Loss of ten-eleven translocation 2 induces cardiac hypertrophy and fibrosis through modulating ERK signaling pathway.

The ten-eleven translocation (Tet) family of dioxygenases convert 5-methylcytosine to 5-hydroxymethylcytosine (5hmC). Previous studies have shown that 5hmC-mediated epigenetic modifications play essential roles in diverse biological processes and diseases. Here, we show that Tet proteins and 5hmC display dynamic features during postnatal cardiac development and that Tet2 is the predominant dioxygenase present in heart. Tet2 knockout results in abnormal cardiac function, progressive cardiac hypertrophy and fibrosis. Mechanistically, Tet2 deficiency leads to reduced hydroxymethylation in the cardiac genome and alters the cardiac transcriptome. Mechanistically, Tet2 loss leads to a decrease of Hspa1b expression, a regulator of the extracellular signal-regulated protein kinase (Erk) signaling pathway, which leads to over-activation of Erk signaling. Acute Hspa1b knock down (KD) increased the phosphorylation of Erk and induced hypertrophy of cardiomyocytes, which could be blocked by Erk signaling inhibitor. Consistently, ectopic expression of Hspa1b was able to rescue the deficits of cardiomyocytes induced by Tet2 depletion. Taken together, our study's results reveal the important roles of Tet2-mediated DNA hydroxymethylation in cardiac development and function.

Ogt-mediated O-GlcNAcylation inhibits astrocytes activation through modulating NF-κB signaling pathway.

Previous studies have shown that Ogt-mediated O-GlcNAcylation is essential for neuronal development and function. However, the function of O-GlcNAc transferase (Ogt) and O-GlcNAcylation in astrocytes remains largely unknown. Here we show that Ogt deficiency induces inflammatory activation of astrocytes in vivo and in vitro, and impairs cognitive function of mice. The restoration of O-GlcNAcylation via GlcNAc supplementation inhibits the activation of astrocytes, inflammation and improves the impaired cognitive function of Ogt deficient mice. Mechanistically, Ogt interacts with NF-κB p65 and catalyzes the O-GlcNAcylation of NF-κB p65 in astrocytes. Ogt deficiency induces the activation of NF-κB signaling pathway by promoting Gsk3ß binding. Moreover, Ogt depletion induces the activation of astrocytes derived from human induced pluripotent stem cells. The restoration of O-GlcNAcylation inhibits the activation of astrocytes, inflammation and reduces Aß plaque of AD mice in vitro and in vivo. Collectively, our study reveals a critical function of Ogt-mediated O-GlcNAcylation in astrocytes through regulating NF-κB signaling pathway.

O-GlcNAcylation regulates the methionine cycle to promote pluripotency of stem cells.

Methionine metabolism is critical for the maintenance of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) pluripotency. However, little is known about the regulation of the methionine cycle to sustain ESC pluripotency. Here, we show that adenosylhomocysteinase (AHCY), an important enzyme in the methionine cycle, is critical for the maintenance and differentiation of mouse embryonic stem cells (mESCs). We show that mESCs exhibit high levels of methionine metabolism, whereas decreasing methionine metabolism via depletion of AHCY promotes mESCs to differentiate into the three germ layers. AHCY is posttranslationally modified with an O-linked ß-N-acetylglucosamine sugar (O-GlcNAcylation), which is rapidly removed upon differentiation. O-GlcNAcylation of threonine 136 on AHCY increases its activity and is important for the maintenance of trimethylation of histone H3 lysine 4 (H3K4me3) to sustain mESC pluripotency. Blocking glycosylation of AHCY decreases the ratio of S-adenosylmethionine versus S-adenosylhomocysteine (SAM/SAH), reduces the level of H3K4me3, and poises mESC for differentiation. In addition, blocking glycosylation of AHCY reduces somatic cell reprogramming. Thus, our findings reveal a critical role of AHCY and a mechanistic understanding of O-glycosylation in regulating ESC pluripotency and differentiation.

Fto-modulated lipid niche regulates adult neurogenesis through modulating adenosine metabolism.

Adult neurogenesis is regulated by diverse factors including the local environment, i.e. the neurogenic niche. However, whether the lipid in the brain regulates adult neurogenesis and related mechanisms remains largely unknown. In the present study, we found that lipid accumulates in the brain during postnatal neuronal development. Conditional knockout of Fto (cKO) in lipid not only reduced the level of lipid in the brain but also impaired the learning and memory of mice. In addition, Fto deficiency in lipid did not affect the proliferation of adult neural stem cells (aNSCs), but it did inhibit adult neurogenesis by inducing cell apoptosis. Mechanistically, specific deleting Fto in lipid altered gene expression and increased adenosine secretion of adipocytes. The treatment of adenosine promoted the apoptosis of newborn neurons. As a whole, these results reveal the important function of the lipid niche and its associated mechanism in regulating adult neurogenesis.

Braiding Ultrathin Au Nanowires into Ropes.

Braiding is a common skill in daily life but rare at the nanoscale. Most of the current nanohelices are directly grown or assembled without involving mechanical interactions, and they are thus distinctively different from ropes in terms of functions and mechanisms. Here, by coaxially twisting multiple ultrathin Au nanowires, nanoropes are synthesized with elegant helical patterns that are consistent with the macroscopic equivalents. The strain relaxation of lattice transformation causes the nanowires to pursue the maximum degree of twisting, while the mutual packing interactions in a bundle prevent sideways emergence of U-turns. The consistent chirality of the seemingly independent strands can only arise when a first twisting strand causes morphological deformation in its neighbors, which induces the collective uni-directional twisting. The spontaneous braiding and the "remote" control of the nanowires involve mechanical interactions and possibly energy transmission, thus opening doors to chiral assembly and future smart nanodevices.

Measuring Solvent Exchange in Silica Nanoparticles with Rotor-Based Fluorophore.

Measuring the diffusivity of molecules is the first step toward understanding their dependence and controlling diffusion, but the challenge increases with the decrease of molecular size, particularly for non-fluorescent and non-reactive molecules such as solvents. Here, the capability to monitor the solvent exchange process within the micropores of silica with millisecond time resolution is demonstrated, by simply embedding a rotor-based fluorophore (thioflavin T) in colloidal silica nanoparticles. Basically, the silica provides an extreme case of viscous microenvironment, which is affected by the polarity of the solvents. The fluorescence intensity traces can be well fitted to the Fickian diffusion model, allowing analytical solution of the diffusion process, and revealing the diffusion coefficients. The validation experiments, involving the water-to-ethanol and ethanol-to-water solvent exchange, the comparison of different drying conditions, and the variation in the degree of cross-linking in silica, confirmed the effectiveness and sensitivity of this method for characterizing diffusion in silica micropores. This work focuses on the method development of measuring diffusivity and the high temporal resolution in tracking solvent exchange dynamics over a short distance (within 165 nm) opens enormous possibilities for further studies.

Expression of CCL2 signaling pathway genes in patients with periodontitis and atherosclerosis.

OBJECTIVE: Periodontitis and atherosclerosis are chronic inflammatory diseases characterized by leukocyte infiltration. We investigated the expression of CCL4, CCR5, c-Jun, c-Fos, NF-κB, and CCL2 as well as the possible mechanism involved in the regulation of CCL2 in human periodontitis tissues and atherosclerotic aorta based on previous research on the CCL4/CCR5/c-Jun and c-Fos/CCL2 pathway leading to CCL2 expression in collagen-induced arthritis (CIA) rat. METHODS: Sixty-five volunteers were recruited and the condition of their gingiva and coronary arteries were assessed. The subjects were divided into four groups: healthy control, chronic periodontitis (CP), coronary artery diseases (CAD), and noncoronary artery diseases (non-CAD). Total RNA was isolated from gingiva in periodontitis patients and control populations and from the aorta in patients with and without CAD. PCR was used to examine CCL4, CCR5, c-Jun, c-Fos, NF-κB, and CCL2 levels. The production of CCL2 in the gingiva and aorta was analyzed by immunostaining. RESULTS: PCR revealed that CCL4, CCR5, and CCL2 mRNA levels were increased in CP patients' gingivae and aortas from coronary artery bypass grafting (CABG) patients. Marked c-Jun, c-Fos, and NF-κB gene productions were detected in CP patients' gingivae but did not show statistical differences between the CAD and non-CAD groups. Stronger immunoreactivity against CCL2 was observed in periodontitis gingiva and aorta from CABG patients. CONCLUSIONS: Our findings suggest that the CCL4/CCR5/c-Jun and c-Fos/CCL2 pathways may be involved in CCL2 expression in periodontitis. CCL4, CCR5, and CCL2 might act as possible nodes to link the presence of periodontitis and atherosclerosis.

Fucosyltransferase 8 regulates adult neurogenesis and cognition of mice by modulating the Itga6-PI3K/Akt signaling pathway.

Fucosyltransferase 8 (Fut8) and core fucosylation play critical roles in regulating various biological processes, including immune response, signal transduction, proteasomal degradation, and energy metabolism. However, the function and underlying mechanism of Fut8 and core fucosylation in regulating adult neurogenesis remains unknown. We have shown that Fut8 and core fucosylation display dynamic features during the differentiation of adult neural stem/progenitor cells (aNSPCs) and postnatal brain development. Fut8 depletion reduces the proliferation of aNSPCs and inhibits neuronal differentiation of aNSPCs in vitro and in vivo, respectively. Additionally, Fut8 deficiency impairs learning and memory in mice. Mechanistically, Fut8 directly interacts with integrin α6 (Itga6), an upstream regulator of the PI3k-Akt signaling pathway, and catalyzes core fucosylation of Itga6. Deletion of Fut8 enhances the ubiquitination of Itga6 by promoting the binding of ubiquitin ligase Trim21 to Itga6. Low levels of Itga6 inhibit the activity of the PI3K/Akt signaling pathway. Moreover, the Akt agonist SC79 can rescue neurogenic and behavioral deficits caused by Fut8 deficiency. In summary, our study uncovers an essential function of Fut8 and core fucosylation in regulating adult neurogenesis and sheds light on the underlying mechanisms.

Embryonic soluble human leukocyte antigen-G as a marker of embryo competency in assisted reproductive technology for Chinese women.

OBJECTIVE: To investigate whether embryonic soluble human leukocyte antigen-G (sHLA-G) could be a noninvasive marker for embryo competency in assisted reproductive technology (ART), which is still controversial due to the different detection assays used and the different culture conditions in laboratories. STUDY DESIGN: Based on the standardization of IVF procedures and the embryo culture condition, a total of 205 embryo culture supernatants (ESs) from 92 ART cycles were evaluated for sHLA-G contents by chemiluminescent ELISA assay. RESULTS: sHLA-G presence could be detected in 30.7% of the ESs tested. In the cycles where at least one of the embryos transferred was positive for sHLA-G, 51.9% of patients (27/52) achieved a clinical pregnancy. In cycles where none of the embryos transferred secreted detectable amounts of sHLA-G, the pregnancy rate was only 30.0% (12/40, p < 0.05). The implantation rate in sHLA-G-positive cycles was also significantly higher (31.5%) than that in sHLA-G-negative cycles (14.9%, p < 0.05). CONCLUSION: The results suggested sHLA-G in ESs as a potential marker of embryo competency in ART programs for the Chinese population.

Single/Multi-Source Black-Box Domain Adaption for Sensor Time Series Data.

Unsupervised domain adaption (UDA), which transfers knowledge from a labeled source domain to an unlabeled target domain, has attracted tremendous attention in many machine learning applications. Recently, there have been attempts to apply domain adaption for sensor time series data, such as human activity recognition and gesture recognition. However, existing methods suffer from some drawbacks that hinder further performance improvement. They often require access to source data or source models during training, which is unavailable in some fields because of privacy protection and storage limit. Typically, the source domains may only provide an application programming interface (API) for the target domain to call. On the other hand, current UDA methods have not considered the temporal consistency and low-signal-to-noise ratio (SNR) of sensor time series. To address the challenges, this article presents a black-box domain adaption framework for sensor time series data (B2TSDA). First, we propose a single/multi-source teacher-student learning framework to distill the knowledge from the source domains to a customized target model. Then we design a new temporal consistency loss by combining an adaptive mask method and dynamic threshold method to maintain consistent temporal information and balance the learning difficulties of different classes. For the multisource black-box domain adaption, we further propose a Shapley-enhanced method to determine the contribution of each source domain. Experimental results on both single-source and multisource domain adaption show that our framework has superior performance compared to other black-box UDA methods.

Temporal-Frequency Attention Focusing for Time Series Extrinsic Regression via Auxiliary Task.

Time series extrinsic regression (TSER) aims at predicting numeric values based on the knowledge of the entire time series. The key to solving the TSER problem is to extract and use the most representative and contributed information from raw time series. To build a regression model that focuses on those information suitable for the extrinsic regression characteristic, there are two major issues to be addressed. That is, how to quantify the contributions of those information extracted from raw time series and then how to focus the attention of the regression model on those critical information to improve the model's regression performance. In this article, a multitask learning framework called temporal-frequency auxiliary task (TFAT) is designed to solve the mentioned problems. To explore the integral information from the time and frequency domains, we decompose the raw time series into multiscale subseries in various frequencies via a deep wavelet decomposition network. To address the first problem, the transformer encoder with the multihead self-attention mechanism is integrated in our TFAT framework to quantify the contribution of temporal-frequency information. To address the second problem, an auxiliary task in a manner of self-supervised learning is proposed to reconstruct the critical temporal-frequency features so as to focusing the regression model's attention on those essential information for facilitating TSER performance. We estimated three kinds of attention distribution on those temporal-frequency features to perform auxiliary task. To evaluate the performances of our method under various application scenarios, the experiments are carried out on the 12 datasets of the TSER problem. Also, ablation studies are used to examine the effectiveness of our method.

Identifying cadmium and lead co-accumulation from living rice blade spectrum.

Neither cadmium (Cd) nor lead (Pb) is necessary for crop growth, but they both can accumulate in soil and crop tissues, resulting in land degradation and crop reduction. Few researchers have explored how to detect Cd-Pb co-accumulation in leaves using proximal sensing techniques, especially by low-cost, easy-to-use leaf clips that capture hyperspectral reflections at suitable foliar positions. In this study, a hyperspectral imager was employed to collect images of the rice canopy from a designed greenhouse experiment that included 16 pretreatments of Cd-Pb co-accumulation, followed by spectral extractions from 3 foliar positions: the blade root, the middle of the leaf, and the leaf apex. A support vector machine with leave-one-out cross-validation was performed to diagnose the contaminative levels based on the feature wavelengths selected by an improved successive projection algorithm. Partial least squares regression was used to predict Cd-Pb concentrations in rice blades. The results indicated that diagnostic accuracies were varied using spectra of different foliar positions. The blade root and leaf apex of rice blades were the optimal foliar position for detecting Cd and Pb contamination, respectively. At the optimal foliar positions, diagnostic accuracies exceeded 0.80 for distinguishing whether the rice is subject to Cd-Pb contamination. The Cd prediction performed 'very good' with a residual prediction deviation (RPD) of 2.21, a R2 of 0.79, and a root mean square error (RMSE)of 6.14, while that of Pb was 1.62, 0.61, and 186.54. Important wavelengths were identified at 659-694 nm and 667-694 nm to detect Cd and Pb contamination. In summary, our results verified the feasibility and clarified the optimal foliar positions of rice blades to detect Cd-Pb contamination. The wavelengths selecting have the great potential in the design of future leaf clips, and the optimal foliar position can provide suggestions to improve diagnostic performances in field applications.

Inorganic-organic coprecipitation: spontaneous formation of enclosed and porous silica compartments with enriched biopolymers.

We show that it is possible to spontaneously form all-enclosed compartments with microporous shells and enriched biopolymers via simple coprecipitation of silica and biopolymers. The reaction involves mild conditions and tolerates the random mixing of multiple reagents. Such a synthetic advance points to a new direction for resolving the chicken-egg dilemma of how the early life forms were hosted: without a physical barrier it would be difficult to maintain organized reactions, but without organized reactions, it would be difficult to create a cell membrane. In our synthesis, the divalent cation Ca2+ plays a critical role in the co-precipitation and in creating hollow compartments after simple dilution with water. The precursor of silica, poly(silicic acid), is a negatively charged, cross-linked polymer. It could be co-precipitated with negatively charged biopolymers such as DNA and proteins, whereas the remaining silica precursor forms a conformal and microporous shell on the surface of the initial precipitate. After etching, the biopolymers are retained inside the hollow compartments. The fact that multiple favorable conditions are easily brought together in enclosed compartments opens new possibilities in theorizing the host of early life forms.

MicroRNA-650 Regulates the Pathogenesis of Alzheimer's Disease Through Targeting Cyclin-Dependent Kinase 5.

Alzheimer's disease (AD) pathogenesis feature progressive neurodegeneration, amyloid-ß plaque formation, and neurofibrillary tangles. Ample evidence has indicated the involvement of epigenetic pathways in AD pathogenesis. Here, we show that the expression of microRNA 650 (miR-650) is altered in brains from AD patients. Furthermore, we found that the processing of primary miR-650 to mature miR-650 is misregulated. Bioinformatic analysis predicted that miR-650 targets the expression of three AD-associated components: Apolipoprotein E (APOE), Presenilin 1 (PSEN1), and Cyclin-Dependent Kinase 5 (CDK5), and we have experimentally confirmed that miR-650 is able to significantly reduce the expression of APOE, PSEN1, and CDK5 in vitro. Importantly, the overexpression of miR-650 was further shown to significantly alter the CDK5 level and ameliorate AD pathologies in APP-PSEN1 transgenic mice. Overall, our results indicate that miR-650 influences AD pathogenesis through regulation of CDK5.

TREM2hi resident macrophages protect the septic heart by maintaining cardiomyocyte homeostasis.

Sepsis-induced cardiomyopathy (SICM) is common in septic patients with a high mortality and is characterized by an abnormal immune response. Owing to cellular heterogeneity, understanding the roles of immune cell subsets in SICM has been challenging. Here we identify a unique subpopulation of cardiac-resident macrophages termed CD163+RETNLA+ (Mac1), which undergoes self-renewal during sepsis and can be targeted to prevent SICM. By combining single-cell RNA sequencing with fate mapping in a mouse model of sepsis, we demonstrate that the Mac1 subpopulation has distinct transcriptomic signatures enriched in endocytosis and displays high expression of TREM2 (TREM2hi). TREM2hi Mac1 cells actively scavenge cardiomyocyte-ejected dysfunctional mitochondria. Trem2 deficiency in macrophages impairs the self-renewal capability of the Mac1 subpopulation and consequently results in defective elimination of damaged mitochondria, excessive inflammatory response in cardiac tissue, exacerbated cardiac dysfunction and decreased survival. Notably, intrapericardial administration of TREM2hi Mac1 cells prevents SICM. Our findings suggest that the modulation of TREM2hi Mac1 cells could serve as a therapeutic strategy for SICM.

NAD+ Modulates the Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells via Akt Signaling Pathway.

Nicotinamide adenine dinucleotide hydrate (NAD+) acts as the essential component of the tricarboxylic citric acid (TCA) cycle and has important functions in diverse biological processes. However, the roles of NAD+ in regulating adult neural stem/progenitor cells (aNSPCs) remain largely unknown. Here, we show that NAD+ exposure leads to the reduced proliferation and neuronal differentiation of aNSPCs and induces the apoptosis of aNSPCs. In addition, NAD+ exposure inhibits the morphological development of neurons. Mechanistically, RNA sequencing revealed that the transcriptome of aNSPCs is altered by NAD+ exposure. NAD+ exposure significantly decreases the expression of multiple genes related to ATP metabolism and the PI3k-Akt signaling pathway. Collectively, our findings provide some insights into the roles and mechanisms in which NAD+ regulates aNSPCs and neuronal development.

FTO mediates LINE1 m6A demethylation and chromatin regulation in mESCs and mouse development.

N6-methyladenosine (m6A) is the most abundant internal modification on mammalian messenger RNA. It is installed by a writer complex and can be reversed by erasers such as the fat mass and obesity-associated protein FTO. Despite extensive research, the primary physiological substrates of FTO in mammalian tissues and development remain elusive. Here, we show that FTO mediates m6A demethylation of long-interspersed element-1 (LINE1) RNA in mouse embryonic stem cells (mESCs), regulating LINE1 RNA abundance and the local chromatin state, which in turn modulates the transcription of LINE1-containing genes. FTO-mediated LINE1 RNA m6A demethylation also plays regulatory roles in shaping chromatin state and gene expression during mouse oocyte and embryonic development. Our results suggest broad effects of LINE1 RNA m6A demethylation by FTO in mammals.

Emerging Roles of N6-Methyladenosine Modification in Neurodevelopment and Neurodegeneration.

N6-methyladenosine (m6A), the most abundant modification in messenger RNAs (mRNAs), is deposited by methyltransferases ("writers") Mettl3 and Mettl14 and erased by demethylases ("erasers") Fto and Alkbh5. m6A can be recognized by m6A-binding proteins ("readers"), such as Yth domain family proteins (Ythdfs) and Yth domain-containing protein 1 (Ythdc1). Previous studies have indicated that m6A plays an essential function in various fundamental biological processes, including neurogenesis and neuronal development. Dysregulated m6A modification contributes to neurological disorders, including neurodegenerative diseases. In this review, we summarize the current knowledge about the roles of m6A machinery, including writers, erasers, and readers, in regulating gene expression and the function of m6A in neurodevelopment and neurodegeneration. We also discuss the perspectives for studying m6A methylation.

Pressure ulcers in patients with diabetes: a bibliometrics analysis.

BACKGROUND: Pressure ulcers (PU) refer to local tissue ulceration and necrosis caused by long-term compression and friction brought on by tissue ischemia and hypoxia. Diabetic wounds do not easily heal, and once a pressure ulceration occurs, it is difficult to deal with. The purpose of this study was to analyze the current research status of PUs in diabetic patients. METHODS: The Science Citation Index Expanded (SCI-E) database was searched with terms of "Pressure Ulcer" and "Diabetes". Citespace software was used to analyze the annual distribution of the number of target documents and the distribution of countries, institutions, journals, authors, and keywords used in these works. RESULTS: In all, 1271 documents were retrieved, with a total citation frequency of 47,081, and an h-index of 101. The top 5 countries in terms of the number of publications were the United States, the United Kingdom, China, Australia, and the Netherlands; the top 5 countries in centrality were the Netherlands, the United States, Canada, Japan, and France. The institutions with the greatest number of publications were the University of Amsterdam, Cardiff University, The University of Washington, and the University of Manchester. The institutions with the highest centrality were the University of Amsterdam, the University of Groningen, the University of Washington, the University of Adelaide, Baylor College of Medicine, and Queensland University of Technology. The authors with a highest number of publications were Bus SA, Apelqvist J, and the International Working Group on the Diabetic Foot, and Hinchliffe RJ. Only 2 authors had a centrality score above 0.01. Journals such as Diabetes Metabolism Research and Reviews, Diabetes Care, and Journal of Wound Care showed considerable influence in this field. Keyword analysis indicated that the use of keywords in this field is not uniform, and the focus of research on PUs in diabetic patients lies the risk and management of foot ulcers. CONCLUSIONS: There are few studies concerning PUs in patients with diabetes and little collaboration between authors. The current focus in this field is on the risk and management of foot ulcers.

RYBP modulates embryonic neurogenesis involving the Notch signaling pathway in a PRC1-independent pattern.

RYBP (Ring1 and YY1 binding protein), an essential component of the Polycomb repressive complex 1 (PRC1), plays pivotal roles in development and diseases. However, the roles of Rybp in neuronal development remains completely unknown. In the present study, we have shown that the depletion of Rybp inhibits proliferation and promotes neuronal differentiation of embryonic neural progenitor cells (eNPCs). In addition, Rybp deficiency impairs the morphological development of neurons. Mechanistically, Rybp deficiency does not affect the global level of ubiquitination of H2A, but it inhibits Notch signaling pathway in eNPCs. The direct interaction between RYBP and CIR1 facilitates the binding of RBPJ to Notch intracellular domain (NICD) and consequently activated Notch signaling. Rybp loss promotes CIR1 competing with RBPJ to bind with NICD, and inhibits Notch signaling. Furthermore, ectopic Hes5, Notch signaling downstream target, rescues Rybp-deficiency-induced deficits. Collectively, our findings show that RYBP regulates embryonic neurogenesis and neuronal development through modulating Notch signaling in a PRC1-independent manner.