Characterization of age-associated gene expression changes in mouse sweat glands.

Evaporation of sweat on the skin surface is the major mechanism for dissipating heat in humans. The secretory capacity of sweat glands (SWGs) declines during aging, leading to heat intolerance in the elderly, but the mechanisms responsible for this decline are poorly understood. We investigated the molecular changes accompanying SWG aging in mice, where sweat tests confirmed a significant reduction of active SWGs in old mice relative to young mice. We first identified SWG-enriched mRNAs by comparing the skin transcriptome of Eda mutant Tabby male mice, which lack SWGs, with that of wild-type control mice by RNA-sequencing analysis. This comparison revealed 171 mRNAs enriched in SWGs, including 47 mRNAs encoding 'core secretory' proteins such as transcription factors, ion channels, ion transporters, and trans-synaptic signaling proteins. Among these, 28 SWG-enriched mRNAs showed significantly altered abundance in the aged male footpad skin, and 11 of them, including Foxa1, Best2, Chrm3, and Foxc1 mRNAs, were found in the 'core secretory' category. Consistent with the changes in mRNA expression levels, immunohistology revealed that higher numbers of secretory cells from old SWGs express the transcription factor FOXC1, the protein product of Foxc1 mRNA. In sum, our study identified mRNAs enriched in SWGs, including those that encode core secretory proteins, and altered abundance of these mRNAs and proteins with aging in mouse SWGs.

The crucial relationship between miRNA-27 and CSE/H2S, and the mechanism of action of GLP-1 in myocardial hypertrophy.

Cardiac hypertrophy is the most prevalent compensatory heart disease that ultimately leads to spontaneous heart failure. Mounting evidence suggests that microRNAs (miRs) and endogenous hydrogen sulfide (H2S) play a crucial role in the regulation of cardiac hypertrophy. In this study, we aimed to investigate whether inhibition of miR-27a could protect against cardiac hypertrophy by modulating H2S signaling. We established a model of cardiac hypertrophy by obtaining hypertrophic tissue from mice subjected to transverse aortic constriction (TAC) and from cells treated with angiotensin-II. Molecular alterations in the myocardium were quantified using quantitative real time PCR (qRT-PCR), Western blotting, and ELISA. Morphological changes were characterized by hematoxylin and eosin (HE) staining and Masson's trichrome staining. Functional myocardial changes were assessed using echocardiography. Our results demonstrated that miR-27a levels were elevated, while H2S levels were reduced in TAC mice and myocardial hypertrophy. Further luciferase and target scan assays confirmed that cystathionine-γ-lyase (CSE) was a direct target of miR-27a and was negatively regulated by it. Notably, enhancement of H2S expression in the heart was observed in mice injected with recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-27a and in cells transfected with a miR-27a inhibitor during cardiac hypertrophy. However, this effect was abolished by co-transfection with CSE siRNA and the miR-27a inhibitor. Conversely, injecting rAAV9-miR-27a yielded opposite results. Interestingly, our findings demonstrated that glucagon-like peptide-1 (GLP-1) agonists could mitigate myocardial damage by down-regulating miR-27a and up-regulating CSE. In summary, our study suggests that inhibition of miR-27a holds therapeutic promise for the treatment of cardiac hypertrophy by increasing H2S levels. Furthermore, our findings unveil a novel mechanism of GLP-1 agonists involving the miR-27a/H2S pathway in the management of cardiac hypertrophy.

Injectable and Conductive Nanomicelle Hydrogel with α-Tocopherol Encapsulation for Enhanced Myocardial Infarction Repair.

Substantial advancements have been achieved in the realm of cardiac tissue repair utilizing functional hydrogel materials. Additionally, drug-loaded hydrogels have emerged as a research hotspot for modulating adverse microenvironments and preventing left ventricular remodeling after myocardial infarction (MI), thereby fostering improved reparative outcomes. In this study, diacrylated Pluronic F127 micelles were used as macro-cross-linkers for the hydrogel, and the hydrophobic drug α-tocopherol (α-TOH) was loaded. Through the in situ synthesis of polydopamine (PDA) and the incorporation of conductive components, an injectable and highly compliant antioxidant/conductive composite FPDA hydrogel was constructed. The hydrogel exhibited exceptional stretchability, high toughness, good conductivity, cell affinity, and tissue adhesion. In a rabbit model, the material was surgically implanted onto the myocardial tissue, subsequent to the ligation of the left anterior descending coronary artery. Four weeks postimplantation, there was discernible functional recovery, manifesting as augmented fractional shortening and ejection fraction, alongside reduced infarcted areas. The findings of this investigation underscore the substantial utility of FPDA hydrogels given their proactive capacity to modulate the post-MI infarct microenvironment and thereby enhance the therapeutic outcomes of myocardial infarction.

Deep Survival Analysis With Latent Clustering and Contrastive Learning.

Survival analysis is employed to analyze the time before the event of interest occurs, which is broadly applied in many fields. The existence of censored data with incomplete supervision information about survival outcomes is one key challenge in survival analysis tasks. Although some progress has been made on this issue recently, the present methods generally treat the instances as separate ones while ignoring their potential correlations, thus rendering unsatisfactory performance. In this study, we propose a novel Deep Survival Analysis model with latent Clustering and Contrastive learning (DSACC). Specifically, we jointly optimize representation learning, latent clustering and survival prediction in a unified framework. In this way, the clusters distribution structure in latent representation space is revealed, and meanwhile the structure of the clusters is well incorporated to improve the ability of survival prediction. Besides, by virtue of the learned clusters, we further propose a contrastive loss function, where the uncensored data in each cluster are set as anchors, and the censored data are treated as positive/negative sample pairs according to whether they belong to the same cluster or not. This design enables the censored data to make full use of the supervision information of the uncensored samples. Through extensive experiments on four popular clinical datasets, we demonstrate that our proposed DSACC achieves advanced performance in terms of both C-index (0.6722, 0.6793, 0.6350, and 0.7943) and Integrated Brier Score (IBS) (0.1616, 0.1826, 0.2028, and 0.1120).

Sex difference in atrial scar prevalence: What can we learn from the STABLE-SR-III trial?

BACKGROUND: Female sex has long been recognized to present a higher risk of stroke and atrial fibrillation (AF) recurrence after circumferential pulmonary vein isolation (CPVI) than in males. However, the underlying mechanisms and benefits of additional low-voltage area (LVA) modification in women remain unknown. OBJECTIVE: The purpose of this study was to investigate differences in atrial substrate and efficacy of additive LVA ablation between sex subgroups. METHODS: Patients with paroxysmal atrial fibrillation (PAF) aged 65-80 years were randomly assigned to either CPVI plus LVA modification (STABLE-SR) group or CPVI alone group. The primary outcome was freedom from atrial arrhythmias after a single ablation procedure. RESULTS: Of 414 patients included in STABLE-SR-III, 204 (49.3%) were women (mean age 70.5 ± 4.7 years). Women demonstrated significantly higher LVA prevalence (51.5% vs 32.9%; P <.001) and LVA burden (6.5% vs 2.9%; P <.001) than men. In the STABLE-SR group, additional LVA ablation was associated with a 63% reduction in recurrence for women compared with the CPVI alone group (10.8% vs 29.4%; adjusted hazard ratio 0.37; 95% confidence interval 0.18-0.75; P for interaction = .040). However, this finding was not observed in men (18.7% vs 18.5%). In the female subgroup, both group 1 (CPVI + LVA modification) and group 3 (CPVI alone in females without LVA) had similar clinical outcomes, which were much better than in Group 2 (CPVI alone in women with LVA) (90% vs 83.8% vs 63.6%; P = .003). CONCLUSION: In older patients with PAF, women demonstrated more advanced atrial substrate, including higher prevalence and burden of LVA compared with men. Women may receive greater benefit from additional LVA modification than men.

Molecular-Level Interfacial Chemistry Regulation of MXene Enables Energy Storage beyond Theoretical Limit.

Ti3C2Tx MXene often suffers from poor lithium storage behaviors due to its electrochemically unfavorable OH terminations. Herein, we propose molecular-level interfacial chemistry regulation of Ti3C2Tx MXene with phytic acid (PA) to directly activate its OH terminations. Through constructing hydrogen bonds (H-bonds) between oxygen atoms of PA and OH terminations on Ti3C2Tx surface, interfacial charge distribution of Ti3C2Tx has been effectively regulated, thereby enabling sufficient ion-storage sites and expediting ion transport kinetics for high-performance energy storage. The results show that Li ions preferably bind to H-bond acceptors (oxygen atoms from PA), and the flexibility of H-bonds therefore renders their interactions with adsorbed Li ions chemically "tunable", thus alleviating undesirable localized geometric changes of the OH terminations. Meanwhile the H-bond-induced microscopic dipoles can act as directional Li-ion pumps to expedite ion diffusion kinetics with lower energy barrier. As a result, the as-designed Ti3C2Tx/PA achieves a 2.4-fold capacity enhancement compared with pristine Ti3C2Tx (even beyond theoretical capacity), superior long-term cyclability (220.0 mAh g-1 after 2000 cycles at 2.0 A g-1), and broad temperature adaptability (-20 to 50 °C). This work offers a promising interface engineering strategy to regulate microenvironments of inherent terminations for breaking through the energy storage performance of MXenes.

Dietary supplementation of benzoic acid and essential oils combination enhances intestinal resilience against LPS stimulation in weaned piglets.

BACKGROUND: The benefits of combining benzoic acid and essential oils (BAO) to mitigate intestinal impairment during the weaning process have been well established, while the detailed underlying mechanism has not been fully elucidated. Previous research has primarily focused on the reparative effects of BAO on intestinal injury, while neglecting its potential in enhancing intestinal stress resistance. METHODS: In this study, we investigated the pre-protective effect of BAO against LPS-induced stress using a modified experimental procedure. Piglets were pre-supplemented with BAO for 14 d, followed by a challenge with LPS or saline to collect blood and intestinal samples. RESULTS: Our findings demonstrated that BAO supplementation led to significant improvements in piglets' final weight, average daily gain, and feed intake/body gain ratio. Additionally, BAO supplementation positively influenced the composition of intestinal microbiota, increasing beneficial Actinobacteriota and Alloprevotella while reducing harmful Desulfobacterota, Prevotella and Oscillospira. Furthermore, BAO supplementation effectively mitigated oxidative disturbances and inflammatory responses induced by acute LPS challenge. This was evidenced by elevated levels of T-AOC, SOD, and GSH, as well as decreased levels of MDA, TNF-α, and IL-6 in the plasma. Moreover, piglets subjected to LPS challenge and pre-supplemented with BAO exhibited significant improvements in intestinal morphological structure and enhanced integrity, as indicated by restored expression levels of Occludin and Claudin-1 compared to the non-supplemented counterparts. Further analysis revealed that BAO supplementation enhanced the jejunal antioxidative capacity by increasing GSH-Px levels and decreasing MDA levels under the LPS challenge and stimulated the activation of the Nrf2 signaling pathway. Additionally, the reduction of TLR4/NF-κB/MAPK signaling pathways activation and proinflammatory factor were also observed in the jejunal of those piglets fed with BAO. CONCLUSIONS: In summary, our study demonstrates that pre-supplementation of BAO enhances the anti-stress capacity of weaned piglets by improving intestinal microbiota composition, reinforcing the intestinal barrier, and enhancing antioxidative and anti-inflammatory capabilities. These effects are closely associated with the activation of Nrf2 and TLR4/NF-κB/MAPK signaling pathways.

Cardiac-specific overexpression of CREM-IbΔC-X via CRISPR/Cas9 in mice presents a new model of atrial cardiomyopathy with spontaneous atrial fibrillation.

Atrial cardiomyopathy (ACM) forms the substrate for atrial fibrillation (AF) and underlies the potential for atrial thrombus formation and subsequent stroke. However, generating stable animal models that accurately replicate the entire progression of atrial lesions, particularly the onset of AF, presents significant challenges. In the present study, we found that the isoform of CRE-binding protein modulator (CREM-IbΔC-X), which is involved in the regulation of cardiac development and atrial rhythm, was highly expressed in atrial biopsies from patients with AF. Building upon this finding, we employed CRISPR/Cas9 technology to create a mouse model with cardiac-specific overexpression of CREM-IbΔC-X (referred to as CS-CREM mice). This animal model effectively illustrated the development of ACM through electrophysiological and structural remodelings over time. Proteomics and Chip-qPCR analysis of atrial samples revealed significant upregulation of cell-matrix adhesion and extracellular matrix structural components, alongside significant downregulation of genes related to atrial functions in the CS-CREM mice. Furthermore, the corresponding responses to anti-arrhythmia drugs, i.e., amiodarone and propafenone, suggested that CS-CREM mice could serve as an ideal in vivo model for drug testing. Our study introduced a novel ACM model with spontaneous AF by cardiac-specifically overexpressing CREM-IbΔC-X in mice, providing valuable insights into the mechanisms and therapeutic targets of ACM.

Stretchable, Self-Rolled, Microfluidic Electronics Enable Conformable Neural Interfaces of Brain and Vagus Neuromodulation.

Implantable neuroelectronic interfaces have gained significant importance in long-term brain-computer interfacing and neuroscience therapy. However, due to the mechanical and geometrical mismatches between the electrode-nerve interfaces, personalized and compatible neural interfaces remain serious issues for peripheral neuromodulation. This study introduces the stretchable and flexible electronics class as a self-rolled neural interface for neurological diagnosis and modulation. These stretchable electronics are made from liquid metal-polymer conductors with a high resolution of 30 µm using microfluidic printing technology. They exhibit high conformability and stretchability (over 600% strain) during body movements and have good biocompatibility during long-term implantation (over 8 weeks). These stretchable electronics offer real-time monitoring of epileptiform activities with excellent conformability to soft brain tissue. The study also develops self-rolled microfluidic electrodes that tightly wind the deforming nerves with minimal constraint (160 µm in diameter). The in vivo signal recording of the vagus and sciatic nerve demonstrates the potential of self-rolled cuff electrodes for sciatic and vagus neural modulation by recording action potential and reducing heart rate. The findings of this study suggest that the robust, easy-to-use self-rolled microfluidic electrodes may provide useful tools for compatible neuroelectronics and neural modulation.

Piezo1 channel activation facilitates baroreflex afferent neurotransmission with subsequent blood pressure reduction in control and hypertension rats.

Mechanosensitive cation channels such as Piezo1 and Piezo2 are activated by mechanical force like a starched wall of the aorta while blood pressure (BP) rising, which helps to elucidate the underlying mechanism of mechanotransduction of baroreceptor endings. In this study we investigated how Piezo1 channel activation-mediated gender- and afferent-specific BP regulation in rats. We established high-fat diet and fructose drink-induced hypertension model rats (HFD-HTN) and deoxycorticosterone (DOCA)-sensitive hypertension model rats. We showed that the expression levels of Piezo1 and Piezo2 were significantly up-regulated in left ventricle of HFD and DOCA hypertensive rats, whereas the down-regulation of Piezo1 was likely to be compensated by Piezo2 up-regulation in the aorta. Likewise, down-regulated Piezo1 was observed in the nodose ganglion (NG), while up-regulated Piezo2 was found in the nucleus tractus solitarius (NTS), which might synergistically reduce the excitatory neurotransmitter release from the presynaptic membrane. Notably, microinjection of Yoda1 (0.025-2.5 mg/ml) into the NG concentration-dependently reduced BP in both hypertensive rat models as well as in control rats with similar EC50; the effect of Yoda1 was abolished by microinjection of a Piezo1 antagonist GsMTx4 (1.0 µM). Functional analysis in an in vitro aortic arch preparation showed that instantaneous firing frequency of single Ah-fiber of aortic depressor nerve was dramatically increased by Yoda1 (0.03-1.0 µM) and blocked by GsMTx4 (1.0 µM). Moreover, spontaneous synaptic currents recorded from identified 2nd-order Ah-type baroreceptive neurons in the NTS was also facilitated over 100% by Yoda1 (1.0 µM) and completely blocked by GsMTx4 (3.0 µM). These results demonstrate that Piezo1 expressed on Ah-type baroreceptor and baroreceptive neurons in the NG and NTS plays a key role in a sexual-dimorphic BP regulation under physiological and hypertensive condition through facilitation of baroreflex afferent neurotransmission, which is presumably collaborated by Piezo2 expression at different level of baroreflex afferent pathway via compensatory and synergistic mechanisms.

Machine learning models developed and internally validated for predicting chronicity in pediatric immune thrombocytopenia.

BACKGROUND: Primary immune thrombocytopenia (ITP) in children is typically self-limiting; however, 20% to 30% of patients may experience prolonged thrombocytopenia lasting over a year. The challenge is predicting chronicity to ensure personalized treatment approaches. OBJECTIVES: To address this issue, we developed and internally validated 4 machine learning (ML) models using demographic and immunologic characteristics to predict the likelihood of chronicity. METHODS: The present study was conducted at Beijing Children's Hospital from June 2018 to December 2021, aiming to develop predictive models for determining the chronicity of pediatric ITP. Four ML models, based on a logistic regression classifier, random forest classifier, eXtreme Gradient Boosting (XGBoost), and support vector machine, were employed. These models used a set of 16 variables, including 14 immunologic and 2 demographic predictors. The performance evaluation criteria included prediction accuracy, precision, recall, F1 score, and area under the receiver operating characteristic curve (AUROC). RESULTS: Data were collected from 662 patients who were randomly assigned to either a training dataset or a testing dataset using a random number generator. Among them, 26.5% had chronic disease. All models performed well, with AUROC values ranging from 0.81 to 0.84, and XGBoost was selected for its highest AUROC score and interpretability in constructing the predictive model. Age, T helper 17, T helper 17-to-regulatory T cell ratio, T helper 1, and double-negative T cells were identified as significant predictors by the XGBoost algorithm. CONCLUSION: We developed a precise predictive model for chronicity in pediatric ITP using ML during the initial phase. The XGBoost model achieved high predictive accuracy by using individual patient clinical parameters and demonstrated commendable interpretability.

Machine learning model for predicting physical activity related bleeding risk in Chinese boys with haemophilia A.

BACKGROUND: Physical activity is a crucial part of an active lifestyle for haemophiliac children. However, the fear of bleeds has been identified as barriers to participating physical activity for haemophiliac children even with prophylaxis. Lack of evidence and metrics driven by data is key problem. OBJECTIVES: We aim to develop machine learning models based on clinical data with multiple potential factors considered to predict risk of physical activity bleeding for haemophilia children with prophylaxis. METHODS: From this cohort study, we collected information on 98 haemophiliac children with adequate prophylaxis (trough FVIII:C level > 1 %). The involved potential predictor variables include demographic information, treatment information, physical activity, joint evaluation, and pharmacokinetic parameters, etc. We applied CoxPH, Random Survival Forests (RSF) and DeepSurv to construct prediction models for the risk of bleeding during physical activities. All three survival analysis models were internally and externally validated. RESULTS: A total of 98 patients were enrolled in this study. Their median age was 7.9 (5.5, 10.2) years. The CoxPH, RSF and DeepSurv models' discriminative and calibration abilities were all high, and the RSF model had the best performance (Internal validation: C-index, 0.7648 ± 0.0139; Brier Score, 0.1098 ± 0.0015; External validation: C-index, 0.7260 ± 0.0154; Brier Score, 0.0930 ± 0.0018). The prediction curves demonstrated that the developed RSF model can distinguish the risks well between bleeding and non-bleeding patients, as well as patients with different levels of physical activity. Meanwhile, the feature importance analysis confirmed that physical activity bleeding was deduced by comprehensive effects of various factors, and the importance of different factors on bleeding outcome is discrepant. CONCLUSIONS: This study revealed from the mechanism that it is necessary to incorporate multiple factors to accurately predict physical activity related bleeding risk. In clinical practice, the designed machine learning models can provide guidance for children with haemophilia A to positively participate in physical activity.

Heat Stress-Induced Fetal Intrauterine Growth Restriction Is Associated with Elevated LPS Levels Along the Maternal Intestine-Placenta-Fetus Axis in Pregnant Mice.

The exacerbation of the greenhouse effect has made heat stress (HS) an important risk factor for the occurrence of intrauterine growth restriction (IUGR). The experiment aims to uncover the effects of maternal HS on IUGR and its mechanisms. The results showed that HS leads to decreased maternal and fetal birth weights, accompanied by increased serum oxidative stress and cortisol levels. Moreover, HS inflicted significant damage to both the intestinal and placental barriers, altering maternal gut microbiota and increasing intestinal LPS levels. As a result, LPS levels increased in maternal serum, placenta, and fetus. Furthermore, HS damaged the intestinal structure, intensifying inflammation and disrupting the redox balance. The placenta exposed to HS exhibited changes in the placental structure along with disrupted angiogenesis and decreased levels of nutritional transporters. Additionally, the leakage of LPS triggered placental JNK and ERK phosphorylation, ultimately inducing severe placental inflammation and oxidative stress. This study suggests that LPS translocation from the maternal intestine to the fetus, due to a disrupted gut microbiota balance and compromised intestinal and placental barrier integrity, may be the primary cause of HS-induced IUGR. Furthermore, increased LPS leakage leads to placental inflammation, redox imbalance, and impaired nutrient transport, further restricting fetal growth.

Increasing Reduction Potentials of Type 1 Copper Center and Catalytic Efficiency of Small Laccase from Streptomyces coelicolor through Secondary Coordination Sphere Mutations.

The key to type 1 copper (T1Cu) function lies in the fine tuning of the CuII/I reduction potential (E°'T1Cu ) to match those of its redox partners, enabling efficient electron transfer in a wide range of biological systems. While the secondary coordination sphere (SCS) effects have been used to tune E°'T1Cu in azurin over a wide range, these principles are yet to be generalized to other T1Cu-containing proteins to tune catalytic properties. To this end, we have examined the effects of Y229F, V290N and S292F mutations around the T1Cu of small laccase (SLAC) from Streptomyces coelicolor to match the high E°'T1Cu of fungal laccases. Using ultraviolet-visible absorption and electron paramagnetic resonance spectroscopies, together with X-ray crystallography and redox titrations, we have probed the influence of SCS mutations on the T1Cu and corresponding E°'T1Cu . While minimal and small E°'T1Cu increases are observed in Y229F- and S292F-SLAC, the V290N mutant exhibits a major E°'T1Cu increase. Moreover, the influence of these mutations on E°'T1Cu is additive, culminating in a triple mutant Y229F/V290N/S292F-SLAC with the highest E°'T1Cu of 556 mV vs. SHE reported to date. Further activity assays indicate that all mutants retain oxygen reduction reaction activity, and display improved catalytic efficiencies (kcat /KM ) relative to WT-SLAC.

Evaluation of skin sympathetic nervous activity for classification of intracerebral hemorrhage and outcome prediction.

Classification and outcome prediction of intracerebral hemorrhage (ICH) is critical for improving the survival rate of patients. Early or delayed neurological deterioration is common in ICH patients, which may lead to changes in the autonomic nervous system (ANS). Therefore, we proposed a new framework for ICH classification and outcome prediction based on skin sympathetic nervous activity (SKNA) signals. A customized measurement device presented in our previous papers was used to collect data. 117 subjects (50 healthy control subjects and 67 ICH patients) were recruited for this study to obtain their 5-min electrocardiogram (ECG) and SKNA signals. We extracted the signal's time-domain, frequency-domain, and nonlinear features and analyzed their differences between healthy control subjects and ICH patients. Subsequently, we established the ICH classification and outcome evaluation model based on the eXtreme Gradient Boosting (XGBoost). In addition, heart rate variability (HRV) as an ANS assessment method was also included as a comparison method in this study. The results showed significant differences in most features of the SKNA signal between healthy control subjects and ICH patients. The ICH patients with good outcomes have a higher change rate and complexity of SKNA signal than those with bad outcomes. In addition, the accuracy of the model for ICH classification and outcome prediction based on the SKNA signal was more than 91% and 83%, respectively. The ICH classification and outcome prediction based on the SKNA signal proved to be a feasible method in this study. Furthermore, the features of change rate and complexity, such as entropy measures, can be used to characterize the difference in SKNA signals of different groups. The method can potentially provide a new tool for rapid classification and outcome prediction of ICH patients. Index Terms-intracerebral hemorrhage (ICH), skin sympathetic nervous activity (SKNA), classification, outcome prediction, cardiovascular and cerebrovascular diseases.

Anticancer peptides from induced tumor-suppressing cells for inhibiting osteosarcoma cells.

Osteosarcoma (OS) is the most frequent primary bone cancer, which is mainly suffered by children and young adults. While the current surgical treatment combined with chemotherapy is effective for the early stage of OS, advanced OS preferentially metastasizes to the lung and is difficult to treat. Here, we examined the efficacy of ten anti-OS peptide candidates from a trypsin-digested conditioned medium that was derived from the secretome of induced tumor-suppressing cells (iTSCs). Using OS cell lines, the antitumor capabilities of the peptide candidates were evaluated by assaying the alterations in metabolic activities, proliferation, motility, and invasion of OS cells. Among ten candidates, peptide P05 (ADDGRPFPQVIK), a fragment of aldolase A (ALDOA), presented the most potent OS-suppressing capabilities. Its efficacy was additive with standard-of-care chemotherapeutic agents such as cisplatin and doxorubicin, and it downregulated oncoproteins such as epidermal growth factor receptor (EGFR), Snail, and Src in OS cells. Interestingly, P05 did not present inhibitory effects on non-OS skeletal cells such as mesenchymal stem cells and osteoblast cells. Collectively, this study demonstrated that iTSC-derived secretomes may provide a source for identifying anticancer peptides, and P05 may warrant further evaluations for the treatment of OS.

Survey of organ-derived small extracellular vesicles and particles (sEVPs) to identify selective protein markers in mouse serum.

Extracellular vesicles and particles (EVPs) are secreted by organs across the body into different circulatory systems, including the bloodstream, and reflect pathophysiologic conditions of the organ. However, the heterogeneity of EVPs in the blood makes it challenging to determine their organ of origin. We hypothesized that small (s)EVPs (<100 nm in diameter) in the bloodstream carry distinctive protein signatures associated with each originating organ, and we investigated this possibility by studying the proteomes of sEVPs produced by six major organs (brain, liver, lung, heart, kidney, fat). We found that each organ contained distinctive sEVP proteins: 68 proteins were preferentially found in brain sEVPs, 194 in liver, 39 in lung, 15 in heart, 29 in kidney, and 33 in fat. Furthermore, we isolated sEVPs from blood and validated the presence of sEVP proteins associated with the brain (DPP6, SYT1, DNM1L), liver (FABPL, ARG1, ASGR1/2), lung (SFPTA1), heart (CPT1B), kidney (SLC31), and fat (GDN). We further discovered altered levels of these proteins in serum sEVPs prepared from old mice compared to young mice. In sum, we have cataloged sEVP proteins that can serve as potential biomarkers for organ identification in serum and show differential expression with age.

The YAP-TEAD complex promotes senescent cell survival by lowering endoplasmic reticulum stress.

Sublethal cell damage can trigger senescence, a complex adaptive program characterized by growth arrest, resistance to apoptosis and a senescence-associated secretory phenotype (SASP). Here, a whole-genome CRISPR knockout screen revealed that proteins in the YAP-TEAD pathway influenced senescent cell viability. Accordingly, treating senescent cells with a drug that inhibited this pathway, verteporfin (VPF), selectively triggered apoptotic cell death largely by derepressing DDIT4, which in turn inhibited mTOR. Reducing mTOR function in senescent cells diminished endoplasmic reticulum (ER) biogenesis, triggering ER stress and apoptosis due to high demands on ER function by the SASP. Importantly, VPF treatment decreased the numbers of senescent cells in the organs of old mice and mice exhibiting doxorubicin-induced senescence. Moreover, VPF treatment reduced immune cell infiltration and pro-fibrotic transforming growth factor-ß signaling in aging mouse lungs, improving tissue homeostasis. We present an alternative senolytic strategy that eliminates senescent cells by hindering ER activity required for SASP production.

Practical Electrochemical Method to Enhance Needle Visibility during Ultrasound Imaging.

Ultrasound-guided needle interventions play a pivotal role in the diagnosis and treatment processes in clinical practice. However, existing echogenic needles face challenges in achieving a balance between effectiveness, ease of manufacturing, and inexpensiveness. In this study, we developed an echogenic needle that encompassed the aforementioned advantages through the use of the electrolysis technology. The overall contour of the needle after electrolysis was observed using bright-field microscopy, while scanning electron microscopy (SEM) was employed to examine the micro-variations on the needle's surface. Subsequently, we validated the enhanced visualization effects in vitro (pork) and in vivo (anesthetized rabbit's thigh) puncture phantoms. To ensure the safety of the needles after the puncture procedure, we conducted Vickers hardness tests, SEM detection, bright-field microscopy, and DAPI staining. The results demonstrated that the surface roughness of the needle increased with the duration of electrolysis. Taking into account the comprehensive safety tests, the needle, subjected to 40 s of electrolysis, demonstrated a safe and effective enhancement of ultrasound visualization.