mRNA Metabolism in Cardiac Development and Disease: Life After Transcription.

The central dogma of molecular biology illustrates the importance of mRNAs as critical mediators between genetic information encoded at the DNA level and proteomes/metabolomes that determine the diverse functional outcome at the cellular and organ levels. Although the total number of protein-producing (coding) genes in the mammalian genome is ~20,000, it is evident that the intricate processes of cardiac development and the highly regulated physiological regulation in the normal heart, as well as the complex manifestation of pathological remodeling in a diseased heart, would require a much higher degree of complexity at the transcriptome level and beyond. Indeed, in addition to an extensive regulatory scheme implemented at the level of transcription, the complexity of transcript processing following transcription is dramatically increased. RNA processing includes post-transcriptional modification, alternative splicing, editing and transportation, ribosomal loading, and degradation. While transcriptional control of cardiac genes has been a major focus of investigation in recent decades, a great deal of progress has recently been made in our understanding of how post-transcriptional regulation of mRNA contributes to transcriptome complexity. In this review, we highlight some of the key molecular processes and major players in RNA maturation and post-transcriptional regulation. In addition, we provide an update to the recent progress made in the discovery of RNA processing regulators implicated in cardiac development and disease. While post-transcriptional modulation is a complex and challenging problem to study, recent technological advancements are paving the way for a new era of exciting discoveries and potential clinical translation in the context of cardiac biology and heart disease.

Filamin B restricts vaccinia virus spread and is targeted by vaccinia virus protein C4.

Vaccinia virus (VACV) is a large DNA virus that encodes scores of proteins that modulate the host immune response. VACV protein C4 is one such immunomodulator known to inhibit the activation of both the NF-κB signaling cascade and the DNA-PK-mediated DNA sensing pathway. Here, we show that the N-terminal region of C4, which neither inhibits NF-κB nor mediates interaction with DNA-PK, still contributes to virus virulence. Furthermore, this domain interacts directly and with high affinity to the C-terminal domain of filamin B (FLNB). FLNB is a large actin-binding protein that stabilizes the F-actin network and is implicated in other cellular processes. Deletion of FLNB from cells results in larger VACV plaques and increased infectious viral yield, indicating that FLNB restricts VACV spread. These data demonstrate that C4 has a new function that contributes to virulence and engages the cytoskeleton. Furthermore, we show that the cytoskeleton performs further previously uncharacterized functions during VACV infection. IMPORTANCE: Vaccinia virus (VACV), the vaccine against smallpox and monkeypox, encodes many proteins to counteract the host immune response. Investigating these proteins provides insights into viral immune evasion mechanisms and thereby indicates how to engineer safer and more immunogenic VACV-based vaccines. Here, we report that the N-terminal domain of VACV protein C4 interacts directly with the cytoskeletal protein filamin B (FLNB), and this domain of C4 contributes to virus virulence. Furthermore, VACV replicates and spreads better in cells lacking FLNB, thus demonstrating that FLNB has antiviral activity. VACV utilizes the cytoskeleton for movement within and between cells; however, previous studies show no involvement of C4 in VACV replication or spread. Thus, C4 associates with FLNB for a different reason, suggesting that the cytoskeleton has further uncharacterized roles during virus infection.

Attention-based cross domain graph neural network for prediction of drug-drug interactions.

Drug-drug interactions (DDI) may lead to adverse reactions in human body and accurate prediction of DDI can mitigate the medical risk. Currently, most of computer-aided DDI prediction methods construct models based on drug-associated features or DDI network, ignoring the potential information contained in drug-related biological entities such as targets and genes. Besides, existing DDI network-based models could not make effective predictions for drugs without any known DDI records. To address the above limitations, we propose an attention-based cross domain graph neural network (ACDGNN) for DDI prediction, which considers the drug-related different entities and propagate information through cross domain operation. Different from the existing methods, ACDGNN not only considers rich information contained in drug-related biomedical entities in biological heterogeneous network, but also adopts cross-domain transformation to eliminate heterogeneity between different types of entities. ACDGNN can be used in the prediction of DDIs in both transductive and inductive setting. By conducting experiments on real-world dataset, we compare the performance of ACDGNN with several state-of-the-art methods. The experimental results show that ACDGNN can effectively predict DDIs and outperform the comparison models.

Morphological and regional spontaneous functional aberrations in the brain associated with Crohn's disease: a systematic review and coordinate-based meta-analyses.

Crohn's disease is an acknowledged "brain-gut" disorder with unclear physiopathology. This study aims to identify potential neuroimaging biomarkers of Crohn's disease. Gray matter volume, cortical thickness, amplitude of low-frequency fluctuations, and regional homogeneity were selected as indices of interest and subjected to analyses using both activation likelihood estimation and seed-based d mapping with permutation of subject images. In comparison to healthy controls, Crohn's disease patients in remission exhibited decreased gray matter volume in the medial frontal gyrus and concurrently increased regional homogeneity. Furthermore, gray matter volume reduction in the medial superior frontal gyrus and anterior cingulate/paracingulate gyri, decreased regional homogeneity in the median cingulate/paracingulate gyri, superior frontal gyrus, paracentral lobule, and insula were observed. The gray matter changes of medial frontal gyrus were confirmed through both methods: decreased gray matter volume of medial frontal gyrus and medial superior frontal gyrus were identified by activation likelihood estimation and seed-based d mapping with permutation of subject images, respectively. The meta-regression analyses showed a positive correlation between regional homogeneity alterations and patient age in the supplementary motor area and a negative correlation between gray matter volume changes and patients' anxiety scores in the medial superior frontal gyrus. These anomalies may be associated with clinical manifestations including abdominal pain, psychiatric disorders, and possibly reflective of compensatory mechanisms.

Myocardial infarction drives trained immunity of monocytes, accelerating atherosclerosis.

BACKGROUND AND AIMS: Survivors of acute coronary syndromes face an elevated risk of recurrent atherosclerosis-related vascular events despite advanced medical treatments. The underlying causes remain unclear. This study aims to investigate whether myocardial infarction (MI)-induced trained immunity in monocytes could sustain proatherogenic traits and expedite atherosclerosis. METHODS: Apolipoprotein-E deficient (ApoE-/-) mice and adoptive bone marrow transfer chimeric mice underwent MI or myocardial ischaemia-reperfusion (IR). A subsequent 12-week high-fat diet (HFD) regimen was implemented to elucidate the mechanism behind monocyte trained immunity. In addition, classical monocytes were analysed by flow cytometry in the blood of enrolled patients. RESULTS: In MI and IR mice, blood monocytes and bone marrow-derived macrophages exhibited elevated spleen tyrosine kinase (SYK), lysine methyltransferase 5A (KMT5A), and CCHC-type zinc finger nucleic acid-binding protein (CNBP) expression upon exposure to a HFD or oxidized LDL (oxLDL) stimulation. MI-induced trained immunity was transmissible by transplantation of bone marrow to accelerate atherosclerosis in naive recipients. KMT5A specifically recruited monomethylation of Lys20 of histone H4 (H4K20me) to the gene body of SYK and synergistically transactivated SYK with CNBP. In vivo small interfering RNA (siRNA) inhibition of KMT5A or CNBP potentially slowed post-MI atherosclerosis. Sympathetic denervation with 6-hydroxydopamine reduced atherosclerosis and inflammation after MI. Classical monocytes from ST-elevation MI (STEMI) patients with advanced coronary lesions expressed higher SYK and KMT5A gene levels. CONCLUSIONS: The findings underscore the crucial role of monocyte trained immunity in accelerated atherosclerosis after MI, implying that SYK in blood classical monocytes may serve as a predictive factor for the progression of atherosclerosis in STEMI patients.

A fungal microRNA-like RNA regulated effector promotes pathogen infection by targeting a host defense-related transcription factor.

Effectors play important roles in facilitating the infection of plant pathogenic fungi. However, the gene expression regulatory mechanism of effector genes, in particular at the post-transcriptional level, is largely unknown. In this study, we uncovered the post-transcriptional regulation of an effector gene VmSP1 by a miRNA-like RNA (Vm-milR16) facilitating the infection of the apple tree Valsa canker pathogen Valsa mali. Genetic and molecular biological assays indicated that the expression of VmSP1 could be suppressed by Vm-milR16-mediated mRNA cleavage in a sequence-specific manner. During V. mali infection, Vm-milR16 was downregulated, whereas VmSP1 was upregulated, which further indicated the regulation relationship. VmSP1 was further demonstrated to be a secreted protein and could suppress plant immunity. Deletion of VmSP1 did not affect the vegetative growth but significantly reduced the virulence of V. mali. Further study indicated that VmSP1 could interact with the transcription factor MdbHLH189 of apple. Transiently overexpression of MdbHLH189 enhanced host resistance to V. mali by enhancing the expression of apple defense-related genes, together with the increased callose deposition. Silencing of MdbHLH189 compromised host resistance to V. mali. Our findings uncovered the novel epigenetic regulation mechanism of a virulence-associated effector gene mediated by a fungal milRNA at the post-transcriptional level, and the results enriched the understanding of the function and action mechanism of effectors in tree pathogenic fungi.

Biomimetic Nanoplatform for Dual-Targeted Clearance of Activated and Senescent Cancer-Associated Fibroblasts to Improve Radiation Resistance in Breast Cancer.

Radiation resistance in breast cancer resulting in residual lesions or recurrence is a significant cause to radiotherapy failure. Cancer-associated fibroblasts (CAFs) and radiotherapy-induced senescent CAFs can further lead to radiation resistance and tumor immunosuppressive microenvironment. Here, an engineering cancer-cell-biomimetic nanoplatform is constructed for dual-targeted clearance of CAFs as well as senescent CAFs. The nanoplatform is prepared by 4T1 cell membrane vesicles chimerized with FAP single-chain fragment variable as the biomimetic shell for targeting of CAFs and senescent CAFs, and PLGA nanoparticles (NPs) co-encapsulated with nintedanib and ABT-263 as the core for clearance of CAFs and senescent CAFs, which are noted as FAP-CAR-CM@PLGA-AB NPs. It is evidenced that FAP-CAR-CM@PLGA-AB NPs directly suppressed the tumor-promoting effect of senescent CAFs. It also exhibits prolonged blood circulation and enhanced tumor accumulation, dual-cleared CAFs and senescent CAFs, improved radiation resistance in both acquired and patient-derived radioresistant tumor cells, and effective antitumor effect with the tumor suppression rate of 86.7%. In addition, FAP-CAR-CM@PLGA-AB NPs reverse the tumor immunosuppressive microenvironment and enhance systemic antitumor immunity. The biomimetic system for dual-targeted clearance of CAFs and senescent CAFs provides a potential strategy for enhancing the radio-sensitization of breast cancer.

Treg-Derived Extracellular Vesicles: Roles in Diseases and Theranostics.

Regulatory T cells (Tregs), a subset of CD4+ T cells, are indispensable in maintaining immune self-tolerance and have been utilized in various diseases. Treg-derived extracellular vesicles (Treg-EVs) have been discovered to play an important role in the mechanism of Treg functions. As cell-derived membranous particles, EVs carry multiple bioactive substances that possess tremendous potential for theranostics. Treg-EVs are involved in numerous physiological and pathological processes, carrying proteins and miRNAs inherited from the parental cells. To comprehensively understand the function of Treg-EVs, here we reviewed the classification of Treg-EVs, the active molecules in Treg-EVs, their various applications in diseases, and the existing challenges for Treg-EVs based theranostics. This Review aims to clarify the feasibility and potential of Treg-EVs in diseases and theranostics, facilitating further research and application of Treg-EVs.

Hypertension associated with niraparib in cancer patients: A pharmacovigilance analysis based on the FAERS database and meta-analysis of randomized controlled trials.

BACKGROUND: Niraparib plays a crucial role in the treatment of ovarian cancer. A comprehensive understanding of the incidence and risk of hypertension associated with niraparib would be of vital importance to healthcare practitioners. METHODS: In this study, an observational, retrospective, pharmacovigilance study was conducted based on the FDA Adverse Event Reporting System (FAERS) database. Cases of hypertension related to niraparib were extracted for disproportionality analysis from the first quarter (Q1) of 2017 to Q1 of 2023. Moreover, a separate meta-analysis was performed using the randomized controlled trials (RCTs) on niraparib for cancer treatment published in PubMed, Embase, and Web of Science from inception to May 31st, 2023. The primary outcomes were the incidence and risk of hypertension associated with niraparib. RESULTS: In the FAERS, 1196 hypertension cases were found to be related to niraparib treatment. Notably, niraparib exhibited the highest level of disproportionality, as indicated by a reporting odds ratio (ROR) of 2.85 (95% CI, 2.69-3.01), suggesting a greater likelihood of causing hypertension compared to other poly-ADP-ribose polymerase (PARP) inhibitors (P < 0.01). Our safety meta-analysis included five pivotal RCTs of niraparib that reported hypertension. In comparison to placebo treatment, the meta-analysis demonstrated a significant increase in the risk of hypertension with niraparib (OR 2.84 [95% CI, 2.17-3.72], P < 0.01), with no heterogeneity observed among the studies (I2 = 0%, χ2 = 2.02, P = 0.73). The incidence of niraparib-induced hypertension was determined to be 16.9% (95% CI, 14.9-18.9; I2 = 34%). CONCLUSIONS: These findings suggest that hypertension is a distinctive adverse event associated with niraparib compared to other PARP inhibitors. Niraparib significantly increases the risk of hypertension that needs early recognition and management in clinical medication.

LncRNA PSR Regulates Vascular Remodeling Through Encoding a Novel Protein Arteridin.

RATIONALE: Vascular smooth muscle cells (VSMCs) phenotype switch from contractile to proliferative phenotype is a pathological hallmark in various cardiovascular diseases. Recently, a subset of long noncoding RNAs was identified to produce functional polypeptides. However, the functional impact and regulatory mechanisms of long noncoding RNAs in VSMCs phenotype switching remain to be fully elucidated. OBJECTIVES: To illustrate the biological function and mechanism of a VSMC-enriched long noncoding RNA and its encoded peptide in VSMC phenotype switching and vascular remodeling. RESULTS: We identified a VSMC-enriched transcript encoded by a previously uncharacterized gene, which we called phenotype switching regulator (PSR), which was markedly upregulated during vascular remodeling. Although PSR was annotated as a long noncoding RNA, we demonstrated that the lncPSR (PSR transcript) also encoded a protein, which we named arteridin. In VSMCs, both arteridin and lncPSR were necessary and sufficient to induce phenotype switching. Mechanistically, arteridin and lncPSR regulate downstream genes by directly interacting with a transcription factor YBX1 (Y-box binding protein 1) and modulating its nuclear translocation and chromatin targeting. Intriguingly, the PSR transcription was also robustly induced by arteridin. More importantly, the loss of PSR gene or arteridin protein significantly attenuated the vascular remodeling induced by carotid arterial injury. In addition, VSMC-specific inhibition of lncPSR using adeno-associated virus attenuated Ang II (angiotensin II)-induced hypertensive vascular remodeling. CONCLUSIONS: PSR is a VSMC-enriched gene, and its transcript IncPSR and encoded protein (arteridin) coordinately regulate transcriptional reprogramming through a shared interacting partner, YBX1. This is a previously uncharacterized regulatory circuit in VSMC phenotype switching during vascular remodeling, with lncPSR/arteridin as potential therapeutic targets for the treatment of VSMC phenotype switching-related vascular remodeling.

Prediction of short-term progression of COVID-19 pneumonia based on chest CT artificial intelligence: during the Omicron epidemic.

BACKGROUND AND PURPOSE: The persistent progression of pneumonia is a critical determinant of adverse outcomes in patients afflicted with COVID-19. This study aimed to predict personalized COVID-19 pneumonia progression between the duration of two weeks and 1 month after admission by integrating radiological and clinical features. METHODS: A retrospective analysis, approved by the Institutional Review Board, encompassed patients diagnosed with COVID-19 pneumonia between December 2022 and February 2023. The cohort was divided into training and validation groups in a 7:3 ratio. A trained multi-task U-Net network was deployed to segment COVID-19 pneumonia and lung regions in CT images, from which quantitative features were extracted. The eXtreme Gradient Boosting (XGBoost) algorithm was employed to construct a radiological model. A clinical model was constructed by LASSO method and stepwise regression analysis, followed by the subsequent construction of the combined model. Model performance was assessed using ROC and decision curve analysis (DCA), while Shapley's Additive interpretation (SHAP) illustrated the importance of CT features. RESULTS: A total of 214 patients were recruited in our study. Four clinical characteristics and four CT features were identified as pivotal components for constructing the clinical and radiological models. The final four clinical characteristics were incorporated as well as the RS_radiological model to construct the combined prediction model. SHAP analysis revealed that CT score difference exerted the most significant influence on the predictive performance of the radiological model. The training group's radiological, clinical, and combined models exhibited AUC values of 0.89, 0.72, and 0.92, respectively. Correspondingly, in the validation group, these values were observed to be 0.75, 0.72, and 0.81. The DCA curve showed that the combined model exhibited greater clinical utility than the clinical or radiological models. CONCLUSION: Our novel combined model, fusing quantitative CT features with clinical characteristics, demonstrated effective prediction of COVID-19 pneumonia progression from 2 weeks to 1 month after admission. This comprehensive model can potentially serve as a valuable tool for clinicians to develop personalized treatment strategies and improve patient outcomes.

Angular uniformity improvement of diffractive waveguide display based on region geometry optimization.

Augmented reality (AR) near-eye displays have significantly progressed due to advances in nanostructure fabrication. However, for diffractive waveguide AR displays requiring exit pupil expansion, the angular uniformity of each exit pupil position still needs to improve. In this paper, an angular uniformity improvement method based on region geometry optimization is proposed. This optimization method essentially introduces the interaction number of the light with the grating as one of the variables to manipulate the energy distribution. This distribution is obtained by the rigorous coupled wave analysis (RCWA) method and ray tracing process and is further optimized by a multi-objective genetic algorithm. A model is built, and the feasibility of the proposed method is verified. The diffractive waveguide system has a 10m m×10m m exit pupil size at the eye relief of 25 mm and a field of view (FOV) of 21∘×12∘. After the optimization, the overall optical efficiency of the central field and the angular uniformity at the center exit pupil position increased from 0.9% and 66% to 3.1% and 80%, respectively.

Predictive value of radiomic features extracted from primary lung adenocarcinoma in forecasting thoracic lymph node metastasis: a systematic review and meta-analysis.

BACKGROUND: The application of radiomics in thoracic lymph node metastasis (LNM) of lung adenocarcinoma is increasing, but diagnostic performance of radiomics from primary tumor to predict LNM has not been systematically reviewed. Therefore, this study sought to provide a general overview regarding the methodological quality and diagnostic performance of using radiomic approaches to predict the likelihood of LNM in lung adenocarcinoma. METHODS: Studies were gathered from literature databases such as PubMed, Embase, the Web of Science Core Collection, and the Cochrane library. The Radiomic Quality Score (RQS) and the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) were both used to assess the quality of each study. The pooled sensitivity, specificity, and area under the curve (AUC) of the best radiomics models in the training and validation cohorts were calculated. Subgroup and meta-regression analyses were also conducted. RESULTS: Seventeen studies with 159 to 1202 patients each were enrolled between the years of 2018 to 2022, of which ten studies had sufficient data for the quantitative evaluation. The percentage of RQS was between 11.1% and 44.4% and most of the studies were considered to have a low risk of bias and few applicability concerns in QUADAS-2. Pyradiomics and logistic regression analysis were the most commonly used software and methods for radiomics feature extraction and selection, respectively. In addition, the best prediction models in seventeen studies were mainly based on radiomics features combined with non-radiomics features (semantic features and/or clinical features). The pooled sensitivity, specificity, and AUC of the training cohorts were 0.84 (95% confidence interval (CI) [0.73-0.91]), 0.88 (95% CI [0.81-0.93]), and 0.93(95% CI [0.90-0.95]), respectively. For the validation cohorts, the pooled sensitivity, specificity, and AUC were 0.89 (95% CI [0.82-0.94]), 0.86 (95% CI [0.74-0.93]) and 0.94 (95% CI [0.91-0.96]), respectively. CONCLUSIONS: Radiomic features based on the primary tumor have the potential to predict preoperative LNM of lung adenocarcinoma. However, radiomics workflow needs to be standardized to better promote the applicability of radiomics. TRIAL REGISTRATION: CRD42022375712.

Isobavachalcone induces hepatotoxicity in zebrafish embryos and HepG2 cells via the System Xc--GSH-GPX4 signaling pathway in ferroptosis response.

Isobavachalcone (IBC) is a flavonoid component of the traditional Chinese medicine Psoraleae Fructus, with a range of pharmacological properties. However, IBC causes some hepatotoxicity, and the mechanism of toxicity is unclear. The purpose of this paper was to investigate the possible mechanism of toxicity of IBC on HepG2 cells and zebrafish embryos. The results showed that exposure to IBC increased zebrafish embryo mortality and decreased hatchability. Meanwhile, IBC induced liver injury and increased expression of ALT and AST activity. Further studies showed that IBC caused the increase of ROS and MDA the decrease of CAT, GSH, and GSH-Px; the increase of Fe2+ content; and the changes of ferroptosis related genes (acsl4, gpx4, and xct) and iron storage related genes (tf, fth, and fpn) in zebrafish embryos. Through in vitro verification, it was found that IBC also caused oxidative stress and increased Fe2+ content in HepG2 cells. IBC caused depolarization of mitochondrial membrane potential (MMP) and reduction of mitochondrial ATP, as well as altered expression of ACSl4, SLC7A11, GPX4, and FTH1 proteins. Treatment of HepG2 cells with ferrostatin-1 could reverse the effect of IBC. Targeting the System Xc--GSH-GPX4 pathway of ferroptosis and preventing oxidative stress damage might offer a theoretical foundation for practical therapy and prevention of IBC-induced hepatotoxicity.

Effect of proanthocyanidins on blood lipids: A systematic review and meta-analysis.

Proanthocyanidins (PCs) are natural antioxidant polyphenols and their effect on the regulation of blood lipids is still controversial. This study was conducted to evaluate the effect of PCs on lipid metabolism. We searched PubMed, Embase, Web of Science, Chinese biomedical literature service system, China National Knowledge Internet, and Wanfang Data with no time restriction until March 18, 2022, using various forms of "proanthocyanidins" and "blood lipid" search terms. Randomized controlled trials investigating the relationship between PCs and lipid metabolism were included. The standard system of Cochrane Collaboration was used to assess the quality of studies. We standardized mean differences (SMDs) with 95% confidence interval (CI) using the random-effects model, Cohen approach. Seventeen studies (17 trials, N = 1138) fulfilled the eligibility criteria. PCs significantly reduced triglyceride, and increased recombinant apolipoprotein A1. Subgroup analysis showed a significant reduction in triglycerides in older adults (≥60 years) and total cholesterol for participants who were not overweight or obese (body mass index <24). An intervention duration of greater than 8 weeks reduced triglyceride and low-density lipoprotein cholesterol levels but increased high-density lipoprotein cholesterol. Different doses of PCs could regulate triglycerides, high-density lipoprotein cholesterol and total cholesterol. PCs have beneficial effects on circulating lipids and may represent a new approach for treating or preventing lipid metabolism disorders. However, more high-quality studies are needed to confirm these results.

Isolation and Characterization of Paenibacillus polymyxa B7 and Inhibition of Aspergillus tubingensis A1 by Its Antifungal Substances.

Screening of Bacillus with antagonistic effects on paddy mold pathogens to provide strain resources for biological control of mold in Oryza sativa L. screening of Bacillus isolates antagonistic towards Aspergillus tubingensis from rhizosphere soil of healthy paddy; classification and identification of antagonistic strains by biological characteristics and 16S rDNA sequence analysis; transcriptome sequencing after RNA extraction from Bacillus-treated Aspergillus tubingensis; and extraction of inhibitory crude proteins of Bacillus by ammonium sulfate precipitation; inhibitory crude protein and Bacillus spp. were treated separately for A. tubingensis and observed by scanning electron microscopy (SEM). An antagonistic strain of Bacillus, named B7, was identified as Paenibacillus polymyxa by 16S rDNA identification and phylogenetic evolutionary tree comparison analysis. Analysis of the transcriptome results showed that genes related to secondary metabolite biosynthesis such as antifungal protein were significantly downregulated. SEM results showed that the mycelium of A. tubingensis underwent severe rupture after treatment with P. polymyxa and antifungal proteins, respectively. In addition, the sporocarp changed less after treatment with P. polymyxa, and the sporangium stalks had obvious folds. P. polymyxa B7 has a good antagonistic effect against A. tubingensis and has potential for biocontrol applications of paddy mold pathogens.

Integrating Olefin Carboamination and Hofmann-Löffler-Freytag Reaction by Radical Deconstruction of Hydrazonyl N-N Bond.

As a type of elementary organic compounds containing N-N single bond, hydrazone involved chemical conversions are extremely extensive, but they are mainly limited to N2-retention and N2-removal modes. We report herein an unprecedented protocol for the realization of division utilization of the N2-moiety of hydrazone by a radical facilitated N-N bond deconstruction strategy. This new conversion mode enables the successful combination of alkene carboamination and Hofmann-Löffler-Freytag reaction by the reaction of N-homoallyl mesitylenesulfonyl hydrazones with ethyl difluoroiodoacetate under photocatalytic redox neutral conditions. Mechanism studies reveal that the reaction undergoes a radical relay involving addition, crucial remote imino-N migration and H-atom transfer. Consequently, a series of structurally significant ϵ-N-sulphonamide-α,α-difluoro-γ-amino acid esters are efficiently produced via continuous C-C bond and dual C-N bonds forging.

Rewiring of 3D Chromatin Topology Orchestrates Transcriptional Reprogramming and the Development of Human Dilated Cardiomyopathy.

BACKGROUND: Transcriptional reconfiguration is central to heart failure, the most common cause of which is dilated cardiomyopathy (DCM). The effect of 3-dimensional chromatin topology on transcriptional dysregulation and pathogenesis in human DCM remains elusive. METHODS: We generated a compendium of 3-dimensional epigenome and transcriptome maps from 101 biobanked human DCM and nonfailing heart tissues through highly integrative chromatin immunoprecipitation (H3K27ac [acetylation of lysine 27 on histone H3]), in situ high-throughput chromosome conformation capture, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin using sequencing, and RNA sequencing. We used human induced pluripotent stem cell-derived cardiomyocytes and mouse models to interrogate the key transcription factor implicated in 3-dimensional chromatin organization and transcriptional regulation in DCM pathogenesis. RESULTS: We discovered that the active regulatory elements (H3K27ac peaks) and their connectome (H3K27ac loops) were extensively reprogrammed in DCM hearts and contributed to transcriptional dysregulation implicated in DCM development. For example, we identified that nontranscribing NPPA-AS1 (natriuretic peptide A antisense RNA 1) promoter functions as an enhancer and physically interacts with the NPPA (natriuretic peptide A) and NPPB (natriuretic peptide B) promoters, leading to the cotranscription of NPPA and NPPB in DCM hearts. We revealed that DCM-enriched H3K27ac loops largely resided in conserved high-order chromatin architectures (compartments, topologically associating domains) and their anchors unexpectedly had equivalent chromatin accessibility. We discovered that the DCM-enriched H3K27ac loop anchors exhibited a strong enrichment for HAND1 (heart and neural crest derivatives expressed 1), a key transcription factor involved in early cardiogenesis. In line with this, its protein expression was upregulated in human DCM and mouse failing hearts. To further validate whether HAND1 is a causal driver for the reprogramming of enhancer-promoter connectome in DCM hearts, we performed comprehensive 3-dimensional epigenome mappings in human induced pluripotent stem cell-derived cardiomyocytes. We found that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced a distinct gain of enhancer-promoter connectivity and correspondingly increased the expression of their connected genes implicated in DCM pathogenesis, thus recapitulating the transcriptional signature in human DCM hearts. Electrophysiology analysis demonstrated that forced overexpression of HAND1 in human induced pluripotent stem cell-derived cardiomyocytes induced abnormal calcium handling. Furthermore, cardiomyocyte-specific overexpression of Hand1 in the mouse hearts resulted in dilated cardiac remodeling with impaired contractility/Ca2+ handling in cardiomyocytes, increased ratio of heart weight/body weight, and compromised cardiac function, which were ascribed to recapitulation of transcriptional reprogramming in DCM. CONCLUSIONS: This study provided novel chromatin topology insights into DCM pathogenesis and illustrated a model whereby a single transcription factor (HAND1) reprograms the genome-wide enhancer-promoter connectome to drive DCM pathogenesis.

Hierarchical Synergistic Structure for High Resolution Strain Sensor with Wide Working Range.

Strain sensors have been attracting tremendous attention for the promising application of wearable devices in recent years. However, the trade-off between high resolution, high sensitivity, and broad detection range is a great challenge for the application of strain sensors. Herein, a novel design of hierarchical synergistic structure (HSS) of Au micro cracks and carbon black (CB) nanoparticles is reported to overcome this challenge. The strain sensor based on the designed HSS exhibit high sensitivity (GF > 2400), high strain resolution (0.2%) even under large loading strain, broad detection range (>40%), outstanding stability (>12000 cycles), and fast response speed simultaneously. Further, the experiments and simulation results demonstrate that the carbon black layer greatly changed the morphology of Au micro-cracks, forming a hierarchical structure of micro-scale Au cracks and nano-scale carbon black particles, thus enabling synergistic effect and the double conductive network of Au micro-cracks and CB nanoparticles. Based on the excellent performance, the sensor is successfully applied to monitoring tiny signals of the carotid pulse during body movement, which illustrates the great potential in the application of health monitoring, human-machine interface, human motion detection, and electronic skin.

Tracing the opposing assimilate and nutrient flows in live conifer needles.

The vasculature along conifer needles is fundamentally different from that in angiosperm leaves as it contains a unique transfusion tissue inside the bundle sheath. In this study, we used specific tracers to identify the pathway of photoassimilates from mesophyll to phloem, and the opposing pathway of nutrients from xylem to mesophyll. For symplasmic transport we applied esculin to the tip of attached pine needles and followed its movement down the phloem. For apoplasmic transport we let detached needles take up a membrane-impermeable contrast agent and used micro-X-ray computed tomography to map critical water exchange interfaces and domain borders. Microscopy and segmentation of the X-ray data enabled us to render and quantify the functional 3D structure of the water-filled apoplasm and the complementary symplasmic domain. The transfusion tracheid system formed a sponge-like apoplasmic domain that was blocked at the bundle sheath. Transfusion parenchyma cell chains bridged this domain as tortuous symplasmic pathways with strong local anisotropy which, as evidenced by the accumulation of esculin, pointed to the phloem flanks as the preferred phloem-loading path. Simple estimates supported a pivotal role of the bundle sheath, showing that a bidirectional movement of nutrient ions and assimilates is feasible and emphasizing the role of the bundle sheath in nutrient and assimilate exchange.