component retained: PLA
) venom was greater than 1.25 µg/g. These values show that CTX is the major factor inducing necrosis. These results suggest that the use of the deNTXs is necessary to enable the mice to survive long enough to develop venom-induced cytolytic effects. CTXs play a major role in
-related necrosis. However, the MND
could not be identified in this study, which meant that the antivenom did not neutralize venom-induced necrosis.
Heart failure (HF) is a major cardiovascular disease worldwide, and the early detection and diagnosis remain challenges. Recently, heart rhythm complexity analysis, derived from non-linear heart rate ...variability (HRV) analysis, has been proposed as a non-invasive method to detect diseases and predict outcomes. In this study, we aimed to investigate the diagnostic value of heart rhythm complexity in HF patients. We prospectively analyzed 55 patients with symptomatic HF with impaired left ventricular ejection fraction and 97 participants without HF symptoms and normal LVEF as controls. Traditional linear HRV parameters and heart rhythm complexity including detrended fluctuation analysis (DFA) and multiscale entropy (MSE) were analyzed. The traditional linear HRV, MSE parameters and DFAα1 were significantly lower in HF patients compared with controls. In regression analysis, DFAα1 and MSE scale 5 remained significant predictors after adjusting for multiple clinical variables. Among all HRV parameters, MSE scale 5 had the greatest power to differentiate the HF patients from the controls in receiver operating characteristic curve analysis (area under the curve: 0.844). In conclusion, heart rhythm complexity appears to be a promising tool for the detection and diagnosis of HF.
In this study, a continuous cell-imaging system with subcellular resolution was developed by integrating a microfluidic platform with lattice lightsheet microscopy (LLSM). To reduce aberrations of ...the lightsheet propagating into the device, a microfluidic channel sealed with a water refractive index-matched thin film was fabricated. When the lightsheet emerged from the water-immersed objectives and penetrated through the water refractive-matched thin film into the microfluidic channel at an incident angle, less light scattering and fewer aberrations were found. Suspended cells flowed across the lattice lightsheet, and an imaging system with the image plane perpendicular to the lightsheet was used to sequentially acquire cell images. By applying a thinner lattice lightsheet, higher-resolution, higher-contrast images were obtained. Furthermore, three-dimensional cell images could be achieved by reconstructing sequential two-dimensional cell images.
In this study, a continuous cell-imaging system with subcellular resolution was developed by integrating a microfluidic platform with lattice lightsheet microscopy (LLSM).
Neuroblastoma, a childhood cancer affecting the sympathetic nervous system, continues to challenge the development of potent treatments due to the limited availability of druggable targets for this ...aggressive illness. Recent investigations have uncovered that phosphoglycerate dehydrogenase (PHGDH), an essential enzyme for de novo serine synthesis, serves as a non-oncogene dependency in high-risk neuroblastoma. In this study, we show that homoharringtonine (HHT) acts as a PHGDH inhibitor, inducing intricate alterations in cellular metabolism, and thus providing an efficient treatment for neuroblastoma. We have experimentally verified the reliance of neuroblastoma on PHGDH and employed molecular docking, thermodynamic evaluations, and X-ray crystallography techniques to determine the bond interactions between HHT and PHGDH. Administering HHT to treat neuroblastoma resulted in effective cell elimination in vitro and tumor reduction in vivo. Metabolite and functional assessments additionally disclosed that HHT treatment suppressed de novo serine synthesis, initiating intricate metabolic reconfiguration and oxidative stress in neuroblastoma. Collectively, these discoveries highlight the potential of targeting PHGDH using HHT as a potent approach for managing high-risk neuroblastoma.
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•PHGDH is a therapeutic target for high-risk neuroblastoma patients.•Structure-based assays have unveiled the FDA-approved drug HHT as a potential PHGDH inhibitor.•In vitro and in vivo models have evaluated the effectiveness of HHT against neuroblastoma.
Human breast milk is widely recognized as the best source of nutrients for healthy growth and development of infants; it contains a diverse microbiota. Here, we characterized the diversity of the ...microbiota in the breast milk of East Asian women and assessed whether delivery mode influenced the microbiota in the milk of healthy breast-feeding mothers. We profiled the microbiota in breast milk samples collected from 133 healthy mothers in Taiwan and in six regions of mainland China (Central, East, North, Northeast, South, and Southwest China) by using 16S rRNA pyrosequencing. Lactation stage (months postpartum when the milk sample was collected) and maternal body mass index did not influence the breast milk microbiota. Bacterial composition at the family level differed significantly among samples from the seven geographical regions. The five most predominant bacterial families were
(mean relative abundance: 24.4%),
(14.0%),
(12.2%),
(6.2%), and
(4.8%). The microbial profiles were classified into three clusters, driven by
(abundance in Cluster 1: 42.1%),
(Cluster 2: 48.5%), or
(Cluster 3: 26.5%). Microbial network analysis at the genus level revealed that the abundances of the Gram-positive
,
, and
were negatively correlated with those of the Gram-negative
,
,
,
, and
. Milk from mothers who had undergone Caesarian section (C-section group) had a significantly higher abundance of
(
< 0.05) and a higher number of unique unclassified operational taxonomic units (OTUs) (
< 0.001) than that from mothers who had undergone vaginal delivery (vaginal group). These findings revealed that (i) geographic differences in the microbial profiles were found in breast milk from mothers living in Taiwan and mainland China, (ii) the predominant bacterial families
,
, and
were key components for forming three respective clusters, and (iii) a significantly greater number of unique OTUs was found in the breast milk from mothers who had undergone C-section than from those who had delivered vaginally.
Mitochondrial division inhibitor 1 (Mdivi-1) is a well-known synthetic compound aimed at inhibiting dynamin-related protein 1 (Drp1) to suppress mitochondrial fission, making it a valuable tool for ...studying mitochondrial dynamics. However, its specific effects beyond Drp1 inhibition remain to be confirmed. In this study, we employed integrative proteomics and phosphoproteomics to delve into the molecular responses induced by Mdivi-1 in SK-N-BE(2)C cells. A total of 3070 proteins and 1945 phosphorylation sites were identified, with 880 of them represented as phosphoproteins. Among these, 266 proteins and 97 phosphorylation sites were found to be sensitive to the Mdivi-1 treatment. Functional enrichment analysis unveiled their involvement in serine biosynthesis and extrinsic apoptotic signaling pathways. Through targeted metabolomics, we observed that Mdivi-1 enhanced intracellular serine biosynthesis while reducing the production of C24:1-ceramide. Within these regulated phosphoproteins, dynamic dephosphorylation of proteasome subunit alpha type 3 serine 250 (PSMA3-S250) occurred after Mdivi-1 treatment. Further site-directed mutagenesis experiments revealed that the dephosphorylation-deficient mutant PSMA3-S250A exhibited a decreased cell survival. This research confirms that Mdivi-1’s inhibition of mitochondrial division leads to various side effects, ultimately influencing cell survival, rather than solely targeting Drp1 inhibition.
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