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Abstract Multichannel meta-imaging, inspired by the parallel-processing capability of neuromorphic computing, offers considerable advancements in resolution enhancement and edge discrimination in imaging systems, extending even into the mid- to far-infrared spectrum. Currently typical multichannel infrared imaging systems consist of separating optical gratings or merging multi-cameras, which require complex circuit design and heavy power consumption, hindering the implementation of advanced human-eye-like imagers. Here, we present printable graphene plasmonic photodetector arrays driven by a ferroelectric superdomain for multichannel meta-infrared imaging with enhanced edge discrimination. The fabricated photodetectors exhibited multiple spectral responses with zero-bias operation by directly rescaling the ferroelectric superdomain instead of reconstructing the separated gratings. We also demonstrated enhanced and faster shape classification (98.1%) and edge detection (98.2%) using our multichannel infrared images compared with single-channel detectors. Our proof-of-concept photodetector arrays simplify multichannel infrared imaging systems and offer potential solutions in efficient edge detection in human-brain-type machine vision.

In the fall accident on stairs, a human body receives a multiple impact on the body including on the head in a short time, as a result it often results in being unidentified which impact gives what kind of damage in the human body. However, it is important in addition to emergency treatment to know the process of the accident when brain may be injured to predict prognostic process. In this paper, the fatal accident by the fall on the stairs is analyzed, in which the cause of death was cerebral contusion, and plural damage traces were observed on a body including the head. In the first stage of the accident analysis, possible fall motions are reproduced repeatedly based on multibody dynamics, and the fall motion that the physical damage trace fitted the reported position of the blow is chosen from them. In the next stage, finite element analyses are performed in which the initial condition in a posture and the initial velocity for each impact obtained from the fall motion are given as initial condition, and the possibility of the head injuries are evaluated. The analysis results indicates that in the case, there is a high likelihood of falling during descending the stairs, followed by sliding down with rotation. During this sequence, the head experiences three impacts, each impact indicated the potential for causing specific types of injuries.

Abstract Doxorubicin (DOX) is a chemotherapeutic agent widely used for tumor treatment. Nonetheless its clinical application is heavily limited by its cardiotoxicity. There is accumulated evidence that transplantation of mesenchymal stem cell-derived exosomes (MSC-EXOs) can protect against Dox-induced cardiomyopathy (DIC). This study aimed to examine the cardioprotective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) against DIC and explore the potential mechanisms. EXOs were isolated from the cultural supernatant of human BM-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) by ultracentrifugation. A mouse model of DIC was induced by intraperitoneal injection of Dox followed by tail vein injection of PBS, BM-MSC-EXOs, or iPSC-MSC-EXOs. Cardiac function, cardiomyocyte senescence and mitochondrial dynamics in each group were assessed. In vitro, neonatal mouse cardiomyocytes (NMCMs) were subjected to Dox and treated with BM-MSC-EXOs or iPSC-MSC-EXOs. The mitochondrial morphology and cellular senescence of NMCMs were examined by Mitotracker staining and senescence-associated-β-galactosidase assay, respectively. Compared with BM-MSC-EXOs, mice treated with iPSC-MSC-EXOs displayed improved cardiac function and decreased cardiomyocyte mitochondrial fragmentation and senescence. In vitro, iPSC-MSC-EXOs were superior to BM-MSC-EXOs in attenuation of cardiomyocyte mitochondrial fragmentation and senescence caused by DOX. MicroRNA sequencing revealed a higher level of miR-9-5p in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, iPSC-MSC-EXOs transported miR-9-5p into DOX-treated cardiomyocytes, thereby suppressing cardiomyocyte mitochondrial fragmentation and senescence via regulation of the VPO1/ERK signal pathway. These protective effects and cardioprotection against DIC were largely reversed by knockdown of miR-9-5p in iPSC-MSC-EXOs. Our results showed that miR-9-5p transferred by iPSC-MSC-EXOs protected against DIC by alleviating cardiomyocyte senescence via inhibition of the VPO1/ERK pathway. This study offers new insight into the application of iPSC-MSC-EXOs as a novel therapeutic strategy for DIC treatment. Graphical Abstract

Abdominal Aortic Aneurysm (AAA) is a life-threatening vascular disease characterized by the weakening and ballooning of the abdominal aorta, which has no effective therapeutic approaches due to unclear molecular mechanisms. Using single-cell RNA sequencing, we analyzed the molecular profile of individual cells within control and AAA abdominal aortas. We found cellular heterogeneity, with increased plasmacytoid dendritic cells and reduced endothelial cells and vascular smooth muscle cells (VSMCs) in AAA. Up-regulated genes in AAA were associated with muscle tissue development and apoptosis. Genes controlling VSMCs aberrant switch from contractile to synthetic phenotype were significantly enriched in AAA. Additionally, VSMCs in AAA exhibited cell senescence and impaired oxidative phosphorylation. Similar observations were made in a mouse model of AAA induced by Angiotensin II, further affirming the relevance of our findings to human AAA. The concurrence of gene expression changes between human and mouse highlighted the impairment of oxidative phosphorylation as a potential target for intervention. Nicotinamide phosphoribosyltransferase (NAMPT, also named VISFATIN) signaling emerged as a signature event in AAA. NAMPT was significantly downregulated in AAA. NAMPT-extracellular vesicles (EVs) derived from mesenchymal stem cells restored NAMPT levels, and offered protection against AAA. Furthermore, NAMPT-EVs not only repressed injuries, such as cell senescence and DNA damage, but also rescued impairments of oxidative phosphorylation in both mouse and human AAA models, suggesting NAMPT supplementation as a potential therapeutic approach for AAA treatment. These findings shed light on the cellular heterogeneity and injuries in AAA, and offered promising therapeutic intervention for AAA treatment.

Background: Diabetic cardiomyopathy (DC), a frequent complication of type 2 diabetes mellitus (T2DM), is mainly associated with severe adverse outcomes. Previous research has highlighted the role of Lysophosphatidylcholine (LPC) in inducing myocardial injury; however, the specific mechanisms through which LPC mediate such injury in DC remain elusive. The existing knowledge gap underscores the need for additional clarification. Consequently, this study aimed to explore the impact and underlying mechanisms of LPC on myocardial injury in DC. Methods: A total of 55 patients diagnosed with T2DM and 62 healthy controls were involved. A combination of 16s rRNA sequencing, metabolomic analysis, transcriptomic RNA-sequencing (RNA-seq), and whole exome sequencing (WES) was performed on fecal and peripheral blood samples collected from the participants. Following this, correlation analysis was carried out, and the results were further validated through the mouse model of T2DM. Results: Four LPC variants distinguishing T2DM patients from healthy controls were identified, all of which were upregulated in T2DM patients. Specifically, Lysopc (16:0, 2 N isoform) and LPC (16:0) exhibited a positive correlation with nuclear factor kappa B subunit 2 (NFKB2) and a negative correlation with Zinc finger protein 480 (ZNF480) Furthermore, the expression levels of Toll-like receptor 4 (TLR4), c-Jun, c-Fos, and NFKB2 were upregulated in the peripheral blood of T2DM patients and in the myocardial tissue of T2DM mice, whereas ZNF480 expression level was downregulated. Lastly, myocardial injury was identified in T2DM mice. Conclusions: The results indicated that LPC could induce myocardial injury in DC through the TLR4/ZNF480/AP-1/NF-kB pathway, providing a precise target for the clinical diagnosis and treatment of DC.

The understanding of the function of perivascular adipose tissue (PVAT) in vascular aging has significantly changed due to the increasing amount of information regarding its biology. Adipose tissue surrounding blood vessels is increasingly recognized as a key regulator of vascular disorders. It has significant endocrine and paracrine effects on the vasculature and is mediated by the production of a variety of bioactive chemicals. It also participates in a number of pathological regulatory processes, including oxidative stress, immunological inflammation, lipid metabolism, vasoconstriction, and dilation. Mechanisms of homeostasis and interactions between cells at the local level tightly regulate the function and secretory repertoire of PVAT, which can become dysregulated during vascular aging. The PVAT secretion group changes from being reducing inflammation and lowering cholesterol to increasing inflammation and increasing cholesterol in response to systemic or local inflammation and insulin resistance. In addition, the interaction between the PVAT and the vasculature is reciprocal, and the biological processes of PVAT are directly influenced by the pertinent indicators of vascular aging. The architectural and biological traits of PVAT, the molecular mechanism of crosstalk between PVAT and vascular aging, and the clinical correlation of vascular age-related disorders are all summarized in this review. In addition, this paper aims to elucidate and evaluate the potential benefits of therapeutically targeting PVAT in the context of mitigating vascular aging. Furthermore, it will discuss the latest advancements in technology used for targeting PVAT.

Accurately estimating global soil heterotrophic respiration (RH) is crucial in evaluating whether terrestrial ecosystems act as carbon sources or sinks. However, current global RH estimates were significantly restricted by the scarcity of in situ RH observations and their biased distribution, leading to considerable uncertainties. This study developed a novel data-driven model of global RH based on the environmentally similar zones of global in situ RH sites with daily and subdaily observations and remote sensing data with high spatial and temporal resolutions. Compared with the unified modeling method using all available data as the training samples of data-driven models, our zone modeling method was more accurate. The relationship between observed and predicted RH was improved, with the R2 value increasing from 0.41 to 0.53 and the RMSE decreasing from 0.87 to 0.78 g C m−2 d−1. Our study effectively improved the problem that the data-driven models were highly affected by the spatial representativeness of in situ RH observations and achieved a significantly improved accuracy for global RH estimation entirely based on remote sensing data. Future research focusing on improving the sparse sampling of in situ RH sites and the availability of remote sensing data will help to reduce the uncertainties of our study.

This study aimed to clarify the differences between the previously reported mechanisms of sports-related concussion (SRC) injuries without a loss of consciousness in contact and collision sports and the mechanisms of SRC injuries in our cases. Based on two videos of SRC injuries occurring during a men’s rhythmic gymnastics competition (three people were injured), the risk of SRC occurrence was estimated from various parameters using a multibody analysis and eight brain injury evaluation criteria. In the present study, the three SRC impacts that occurred in men’s rhythmic gymnastics showed significant characteristics in duration compared to previously reported cases in the contact sports. This suggests that the occurrence of SRC may have been caused by a different type of impact from that which causes SRC in contact sports (e.g., tackling). In addition, calculation of the strain indicating the rate of brain deformation suggested a risk of nerve swelling in all cases involving type 2 axonal injuries. Therefore, when reexamining sports-related head injuries, it is important to recognize the characteristics and mechanisms of SRC that occur in each different sport, as well as the symptoms and course of SRC after injury.

Sepsis-induced myocardial dysfunction (SMD) is the major cause of death in sepsis. Nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3)-mediated pyroptosis contributes to the occurrence and development of SMD. Although Apelin confers direct protection against SMD, the potential mechanisms remain unclear. This study aimed to determine whether Apelin protects against SMD via regulation of NLRP3-mediated pyroptosis of cardiomyocytes. Experimental SMD was induced in wild-type (WT) control mice and Apelin knockout (Apelin−/−) mice by cecal ligation and puncture (CLP). Neonatal mouse cardiomyocytes (NMCs) were treated with lipopolysaccharide (LPS) to simulate the physiological environment of SMD in vitro. The expression of Apelin was greatly decreased in the plasma from septic patients and septic mouse heart. Knockout of Apelin aggravated SMD, evidenced by decreased cardiac function, and increased cardiac fibrosis and NLRP3 inflammasome and pyroptosis levels in CLP-treated Apelin−/− mice compared with WT mice. Overexpression of Apelin activated the AMPK pathway and thereby inhibited NLRP3 inflammasome–mediated pyroptosis of NMCs induced by LPS in vitro These protective effects were partially abrogated by AMPK inhibitor. In conclusion, Apelin attenuated SMD by inhibiting NLRP3-mediated pyroptosis via activation of the AMPK pathway. Apelin may serve as a promising therapeutic target for SMD.

Abstract This study investigated the effects of supplementation Moringa oleifera leaf (MOL) on relieving oxidative stress, anti‐inflammation, changed the relative abundance of multiple intestinal flora and blood biochemical indices during letrozole‐induced polycystic ovary syndrome (PCOS). Previous studies have shown that MOL has anti‐inflammatory, anti‐oxidation, insulin‐sensitizing effects. However, whether MOL has beneficial effects on PCOS remains to be elucidated. In the current study, 10‐week‐old female Sprague–Dawley rats received letrozole to induce PCOS‐like rats, and subsequently were treated with a MOL diet. Then, the body weight and estrus cycles were measured regularly in this period. Finally, the ovarian morphology, blood biochemical indices, anti‐oxidative, intestinal flora, and anti‐inflammation were observed at the end of the experiment. We found that MOL supplementation markedly decreased the body weight, significantly upregulated the expression of Sirt1, FoxO1, PGC‐1α, IGF1, and substantially modulated the sex hormone level and improved insulin resistance, which may be associated with the relieves oxidative stress. Moreover, the supplementation of MOL changed the relative abundance of multiple intestinal flora, the relative abundance of Fusobacterium, Prevotella were decreased, and Blautia and Parabacteroides were increased. These results indicate that MOL is potentially a supplementary medication for the management of PCOS.

In this study, to discuss the influence of concussion risk from the long-term use of American football helmets on collegiate teams, accident cases during the game are replicated based on game videos by simulations using whole-body numerical models and helmeted finite element human head models. The concussion risks caused by collisions were estimated using the mechanical parameters inside the skull obtained from finite element analyses. In the analyses, the different material properties of helmets identified by free-fall experiments using headform impactor-embedded helmets were used to represent brand-new and long-term-use helmets. After analyzing the five cases, it was observed that wearing a new helmet instead of a long-term-use one resulted in a reduction in the risk of concussion by 1 to 44%. More energy is attenuated by the deformation of the liners of the brand-new helmet, so the energy transferred to the head is smaller than that when wearing the long-term-use helmet. Thus, the long-term use of the helmet reduces its ability to protect the head.

Abstract Senescence of vascular smooth muscle cells (VSMCs) contributes to the formation of abdominal aortic aneurysm (AAA). Although mesenchymal stem cell exosomes (MSC-EXO) have been confirmed to restrict the development of AAA, their biological activity depends largely on the physiological state of the MSCs. This study aimed to compare the effects of adipose-derived MSC-EXO from healthy donors (HMEXO) and AAA patients (AMEXO) on senescence of VSMCs in AAA and explore the underlying mechanisms. An ApoE-/- mouse model of AAA was used to investigate the therapeutic effects of HMEXO, AMEXO or miR-19b-3p-AMEXO on AAA development. This in vitro model of AAA was established by treating VSMCs with Ang II (Angiotensin II). The senescence of VSMCs was determined by senescence-associated β-galactosidase (SA-β-gal) staining. The morphology of mitochondria in VSMCs was examined by MitoTracker staining. HMEXO exhibited superior capacity compared with AMEXO to inhibit VSMC senescence and attenuate AAA formation in Ang II–treated ApoE-/- mice. In vitro, both AMEXO and HMEXO inhibited Ang II-induced VSMC senescence via downregulation of mitochondrial fission. Notably, compared with HMEXO, the ability of AMEXO to inhibit VSMC senescence was significantly decreased. miRNA sequencing and the expression of miR-19b-3p was significantly decreased in AMEXO compared with HMEXO. Luciferase assay suggested that MST4 (Mammalian sterile-20-like kinase 4) is a potential target of miR-19b-3p. Mechanistically, miR-19b-3p in HMEXO ameliorated VSMC senescence by inhibiting mitochondrial fission via regulation of the MST4/ERK/Drp1 signaling pathway. Overexpression of miR-19b-3p in AMEXO improved their beneficial effect on AAA formation. Our study reveals that MSC-exosomal miR-19b-3p exerts protective effects against Ang II-induced AAA and VSMC senescence via regulation of the MST4/ERK/Drp1 pathway. The pathological state of AAA patients alters the miRNA components of AMEXO and impairs their therapeutic benefits.

Background: The cellular senescence of mesenchymal stem cells (MSCs) limits their application in regenerative medicine. This study aimed to clarify the role of TNF receptor-associated factor 3 interacting protein 2 (TRAF3IP2), a pro-inflammatory cytoplasmic adaptor protein, in regulating MSC senescence and to explore the potential mechanisms. Methods: MSC senescence was determined by senescence-associated β-galactosidase (SA-β-gal) staining. The expression of TRAF3IP2 and senescence-related proteins was detected by Western blotting. The nicotinamide adenine dinucleotide (NAD+) level and nicotinamide phosphoribosyl transferase (NAMPT) expression in MSCs was measured. Results: Compared with that in MSCs isolated from young donors (YMSCs), the expression of TRAF3IP2 was greatly increased in MSCs derived from aged donors (AMSCs). Overexpression of TRAF3IP2 accelerated YMSC senescence whereas downregulation significantly rescued cellular senescence. The protein level of NAMPT and the level of NAD+ were significantly decreased in AMSCs compared with YMSCs. Mechanistically, TRAF3IP2 induced MSC senescence via downregulation of NAMPT expression and NAD + level by inhibiting the AMPK signaling pathway. These effects were partially reversed by treatment with an AMPK or NAMPT activator. Conclusion: We revealed that TRAF3IP2 accelerated MSC senescence via downregulation of NAMPT-mediated NAD biosynthesis by mediation of the AMPK pathway, highlighting a novel means to rejuvenate senescent MSCs.

Abstract Post-earthquake financial loss of structures induced by residual inter-story deformation (RID) has been recently noticed and various strategies have been proposed. A newly-emerged energy-dissipation material, namely, iron-based shape-memory-alloy (Fe-SMA), has gain favor in civil engineering community due to its extraordinary low-cycle fatigue resistance property. Besides, Fe-SMA is believed to help improve structure’s post-earthquake residual inter-story deformation control capacity due to its moderate strain hardening behavior and pseudo-elasticity. This study explores the performance of emerging steel frame systems equipped with energy-dissipation devices fabricated with Fe-SMA. In particular, a brace with built-in Fe-SMA-based U-shaped strips (USSs) is employed serving as the energy-dissipation devices in the proposed system. In this paper, the basic mechanical properties of Fe-SMA are discussed firstly, followed by a description of the working principle of the USSs. The hysteresis behavior of two types of USSs, fabricated with Fe-SMA and conventional mild steel (Q235), were investigated experimentally. Based on the test results, numerical models for the prototype braces equipped with USSs are established using ABAQUS and OpenSEES, and the necessary key material parameters are calibrated. Subsequently, system-level analysis is performed on 5-story prototype steel buildings. Specially, two types of steel frames, i.e., frames with high-strength-steel columns and frames with conventional structural steel-based columns, are established. Concurrently, braces with Fe-SMA-based USSs as well as mild steel-based USSs are considered. The results demonstrated that the Fe-SMA-based energy-dissipation devices along with the steel frames with high-strength-steel columns can provide the most satisfied RID control effectiveness compared with the other yielding structural systems investigated in this paper.

Sclerotinia sclerotiorum is a plant pathogenic fungus that causes white mold or stem rot diseases. It affects mostly dicotyledonous crops, resulting in significant economic losses worldwide. Sclerotia formation is a special feature of S. sclerotiorum, allowing its survival in soil for extended periods and facilitates the spread of the pathogen. However, the detailed molecular mechanisms of how sclerotia are formed and how virulence is achieved in S. sclerotiorum are not fully understood. Here, we report the identification of a mutant that cannot form sclerotia using a forward genetics approach. Next-generation sequencing of the mutant’s whole genome revealed candidate genes. Through knockout experiments, the causal gene was found to encode a cAMP phosphodiesterase (SsPDE2). From mutant phenotypic examinations, we found that SsPDE2 plays essential roles not only in sclerotia formation, but also in the regulation of oxalic acid accumulation, infection cushion functionality and virulence. Downregulation of SsSMK1 transcripts in Sspde2 mutants revealed that these morphological defects are likely caused by cAMP-dependent inhibition of MAPK signaling. Moreover, when we introduced HIGS construct targeting SsPDE2 in Nicotiana benthamiana, largely compromised virulence was observed against S. sclerotiorum. Taken together, SsPDE2 is indispensable for key biological processes of S. sclerotiorum and can potentially serve as a HIGS target to control stem rot in the field.

Abstract Mitochondrial dysfunction is considered to be a key contributor to the development of heart failure. Replacing injured mitochondria with healthy mitochondria to restore mitochondrial bioenergy in myocardium holds great promise for cardioprotection after infarction. This study aimed to investigate whether direct transplantation of exogenous mitochondria derived from mesenchymal stem cells (MSC‐mt) is beneficial and superior in protecting cardiac function in a mouse model of myocardial infarction (MI) compared to mitochondria derived from skin fibroblast (FB‐mt) and to explore the underlying mechanisms from their effects on the endothelial cells. The isolated MSC‐mt presented intact mitochondrial morphology and activity, as determined by electron microscopy, JC‐1 mitochondrial membrane potential assay, and seahorse assay. Direct injection of MSC‐mt into the peri‐infarct region in a mouse MI model enhanced blood vessel density, inhibited cardiac remodeling and apoptosis, thus improving heart function compared with FB‐mt group. The injected MSC‐mt can be tracked in the endothelial cells. In vitro, the fluorescence signal of MSC‐mt can be detected in human umbilical vein endothelial cells (HUVECs) by confocal microscopy and flow cytometry after coculture. Compared to FB‐mt, MSC‐mt more effectively protected the HUVECs from oxidative stress‐induced apoptosis and reduced mitochondrial production of reactive oxygen species. MSC‐mt presented superior capacity in inducing tube formation, enhancing SCF secretion, ATP content and cell proliferation in HUVECs compared to FB‐mt. Mechanistically, MSC‐mt administration alleviated oxidative stress‐induced endothelial senescence via activation of ERK pathway. These findings suggest that using MSCs as sources of mitochondria is feasible and that proangiogenesis could be the mechanism by which MSC‐mt transplantation attenuates MI. MSC‐mt transplantation might serve as a new therapeutic strategy for treating MI.

IntroductionSarcopenia is a clinical syndrome characterized by a progressive and extensive decline in skeletal muscle mass, muscle strength, and function. Sarcopenia and cardiovascular diseases (CVDs) can coexist, which further decreases the quality of life of patients, and increases the mortality rate. MicroRNAs (miRNAs) are unique posttranscriptional regulators of gene expression whose function in aging-related sarcopenia and CVDs has recently begun to unravel. The aim of the present study is to investigate the relationship between sarcopenia and cardiovascular risk factors (CVRF) in the Chinese elderly and describe the circulating miRNAs in sarcopenia patients with the intention of identifying novel diagnostic and therapeutic tools.MethodsThe well-established CVRF of diabetes, hypertension, and dyslipidemia were assessed. Multiple logistic regression analyses and linear regressions were used to evaluate the components of CVRF and the number of CVRF in elderly patients with sarcopenia. Moreover, we used real-time RT-PCR to measure the abundance of the CVRF-related miRNAs in the plasma of a cohort of 93 control and sarcopenia individuals, including miR-29b, miR-181a, and miR-494.ResultsWe found that CVRF was associated with a high prevalence of sarcopenia in elderly Chinese populations After adjusting for potential confounders. Furthermore, hypertension and dyslipidemia, but not diabetes, were found to be significantly associated with sarcopenia. A linear increase in the prevalence of sarcopenia was found to be associated with the number of CVRF components in the elderly population. We found that plasma miR-29b levels were significantly down-regulated in response to sarcopenia in the elderly with CVRF. In particular, there was a remarkable correlation between miR-29b and appendicular skeletal muscle mass (ASM)/height2. Collectively, knowledge of CVRF, particularly hypertension and dyslipidemia, may help predict the risk of sarcopenia in the elderly. Our data also show that circulating miR-29b can be considered as possible biomarkers for sarcopenia, which may also be used in the CVD assessment of these patients.DiscussionWe found that the prevalence of sarcopenia was significantly proportional to the number of CVRF components. In particular, hypertension and dyslipidemia were significantly associated with a higher risk of sarcopenia in the adjusted models. Moreover, our study has been proven that c-miRNAs may be considered as possible biomarkers for sarcopenia as a new diagnostic tool to monitor response to treatment. There is also a pressing need for further research on sarcopenia and CVRF to understand their relationship and mechanism. These can provide more evidence to develop potential interventions to improve clinical outcomes.

Abstract Background Application of mesenchymal stem cell-derived exosomes (MSC-EXO) has emerged as a novel therapeutic strategy for myocardial infarction (MI). Our previous study showed that pretreatment with hemin, a potent heme oxygenase-1 (HO-1) inducer, enhanced the cardioprotective effects of MSCs in a mouse model of MI. This study aimed to investigate the therapeutic effects of EXO derived from hemin-pretreated MSCs (Hemin-MSC-EXO) in MI and explore the potential mechanisms. Methods MSC-EXO and Hemin-MSC-EXO were collected and characterized. MSC-EXO and Hemin-MSC-EXO were intramuscularly injected into the peri-infarct region in a mouse model of MI. Heart function of mice was assessed by echocardiography. The mitochondrial morphology of neonatal mice cardiomyocytes (NMCMs) under serum deprivation and hypoxic (SD/H) conditions was examined by Mitotracker staining. The cellular senescence of NMCMs was determined by senescence-associated-β-galactosidase assay. A loss-of-function approach was adopted to determine the role of Hemin-MSC-exosomal-miR-183-5p in the regulation of cardiomyocyte senescence Results EXO were successfully isolated from the supernatant of MSCs and Hemin-pretreated MSCs. Compared with MSC-EXO, injection of Hemin-MSC-EXO significantly improved cardiac function and reduced fibrosis. Both MSC-EXO and Hemin-MSC-EXO ameliorated cardiomyocyte senescence and mitochondrial fission in vitro and in vivo, and the latter exhibited better protective effects. MicroRNA sequencing revealed a higher level of miR-183-5p in Hemin-MSC-EXO than in MSC-EXO. MiR-183-5p knockdown partially abrogated the protective effects of Hemin-MSC-EXO in attenuating mitochondrial fission and cellular senescence of cardiomyocytes induced by SD/H. High mobility group box-1 (HMGB1) abundance was lower in Hemin-MSC-EXO-treated than MSC-EXO-treated mouse hearts, and HMGB1 was identified as one of the potential target genes of miR-183-5p. Mechanistically, Hemin-MSC-EXO inhibited SD/H-induced cardiomyocyte senescence partially by delivering miR-183-5p into recipient cardiomyocytes via regulation of the HMGB1/ERK pathway. Furthermore, knockdown of miR-183-5p reduced the Hemin-MSC-EXO-mediated cardioprotective effects in a mouse model of MI. Conclusion Our results reveal that Hemin-MSC-EXO are superior to MSC-EXO in treating MI. Exosomal miR-183-5p mediates, at least partially, the cardioprotective effects of Hemin-MSC-EXO by inhibiting cardiomyocyte senescence via regulation of the HMGB1/ERK pathway. This study highlights that MSC-EXO have high translational value in repairing cardiac dysfunction following infarction. Graphic abstract

In this study, based on the EM-DAT (The Emergency Events Database) database, disaster assessment for the “Belt and Road” region was carried out in relation to the $${\rm{SD}}{{\rm{G}}_{13.1.1}}$$ indicator of the Sustainable Development Goals (SDGs) agenda launched in 2015. A new method for diagnosing trends in the $${\rm{SD}}{{\rm{G}}_{13.1.1}}$$ indicators based on the Theil-Sen median method is proposed. In addition, using the data available in the EM-DAT, an overview of disaster records is used to quantify disasters for a total of 73 countries. The disaster trends for the period 2015‒2019 were found to demonstrate the following. (1) As a result of geological and climate conditions, Asia and Africa are high-risk disaster areas and disasters have caused considerable economic losses and affected the populations in developing and underdeveloped countries in these regions. (2) The clear positive value of $$\Delta {\rm{s}}13.1.1$$ found for China reflects the country’s encouraging achievements in disaster prevention and mitigation. (3) The value of $${\rm{SD}}{{\rm{G}}_{13.1.1}}$$ was observed to be increasing in South Asia, northwest Africa and South Africa, with the increase in India and Mauritania being the most serious. The new method proposed in this paper allows the real trend in the $${\rm{SD}}{{\rm{G}}_{13.1.1}}$$ indicator in various countries to be derived and provides critical intelligence support for international disaster risk reduction plans and sustainable development goals.

BackgroundGlioblastoma (GBM) is a malignant brain tumor associated with high morbidity and mortality rates with a poor prognosis. In recent years, studies on prognostic markers such as programmed death ligand 1 (PD-L1) have increased; however, their conclusions remain controversial. Here, relevant literature was reviewed and a meta-analysis was performed to clarify the correlation between PD-L1 expression and overall survival (OS) in GBM.MethodsThe non-foundational literature on PD-L1 expression associated with OS in GBM up to February 2022 was searched in the PubMed, Metstr, Cochrane, and Web of Science databases. Literature was rigorously screened according to inclusion and exclusion criteria, the total hazard ratio (HR), and corresponding 95% confidence intervals (CIs).ResultsCalculating the combined HR value and corresponding 95% CI of HR=1.124 (95% CI: 1.047–1.201, P=0.000, I2 (I-squared)=48.8%), it was shown that PD-L1 expression was significantly associated with low OS in GBM patients. Although I2 = 48.8% < 50%, to make the results more credible, in the cutoff values ≥10% subgroup HR=1.37 (95% CI: 1.07–1.67, P=0.000, I2 = 0%), which was also the result found in the first meta-analysis. In contrast, in the cutoff value ≥5% subgroup HR=1.14 (95% CI: 0.98–1.30, P=0.000, I2 = 59.8%) and in the cutoff value median PD-L1 expression levels subgroup HR=1.05 (95% CI: 0.92–1.18, P=0.000, I2 = 0%), indicating that PD-L1 expression was not associated with low OS in GBM. Furthermore, in four studies, we found no significant correlation between PD-L1 expression and the progression-free survival of GBM (HR=1.14, 95% CI:0.40–1.88, P=0.03, I2 = 29.3%).ConclusionPD-L1 expression was significantly associated with low OS in GBM patients; however, this result needs to be interpreted with caution and requires a large, multicenter clinical study in patients with similar baseline data for further evaluation.

Abstract Background Mesenchymal stem cells (MSCs) can improve cutaneous wound healing via the secretion of growth factors. However, the therapeutic efficacy of MSCs varies depending upon their source. Induced pluripotent stem cells are emerging as a promising source of MSCs with the potential to overcome several limitations of adult MSCs. This study compared the effectiveness of conditioned medium of MSCs derived from induced pluripotent stem cells (iMSC-CdM) with that derived from umbilical cord MSCs (uMSC-CdM) in a mouse cutaneous wound healing model. We also investigated the mechanisms of protection. Methods The iMSC-CdM or uMSC-CdM were topically applied to mice cutaneous wound model. The recovery rate, scar formation, inflammation and angiogenesis were measured. We compared angiogenesis cytokine expression between iMSC-CdM and uMSC-CdM and their protective effects on human umbilical vein endothelial cells (HUVECs) under H2O2-induced injury. The effects of iMSC-CdM on energy metabolism, mitochondria fragmentation and apoptosis were measured. Results Topical application of iMSC-CdM was superior to the uMSC-CdM in accelerating wound closure and enhancing angiogenesis. Expression levels of angiogenetic cytokines were higher in iMSC-CdM than they were in uMSC-CdM. The iMSC-CdM protected HUVECs from H2O2 induced injury more effectively than uMSC-CdM did. Administration of iMSC-CdM stimulated HUVEC proliferation, tube formation and energy metabolism via the ERK pathway. Mechanistically, iMSC-CdM inhibited H2O2-induced mitochondrial fragmentation and apoptosis of HUVECs. Conclusion Collectively, these findings indicate that iMSC-CdM is more effective than uMSC-CdM in treating cutaneous wounds, and in this way, iMSC-CdM may serve as a more constant and sustainable source for cell-free therapeutic approach. Graphical abstract

Glioblastoma multiforme (GBM) has been identified as a frequently occurring adult primary brain cancer that is highly aggressive. Currently, the prognostic outcome for GBM patients is dismal, even with intensive treatment, and the median overall survival (OS) is 14.6 months. Immunotherapy, which is specific at the cellular level and can generate persistent immunosurveillance, is now becoming a promising tool to treat diverse cancers. However, the complicated nature of the tumor microenvironment (TME) makes it challenging to develop anti-GBM immunotherapy because several cell types, cytokines, and signaling pathways are involved in generating the immunosuppressive environment. Novel immunotherapies can illustrate novel tumor-induced immunosuppressive mechanisms. Here, we used unsupervised clustering analysis to identify different subtypes of immune cell infiltration that actuated different prognoses, biological actions, and immunotherapy responses. Gene cluster A, with a hot immune cell infiltration phenotype, had high levels of immune-related genes (IRGs), which were associated with immune pathways including the interferon-gamma response and interferon-alpha response, and had low IDH1 and ATRX mutation frequencies. Gene cluster B, a cold immune cell infiltration subtype, exhibited a high expression of the KCNIP2, SCRT1, CPLX2, JPH3, UNC13A, GABRB3, ARPP21, DLGAP1, NRXN1, DLL3, CA10, MAP2, SEZ6L, GRIA2, and GRIA4 genes and a low expression of immune-related genes, i.e., low levels of immune reactivity. Our study highlighted the complex interplay between immune cell infiltration and genetic mutation in the establishment of the tumor immune phenotype. Gene cluster A was identified as an important subtype with a better prognosis and improved immunotherapy response.

Objective: To evaluate the clinical efficacy of infusion of gemcitabine (GEM) and fluorouracil (5-FU)through the celiac artery and superior mesenteric artery in the treatment of pancreatic carcinoma (PC). Methods: We analyzed 20 patients diagnosed clinically or pathologically with PC, without metastases, who had an estimated survival duration of >3 months in our department from May 2009 to December 2014. Nine patients were treated directly without surgical resection of the tumor, while the other 11 patients were treated after surgery. In all patients, the femoral artery was punctured using the Seldinger technique, and a catheter was placed in the opening of the celiac artery or the superior mesenteric artery. We administered 500 ​mg/m2 GEM and 500 ​mg/m2 5-FU. Observational data included data on clinical efficacy and survival rates during the follow-up period of 3–72 months. Results: Twenty patients were treated 85 times with transcatheter arterial infusion chemotherapy (TAI). The survival rates were 80%, 40%, 35%, 20%, 10%, and 5% at 3, 6, 12, 24, and 72 months, respectively. Conclusion: TAI chemotherapy with GEM and 5-FU may be a therapeutic option for the treatment of PC.

Abstract Background Idiopathic pulmonary fibrosis (IPF) is an age-related disease with no cure. Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy for IPF treatment. Nevertheless, MSCs derived from patients with IPF (IPF-MSCs) become senescent, thereby reducing their beneficial effects in IPF. MicroRNAs (miRNAs) mediate the senescence of MSCs, but the underlying mechanisms are not fully understood. We investigated the mechanisms by which miR-199a-5p regulates IPF-MSC senescence and whether its inhibition could rejuvenate IPF-MSCs and enhance their therapeutic efficacy. Methods Control-MSCs and IPF-MSCs were isolated from the adipose tissue of age-matched healthy and IPF donors, respectively. Cell senescence was examined by senescence-associated β-galactosidase (SA-β-gal) staining. The level of miR-199a-5p was measured by RT-PCR. Autophagy was determined using a transmission electron microscope (TEM). The therapeutic efficacy of anti-miR-199a-5p-IPF-MSCs was assessed using a mouse model of bleomycin-induced lung fibrosis. Results Despite similar surface makers, IPF-MSCs exhibited increased cellular senescence and decreased proliferative capacity compared with control-MSCs. The expression of miR-199a-5p was significantly enhanced in the serum of IPF patients and IPF-MSCs compared with that of healthy donors and control-MSCs. The upregulation of miR-199a-5p induced senescence of control-MSCs, whereas the downregulation rescued IPF-MSC senescence. Mechanistically, miR-155-5p suppressed autophagy of MSCs via the AMPK signaling pathway by downregulating the expression of Sirtuin 1(Sirt1), resulting in cellular senescence. Accordingly, miR-155-5p inhibition promoted autophagy and ameliorated IPF-MSC senescence by activating the Sirt1/AMPK signaling pathway. Compared with IPF-MSCs, the transplantation of anti-miR-199a-5p-IPF-MSCs increased the ability to prevent progression of pulmonary fibrosis in bleomycin-treated mice. Conclusions Our study shows that miR-199a-5p regulates MSC senescence in patients with IPF by regulating the Sirt1/AMPK signaling pathway and miR-199a-5p is a novel target to rejuvenate IPF-MSCs and enhance their beneficial effects.

Abstract Background Exosome transplantation is a promising cell-free therapeutic approach for the treatment of ischemic heart disease. The purpose of this study was to explore whether exosomes derived from Macrophage migration inhibitory factor (MIF) engineered umbilical cord MSCs (ucMSCs) exhibit superior cardioprotective effects in a rat model of AMI and reveal the mechanisms underlying it. Results Exosomes isolated from ucMSCs (MSC-Exo), MIF engineered ucMSCs (MIF-Exo) and MIF downregulated ucMSCs (siMIF-Exo) were used to investigate cellular protective function in human umbilical vein endothelial cells (HUVECs) and H9C2 cardiomyocytes under hypoxia and serum deprivation (H/SD) and infarcted hearts in rats. Compared with MSC-Exo and siMIF-Exo, MIF-Exo significantly enhanced proliferation, migration, and angiogenesis of HUVECs and inhibited H9C2 cardiomyocyte apoptosis under H/SD in vitro. MIF-Exo also significantly inhibited cardiomyocyte apoptosis, reduced fibrotic area, and improved cardiac function as measured by echocardiography in infarcted rats in vivo. Exosomal miRNAs sequencing and qRT-PCR confirmed miRNA-133a-3p significantly increased in MIF-Exo. The biological effects of HUVECs and H9C2 cardiomyocytes were attenuated with incubation of MIF-Exo and miR-133a-3p inhibitors. These effects were accentuated with incubation of siMIF-Exo and miR-133a-3p mimics that increased the phosphorylation of AKT protein in these cells. Conclusion MIF-Exo can provide cardioprotective effects by promoting angiogenesis, inhibiting apoptosis, reducing fibrosis, and preserving heart function in vitro and in vivo. The mechanism in the biological activities of MIF-Exo involves miR-133a-3p and the downstream AKT signaling pathway.

We report the experimental observation of the spin-wave moiré edge and cavity modes using Brillouin light scattering spectromicroscopy in a nanostructured magnetic moiré lattice consisting of two twisted triangle antidot lattices based on an yttrium iron garnet thin film. Spin-wave moiré edge modes are detected at an optimal twist angle and with a selective excitation frequency. At a given twist angle, the magnetic field acts as an additional degree of freedom for tuning the chiral behavior of the magnon edge modes. Micromagnetic simulations indicate that the edge modes emerge within the original magnonic band gap and at the intersection between a mini flatband and a propagation magnon branch. Our theoretical estimate for the Berry curvature of the magnon-magnon coupling suggests a nontrivial topology for the chiral edge modes and confirms the key role played by the dipolar interaction. Our findings shed light on the topological nature of the magnon edge mode for emergent moiré magnonics.

Despite considerable progress in scaling carbon fluxes from eddy covariance sites to globe, significant uncertainties still exist when estimating the global net ecosystem exchange (NEE). In this study, the site-level NEE was estimated from FLUXNET, a global network of eddy covariance towers, using a random forest (RF) model based on remote sensing products and precipitation data. The plant function type (PFT) had the highest relative explanatory power in predicting the global site-level NEE. However, within PFTs, water-related variables (i.e., the total precipitation, remotely sensed evapotranspiration, land surface water index, and the difference between daytime and nighttime land surface temperature) and soil respiration (Rs) were strong predictors of NEE variability. Cross-validation analyses revealed the good performance of RF in predicting the spatiotemporal variability of monthly NEE at 168 global FLUXNET sites, with R2 of 0.72 and RMSE of 0.96 g·C·m−2·day−1. The performance was also good when predicting across-site (R2 = 0.75) and seasonal patterns (R2 = 0.92) over the 58 sites with available data being longer than two years and the 12-month value being present for each year. The RF-estimated NEE showed better relationships with the tower-measured NEE than a global NEE product from FLUXCOM across all PFTs. The difference between the RF-estimated NEE and FLUXCOM NEE was likely linked to the different predictor sets, such as those with more water-related variables and Rs. This study indicates the importance of considering the influence of water-related variables and Rs in the estimation of NEE at the global scale.

Abstract Mesenchymal stem cell (MSC)-based therapy has emerged as a novel strategy to treat many degenerative diseases. Accumulating evidence shows that the function of MSCs declines with age, thus limiting their regenerative capacity. Nonetheless, the underlying mechanisms that control MSC ageing are not well understood. We show that compared with bone marrow-MSCs (BM-MSCs) isolated from young and aged samples, NADH dehydrogenase (ubiquinone) iron-sulfur protein 6 (Ndufs6) is depressed in aged MSCs. Similar to that of Ndufs6 knockout (Ndufs6−/−) mice, MSCs exhibited a reduced self-renewal and differentiation capacity with a tendency to senescence in the presence of an increased p53/p21 level. Downregulation of Ndufs6 by siRNA also accelerated progression of wild-type BM-MSCs to an aged state. In contrast, replenishment of Ndufs6 in Ndufs6−/−-BM-MSCs significantly rejuvenated senescent cells and restored their proliferative ability. Compared with BM-MSCs, Ndufs6−/−-BM-MSCs displayed increased intracellular and mitochondrial reactive oxygen species (ROS), and decreased mitochondrial membrane potential. Treatment of Ndufs6−/−-BM-MSCs with mitochondrial ROS inhibitor Mito-TEMPO notably reversed the cellular senescence and reduced the increased p53/p21 level. We provide direct evidence that impairment of mitochondrial Ndufs6 is a putative accelerator of adult stem cell ageing that is associated with excessive ROS accumulation and upregulation of p53/p21. It also indicates that manipulation of mitochondrial function is critical and can effectively protect adult stem cells against senescence.

Although mesenchymal stem cell- (MSC-) based therapy has shown promising results for myocardial infarction (MI), low cell survival heavily limits its beneficial effects. Apelin plays an essential regulatory role in cell proliferation. This study was aimed at determining whether Apelin-13 pretreatment could improve the survival of MSCs in the ischemic heart and enhance their cardioprotective efficacy against MI. MSCs were pretreated with or without Apelin-13 for 24 hours and then exposed to serum deprivation and hypoxia (SD/H) for 48 hours. The mitochondrial morphology of MSCs was assessed by MitoTracker staining. The apoptosis of MSCs was determined by TUNEL staining. The level of mitochondrial reactive oxygen species (ROS) of MSCs was detected by Mito-Sox staining. MSCs and Apelin-13-pretreated MSCs were transplanted into the peri-infarct region in a mouse MI model. Apelin-13 pretreatment protected MSCs against SD/H-induced mitochondrial fragmentation and apoptosis. Apelin-13 pretreatment reduced ROS generation induced by SD/H in MSCs. Furthermore, Apelin-13 pretreatment enhanced the angiogenesis of MSCs under SD/H conditions. Mechanistically, Apelin-13 pretreatment inhibited SD/H-induced MSC apoptosis by downregulating mitochondrial fission via activation of the ERK pathway, and these effects were partially abrogated by ERK inhibitor U0126. Apelin-13 pretreatment promoted the survival of MSCs in the ischemic heart. Moreover, transplantation with Apelin-13-pretreated MSCs improved heart function and increased angiogenesis accompanied by decreased fibrosis compared with MSC transplantation at 28 days following MI. These findings reveal that pretreatment with Apelin-13 improves MSCs survival and enhances their therapeutic efficacy for MI. Our study provides a novel approach to improve MSC-based therapy for cardiovascular disease.

With the advent of population aging, aging-related diseases have become a challenge for governments worldwide. Sarcopenia has defined as a clinical syndrome associated with age-related loss such as skeletal muscle mass, strength, function, and physical performance. It is commonly seen in elderly patients with chronic diseases. Changes in lean mass are common critical determinants in the pathophysiology and progression of cardiovascular diseases (CVDs). Sarcopenia may be one of the most important causes of poor physical function and decreased cardiopulmonary function in elderly patients with CVDs. Sarcopenia may induce CVDs through common pathogenic pathways such as malnutrition, physical inactivity, insulin resistance, inflammation; these mechanisms interact. In this study, we aimed to investigate the relationship between sarcopenia and CVDs in the elderly. Further research is urgently needed to understand better the relationship, pathophysiology, clinical presentation, diagnostic criteria, and mechanisms of sarcopenia and CVDs, which may shed light on potential interventions to improve clinical outcomes and provide greater insight into the disorders above.

Objectives: The value of chemotherapy in the survival benefits of patients aged > 40 years with osteosarcoma is controversial. We aimed to explore the impact of chemotherapy on the survival benefits of patients aged >40 years with osteosarcoma. Methods: The Surveillance, Epidemiology, and End Results database was used to select eligible patients. The selected patients were divided into the chemotherapy and non-chemotherapy groups. Logistic regression analysis was performed to investigate the potential factors contributing to the selection of chemotherapy. The overall survival (OS) and cancer-specific survival (CSS) of the two groups were compared using the Kaplan–Meier method with a log-rank test. Cox proportional risk models were used to determine the prognostic factors for OS and CSS. Stratified analysis was performed according to tumour grade and stage. Results: A total of 1032 eligible patients were included in our analysis. Of these, 586 and 446 patients were in the chemotherapy and nonchemotherapy groups, respectively. Multivariate logistic analysis indicated that grade III/IV and distant stage were associated with chemotherapy. Kaplan–Meier plots showed that patients did not achieve an improved OS or CSS after receiving chemotherapy. Cox regression analysis indicated that age > 60 years, axial, grade III/IV, and regional and distant stage were independent risk factors for poor prognosis in both OS and CSS. Stratified analysis revealed a survival benefit from chemotherapy in patients with grade III/IV and distant stage. Conclusions: Chemotherapy did not significantly improve OS and CSS in patients aged > 40 years with osteosarcoma. In this age group, survival benefit from chemotherapy was observed in patients with high-grade tumours (grade III/IV) and metastasis (distant stage).

Supine rollover plays an important role in the prevention of pressure sores in long-term bedridden patients. It is of great significance to study the mechanism of human supine rollover movement and to design the rehabilitation rollover mechanism in line with man-machine cooperation. In human supine rollover movement, shoulder and hip are the key parts of force application. Based on anatomical theory, the motion trajectory information of shoulder and hip skeletal rehabilitation parts is collected by combining optical motion capture and rigid body modeling. Following a kinematics simulation analysis, the simulation curve was compared with the experimental curve track; the numerical difference was small. It is proved that the simulation model is correct, and it is also shown that the designed rehabilitation rollover mechanism can better reproduce the natural rolling motion state of the human body. It can meet the requirements of human-machine synergistic assisted lateral roll rehabilitation aids and provides a solution for pressure sore prevention.

Aging generally coincides with a gradual decline in mass and strength of muscles and bone mineral density (BMD). Sarcopenia is closely linked to osteoporosis in the elderly, which can lead to abnormal gait, balance disorders, and dysfunctions, as well as increase in the risks of falls, fractures, weakness, and death. MicroRNAs (miRNAs, miRs) are a kind of short and non-coding RNA molecules but can regulate posttranscriptional protein expression. However, we have known little about their participation in age-associated osteoporosis and sarcopenia. The current study aims to confirm those miRNAs as biomarkers for age-related reduction in muscular atrophy associated with human blood fractures. In our study, 10 fracture-risk-related miRNAs (miR-637, miR-148a-3p, miR-125b-5p, miR-124-3p, miR-122-5p, miR-100-5p, miR-93-5p, miR-21-5p, miR-23a-3p, and miR-24-3p) were analyzed. For the initial screening, we determined the abundance of fracture-risk-associated miRNAs by RT-PCR most frequently detected in enrolled 93 elderly with sarcopenia and non-sarcopenia, respectively. Statistically, the relative expression levels of plasma miR-23a-3p, miR-93-5p, and miR-637 in the sarcopenia group were significantly lower than that in the non-sarcopenia group, while the levels of other miRNAs did not change significantly. Moreover, we showed that the levels of ASM/height2, handgrip strength, and 4-m velocity in the sarcopenia group were significantly lower than in the non-sarcopenia group. Whereafter, we expanded the sample for further detection and analysis and revealed that the levels of plasma miR-23a-3p, miR-93-5p, and miR-637 in the sarcopenia group were significantly lower than that in the non-sarcopenia group, which is consistent with the initial screening experiment. From our analysis, changes in levels of plasma miR-93-5p and miR-637 were dramatically related to ASM/height2. Furthermore, changes in miR-23a and miR-93-5p were significantly affected by ASM/height2 in female individuals, with no significant correlations between miRNAs changes and these diagnostic indexes in male individuals after adjusting sex. The study showed that plasma miRNAs changed in an aging-related sarcopenia manner and were associated with increased fracture risk. In aging patients, plasma miR-23a-3p, miR-93-5p, and miR-637 have the potential as biomarkers of sarcopenia, which can affect the development of physiological dysfunction and may be also used in the fracture risk assessment of these patients.

Circular RNA (circRNA) is a novel subgroup of noncoding RNA in the human transcriptome playing a vital role in the atherosclerosis of cerebrovascular disease. However, the in-depth mechanism by which circRNA regulates the vascular smooth muscle proliferation and migration is still elusive. Here, a novel identified circRNA, circCHFR, was validated to be aberrantly overexpressed in the ox-LDL-induced vascular smooth muscle cell (VSMCs). Functionally, the circCHFR silencing by oligonucleotide transfection suppressed the proliferation and migration ability of VSMCs. Mechanically, bioinformatics tools and luciferase reporter assay state that circCHFR acts as a sponge of miR-370, and miR-370 targets the 3′ UTR of FOXO1. Furthermore, the transcription factor FOXO1 could bind with the promoter region of CCND1 mRNA and promote Cyclin D1 expression. In summary, this finding states the vital role of the circCHFR/miR-370/FOXO1/Cyclin D1 axis and provides a profound understanding about the circRNA in smooth muscle cells and atherosclerosis. Keywords: atherosclerosis, circular RNA, circCHFR, vascular smooth muscle cells, FOXO1, CCND1

Abstract Background Optimal cell type as cell-based therapies for heart failure (HF) remains unclear. We sought to compare the safety and efficacy of direct intramyocardial transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) in a porcine model of HF. Methods Eight weeks after induction of HF with myocardial infarction (MI) and rapid pacing, animals with impaired left ventricular ejection fraction (LVEF) were randomly assigned to receive direct intramyocardial injection of saline (MI group), 2 × 108 hESC-CMs (hESC-CM group), or 2 × 108 hiPSC-MSCs (hiPSC-MSC group). The hearts were harvested for immunohistochemical evaluation after serial echocardiography and hemodynamic evaluation and ventricular tachyarrhythmia (VT) induction by in vivo programmed electrical stimulation. Results At 8 weeks post-transplantation, LVEF, left ventricular maximal positive pressure derivative, and end systolic pressure-volume relationship were significantly higher in the hiPSC-MSC group but not in the hESC-CM group compared with the MI group. The incidence of early spontaneous ventricular tachyarrhythmia (VT) episodes was higher in the hESC-CM group but the incidence of inducible VT was similar among the different groups. Histological examination showed no tumor formation but hiPSC-MSCs exhibited a stronger survival capacity by activating regulatory T cells and reducing the inflammatory cells. In vitro study showed that hiPSC-MSCs were insensitive to pro-inflammatory interferon-gamma-induced human leukocyte antigen class II expression compared with hESC-CMs. Moreover, hiPSC-MSCs also significantly enhanced angiogenesis compared with other groups via increasing expression of distinct angiogenic factors. Conclusions Our results demonstrate that transplantation of hiPSC-MSCs is safe and does not increase proarrhythmia or tumor formation and superior to hESC-CMs for the improvement of cardiac function in HF. This is due to their immunomodulation that improves in vivo survival and enhanced angiogenesis via paracrine effects.

Objective: Although some meta-analyses have shown a correlation between a high neutrophil-to-lymphocyte ratio (NLR) and low survival in patients with gliomas, their conclusions are controversial, and no study has specifically explored the relationship between a high pre-treatment and pre-operative NLR and low survival in patients with glioblastoma (GBM). Therefore, we further investigated this correlation through meta-analysis. Methods: We searched the PubMed, Metstr, and Cochrane databases in March 2022 for published literature related to high pre-treatment and pre-operative NLR and low survival in patients with GBM. The literature was rigorously searched according to inclusion and exclusion criteria to calculate the overall hazard ratio (HR) and 95% confidence interval (CI) corresponding to a high NLR using a random effects model. Results: The total HR for the pre-treatment and pre-operative NLR was 1.46 (95% CI: 1.17–1.75, p = 0.000, I2 = 76.5%), indicating a significant association between a high pre-treatment and pre-operative NLR, and low overall survival in patients with GBM. Sub-group analysis was performed because of the high heterogeneity. The results for the sub-group with a cut-off value of 4 showed an HR of 1.39 (95% CI: 1.12–1.65, p = 0.000, I2 = 22.2%), with significantly low heterogeneity, whereas those for the sub-group without a cut-off value of 4 showed an HR of 1.45 (95% CI: 1.01–1.89, p = 0.000, I2 = 83.3%). Conclusions: The results of this study demonstrate that a high pre-treatment and pre-operative NLR suggests low survival in patients with GBM based on data from a large sample. Furthermore, the meta-regression analysis results indicate that underlying data, such as age and extent of surgical resection, lead to a high degree of heterogeneity, providing a theoretical basis for further research.

Summary: We previously identified an immunomodulatory role of human induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (MSCs) in asthmatic inflammation. Mitochondrial transfer from bone marrow MSCs to epithelial cells can result in the attenuation of acute lung injury in mice. However, the effects of mitochondrial transfer from iPSC-MSCs to epithelial cells in asthma and the mechanisms underlying these effects are unclear. We found that iPSC-MSC transplantation significantly reduced T helper 2 cytokines, attenuated the mitochondrial dysfunction of epithelial cells, and alleviated asthma inflammation in mice. Tunneling nanotubes (TNTs) were formed between iPSC-MSCs and epithelial cells, and mitochondrial transfer from iPSC-MSCs to epithelial cells via TNTs was observed both in vitro and in mice. Overexpression or silencing of connexin 43 (CX43) in iPSC-MSCs demonstrated that CX43 plays a critical role in the regulation of TNT formation by mediating mitochondrial transfer between iPSC-MSCs and epithelial cells. This study provides a therapeutic strategy for targeting asthma inflammation. : In this article, Fu, Lian, and colleagues show that mesenchymal stem cells derived from human induced pluripotent stem cells can transfer their mitochondria to rescue the injured bronchial epithelial cells, which attenuates asthma inflammation. Connexin 43, a component of gap junctions, plays a critical role during the process of mitochondrial transfer by regulating intercellular tunneling nanotube formation. Keywords: iPSC-MSCs, mitochondrial transfer, connexin 43, epithelial cells, asthma

The protective effects of mesenchymal stem cell (MSC)-based therapy for myocardial infarction (MI) are largely hampered as they age. Apelin is an endogenous ligand of its receptor APJ and plays an essential role in regulating multiple biological activities including MSC proliferation and survival. In this study, we investigated whether Apelin regulates MSC senescence and whether its overexpression could rejuvenate aged MSCs (AMSCs) to improve cardiac protection following infarction in mice. MSC senescence was evaluated by senescence-associated β-galactosidase assays. Apelin level was examined by western blotting. Autophagy was determined by transmission electron microscopy. The cardioprotective effect of AMSCs with Apelin overexpression (Apelin-AMSCs) was assessed in a mouse MI model. Apelin expression was dramatically reduced in AMSCs. Interestingly, knockdown of Apelin induced young MSCs (YMSC) senescence, whereas overexpression rescued AMSC senescence. Apelin overexpression also increased AMSC angiogenic capacity. Mechanistically, Apelin overexpression upregulated the autophagy level of AMSCs by activating AMP-activated protein kinase (AMPK) signaling, thereby rejuvenating AMSCs. Compared with AMSCs, transplantation of Apelin-AMSCs achieved better therapeutic efficacy for MI by enhancing cell survival and angiogenesis. In conclusion, our results reveal that Apelin activates AMPK to rejuvenate AMSCs by increasing autophagy and promotes cardioprotection following infarction in mice. This study identified a novel target to rejuvenate AMSCs and enhance their therapeutic efficacy.

Stroke, the most prevalent cerebrovascular disease, causes serious loss of neurological function and is the leading cause of morbidity and mortality worldwide. Despite advances in pharmacological and surgical therapy, treatment for functional rehabilitation following stroke is limited with a consequent serious impact on quality of life. Over the past decades, mesenchymal stem cell (MSCs)-based therapy has emerged as a novel strategy for various diseases including stroke due to their unique properties that include easy isolation, multipotent differentiation potential and strong paracrine capacity. Although MSCs have shown promising results in the treatment of stroke, there remain many challenges to overcome prior to their therapeutic application. In this review, we focus on the following issues: the scientific data from preclinical studies and clinical trials of MSCs in the treatment of stroke; the potential mechanisms underlying MSC-based therapy for stroke; the challenges related to the timing and delivery of MSCs and MSC senescence.

Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary interstitial inflammatory disease of unknown etiology, and is also a sequela in severe patients with the Coronavirus Disease 2019 (COVID-19). Nintedanib and pirfenidone are the only two known drugs which are conditionally recommended for the treatment of IPF by the FDA. However, these drugs pose some adverse side effects such as nausea and diarrhoea during clinical applications. Therefore, it is of great value and significance to identify effective and safe therapeutic drugs to solve the clinical problems associated with intake of western medicine. As a unique medical treatment, Traditional Chinese Medicine (TCM) has gradually exerted its advantages in the treatment of IPF worldwide through a multi-level and multi-target approach. Further, to overcome the current clinical problems of oral and injectable intakes of TCM, pulmonary drug delivery system (PDDS) could be designed to reduce the systemic metabolism and adverse reactions of the drug and to improve the bioavailability of drugs. Through PubMed, Google Scholar, Web of Science, and CNKI, we retrieved articles published in related fields in recent years, and this paper has summarized twenty-seven Chinese compound prescriptions, ten single TCM, and ten active ingredients for effective prevention and treatment of IPF. We also introduce three kinds of inhaling PDDS, which supports further research of TCM combined with PDDS to treat IPF.

The mutation of phosphatase and tensin homolog (PTEN) genes frequently occur in low-grade gliomas (LGGs) and are deeply associated with a poor prognosis and survival rate. In order to identify the crucial signaling pathways and genes associated with the PTEN mutation, we performed bioinformatics analysis on the RNA sequencing results, which were obtained from The Cancer Genome Atlas database. A total of 352 genes were identified as differentially expressed genes (DEGs). The gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that the DEGs were significantly enriched in categories associated with cell division and multiple metabolic progressions. The histological stage was significantly associated with PTEN expression levels. In addition, the PTEN mutation was associated with an abundance of B cells, neutrophils, macrophages, dendritic cells, and CD8+ T cells during tumor infiltration. The results showed that patients with LGGs harboring the PTEN mutation had a poor prognosis and more serious immune cell infiltration occurred depending on the mRNA expression level. These results demonstrated that multiple genes and signaling pathways play a key role in LGG from low grade to high grade, and are associated with PTEN mutations. In this study, we outlined an approach to assess the influence of PTEN mutations on prognosis, overall survival, and messenger RNA (mRNA) expression. Our results provided alternative strategies for the personalized treatment of patients with LGGs harboring the PTEN mutation.

Abstract Background Dyslipidaemia contributes to the progression of coronary artery disease (CAD) toward adverse outcomes. Plasma lipidomic measure may improve the prognostic performances of clinical endpoints of CAD. Our research is designed to identify the correlations between plasma lipid species and the risks of death, major adverse cardiovascular event (MACE) and left ventricular (LV) remodeling in patients with CAD. Methods A total of 1569 Chinese patients with CAD, 1011 single‐centre patients as internal training cohort, and 558 multicentre patients as external validation cohort, were enrolled. The concentration of plasma lipids in both cohorts was determined through widely targeted lipidomic profiling. Least absolute shrinkage and selection operator Cox and multivariate Cox regressions were used to develop prognostic models for death and MACE, respectively. Results Ten (Cer(d18:1/20:1), Cer(d18:1/24:1), PE(30:2), PE(32:0), PE(32:2), PC(O‐38:2), PC(O‐36:4), PC(16:1/22:2), LPC(18:2/0:0) and LPE(0:0/24:6)) and two (Cer(d18:1/20:1) and LPC(20:0/0:0)) lipid species were independently related to death and MACE, respectively. Cer(d18:1/20:1) and Cer(d18:1/24:1) were correlated with LV remodeling (P

The diode behavior of ferroelectric materials was shown to be enhanced using aqueous solution treatment of their surface. The electric current increased for both BaTiO3 and BiFeO3 nano-films after being treated with aqueous solution as compared with their as-grown films. The hydroxyl groups were confirmed to be successfully bonded on the surface, which increased the concentration of oxygen vacancies near the film surface. The rectifying diode effect can be associated with the polarization direction and the movement and redistribution of oxygen vacancies within the ferroelectric thin films. Further the enhanced diode effect for the hydroxylated film was attributed to the increased oxygen vacancies near the top electrode/film interface. The reported finding helps us understand the role of water as the most common polar molecule in the atmosphere on the ferroelectric materials that exist in many industrial devices. This will provide a low-cost strategy for improving the performance of resistive memory.

Temozolomide (TMZ) is the first-line chemotherapy drug that has been used to treat glioma for over a decade, but the benefits are limited by half of the treated patients who acquired resistance. Studies have shown that glioma TMZ resistance is a complex process with multiple factors, which has not been fully elucidated. Ferroptosis, which is a new type of cell death discovered in recent years, has been reported to play an important role in tumor drug resistance. The present study reviews the relationship between ferroptosis and glioma TMZ resistance, and highlights the role of ferroptosis in glioma TMZ resistance. Finally, the investigators discussed the future orientation for ferroptosis in glioma TMZ resistance, in order to promote the clinical use of ferroptosis induction in glioma treatment.

Cardiovascular diseases (CVDs) have become the central matter of death worldwide and have emerged as a notable concern in the healthcare field. There is accumulating evidence that regular exercise training can be as a reliable and widely favorable approach to prevent the heart from cardiovascular events. Non-coding RNAs (ncRNAs) could act as innovative biomarkers and auspicious therapeutic targets to reduce the incidence of CVDs. In this review, we summarized the regulatory effects of ncRNAs in the cardiac-protection provided by exercise to assess potential therapies for CVDs and disease prevention.

Summary: Intervertebral disc degeneration might be amenable to stem cell therapy, but the required cells are scarce. Here, we report the development of a protocol for directed in vitro differentiation of human pluripotent stem cells (hPSCs) into notochord-like and nucleus pulposus (NP)-like cells of the disc. The first step combines enhancement of ACTIVIN/NODAL and WNT and inhibition of BMP pathways. By day 5 of differentiation, hPSC-derived cells express notochordal cell characteristic genes. After activating the TGF-β pathway for an additional 15 days, qPCR, immunostaining, and transcriptome data show that a wide array of NP markers are expressed. Transcriptomically, the in vitro-derived cells become more like in vivo adolescent human NP cells, driven by a set of influential genes enriched with motifs bound by BRACHYURY and FOXA2, consistent with an NP cell-like identity. Transplantation of these NP-like cells attenuates fibrotic changes in a rat disc injury model of disc degeneration. : Zhang et al. report notochord-like and nucleus pulposus (NP)-like cells can be derived from human pluripotent stem cells using a NOTO-eGFP reporter system and a compound-defined protocol. These derived NP-like cells share high similarities with adolescent human NP cells and attenuate injury-induced intervertebral disc degeneration after transplantation. Keywords: human induced pluripotent stem cells, intervertebral disc disease, nucleus pulposus (NP)-like cells, notochord-like cells (NCLs), directed differentiation

Controlling ferroelectric polarization is conventionally achieved by applying electric fields, mechanical force or similar. Here reversible switching of the bulk polarization of a BiFeO3 thin film is demonstrated by pattering aqueous solution on to the surface enabling large-scale switching.

Genome-editing involves the insertion, deletion, or replacement of DNA in the genome of a living organism using “molecular scissors.” Traditional genome editing with engineered nucleases for human stem cells is limited by its low efficiency, high cost, and poor specificity. The CRISPR system has recently emerged as a powerful gene manipulation technique with advantages of high editing efficiency and low cost. Although this technique offers huge potential for gene manipulation in various organisms ranging from prokaryotes to higher mammals, there remain many challenges in human stem cell research. In this review, we highlight the basic biology and application of the CRISPR/Cas9 system in current human stem cell research, discuss its advantages and challenges, and debate the future prospects for human stem cells in regenerative medicine.