Construction of dual sites on FeS2 surface for enhanced electrocatalytic reduction of nitrite to ammonia.

Cost-effective iron sulfides (FeS2) hold great potential as high-performance catalysts for NO2- electroreduction to NH3 (NO2ER), which is hindered by the weak NO2 activation. Herein, the design of nonmetal-doped FeS2 electrocatalysts was initially conducted by density functional theory (DFT) computations. We found that doping with different nonmetal atoms effectively not only regulates the electronic structures of the d-electrons of Fe atoms but also creates the unique p-d hybridized dual active sites, thereby boosting the efficient NO2 activation. Owing to the optimal NO2 adsorption strength, N-doped FeS2 demonstrates a low limiting potential for the NO2--to-NH3 conversion, thus significantly improving NO2ER activity. Direct experimental evidence was provided afterward: an NH3 yield rate of 424.5 µmol/hcm-2 with a 92.4 % Faradaic efficiency was achieved. Our findings not only suggest a promising NO2ER catalyst through theoretical computations to guide experiments but also provide a comprehensive understanding of the structure-properties relationship.

METTL3/METTL14 maintain human nucleoli integrity by mediating SUV39H1/H2 degradation.

Nucleoli are fundamentally essential sites for ribosome biogenesis in cells and formed by liquid-liquid phase separation (LLPS) for a multilayer condensate structure. How the nucleoli integrity is maintained remains poorly understood. Here, we reveal that METTL3/METTL14, the typical methyltransferase complex catalyzing N6-methyladnosine (m6A) on mRNAs maintain nucleoli integrity in human embryonic stem cells (hESCs). METTL3/METTL14 deficiency impairs nucleoli and leads to the complete loss of self-renewal in hESCs. We further show that SUV39H1/H2 protein, the methyltransferases catalyzing H3K9me3 were dramatically elevated in METTL3/METTL14 deficient cells, which causes an accumulation and infiltration of H3K9me3 across the whole nucleolus and impairs the LLPS. Mechanistically, METTL3/METTL14 complex serves as an essential adapter for CRL4 E3 ubiquitin ligase targeting SUV39H1/H2 for polyubiquitination and proteasomal degradation and therefore prevents H3K9me3 accumulation in nucleoli. Together, these findings uncover a previously unknown role of METTL3/METTL14 to maintain nucleoli integrity by facilitating SUV39H1/H2 degradation in human cells.

ZmSPL10, ZmSPL14 and ZmSPL26 act together to promote stigmatic papilla formation in maize through regulating auxin signaling and ZmWOX3A expression.

Maize silk is a specialized type of stigma, covered with numerous papillae for pollen grain capture. However, the developmental process of stigmatic papillae and the underlying regulatory mechanisms have remained largely unknown. Here, we combined the cytological, genetic and molecular studies to demonstrate that three homologous genes ZmSPL10, ZmSPL14 and ZmSPL26 play a central role in promoting stigmatic papilla formation in maize. We show that their triple knockout mutants are nearly complete lack of stigmatic papilla, resulting in a severe reduction in kernel setting. Cellular examination reveals that stigmatic papilla is developed from a precursor cell, which is the smaller daughter cell resulting from asymmetric cell division of a silk epidermal cell. In situ hybridization shows that ZmSPL10, ZmSPL14 and their target genes SPI1, ZmPIN1b, ZmARF28 and ZmWOX3A are preferentially expressed in the precursor cells of stigmatic papillae. Moreover, ZmSPL10, ZmSPL14 and ZmSPL26 directly bind to the promoters of SPI1, ZmPIN1b, ZmARF28 and ZmWOX3A and promote their expression. Further, Zmwox3a knockout mutants display severe defects in stigmatic papilla formation and reduced seed setting. Collectively, our results demonstrate that ZmSPL10, ZmSPL14 and ZmSPL26 act together to promote stigmatic papilla development through regulating auxin signaling and ZmWOX3A expression.

Boosting electrocatalytic nitrate-to-ammonia of single Fe active sites via coordination engineering: From theory to experiments.

Atomically dispersed iron-nitrogen-carbon (Fe-N4-C) catalysts show great promises for the electrocatalytic nitrate (NO3-) reduction to ammonia (NH3). Nevertheless, the microenvironmental engineering of the single Fe active sites for further optimizing the catalytic performance remains a challenge. Herein, we proposed to regulate the coordination environment of single Fe active sites to boost its intrinsic electrocatalytic activity for NO3- -to-NH3 conversion by the incorporation of new heteroatoms, including B, C, O, Si, P, and S. Our results revealed that most of the candidates possess low formation energies, showing great potential for experimental synthesis. Moreover, incorporating heteroatoms effectively modulates the charge redistribution and the d-band center of single Fe active sites, enabling the regulation of the binding strength of nitrogenous intermediates. As a result, the N and C coordinated Fe active site (Fe-N3C) exhibits superior catalytic performance for NO3- electroreduction with a relatively low limiting potential (-0.13 V) due to its optimal adsorption strength with nitrogenous intermediates induced by its moderate charge and d-band center. Importantly, our experimental measures confirmed such theoretical prediction: a maximum NH3 yield rate of 21.07 mg h-1 mgcat.-1 and 95.74 % Faradaic efficiency were achieved for NO3- electroreduction on Fe-N3C catalyst. These findings not only suggest a highly efficient catalyst for nitrate reduction but also provide insight into how to design and prepare electrocatalysts with enhanced catalytic performance.

Heterogeneous Cu2O-SnO2 doped polydopamine fenton-like nanoenzymes for synergetic photothermal-chemodynamic antibacterial application.

Wound infections caused by drug-resistant bacteria pose a great threat to human health, and the development of non-drug-resistant antibacterial approaches has become a research priority. In this study, we developed Cu2O-SnO2 doped polydopamine (CSPDA) triple cubic antibacterial nanoenzymes with high photothermal conversion efficiency and good Fenton-like catalase performance. CSPDA antibacterial nanoplatform can catalyze the generation of hydroxyl radical (·OH) from H2O2 at low concentration (50 µg∙mL-1) under 808 nm near-infrared (NIR) irradiation to achieve a combined photothermal therapy (PTT) and chemodynamic therapy (CDT). And the CSPDA antibacterial nanoplatform displays broad-spectrum and long-lasting antibacterial effects against both Gram-negative Escherichia coli (100 %) and Gram-positive Staphylococcus aureus (100 %) in vitro. Moreover, in a mouse wound model with mixed bacterial infection, the nanoplatform demonstrates a significant in vivo bactericidal effect while remaining good cytocompatible. To conclude, this study successfully develops an efficient and long-lasting bacterial infection treatment system. This system provided different options for future studies on the design of synergistic antimicrobial therapy. Hence, the as-synthesized synergetic photothermal therapy and chemodynamic therapy nanoenzymes have rapid and long-term bactericidal ability, well-conglutinant performance and effectively preventing wound infection for clinical application. STATEMENT OF SIGNIFICANCE: Wound infections caused by drug-resistant bacteria pose a great threat to human health, and the development of non-drug-resistant antibacterial approaches has become a research priority. In this study, we developed Cu2O-SnO2 doped polydopamine (CSPDA) triple cubic yolk-like antibacterial nanoenzymes with high photothermal conversion efficiency and Fenton-like catalase effect for photothermal and Chemodynamic antibacterial therapy, Meanwhile, the nanocomposites exhibit good antibioadhesion in a natural water environment for a long-time immersion. In conclusion, this study successfully develops an efficient and long-lasting bacterial infection treatment system. These findings present a pioneering strategy for future research on the design of synergistic antibacterial and antibioadhesive systems.

AKAP3-mediated type I PKA signaling is required for mouse sperm hyperactivation and fertility†.

The protein kinase A (PKA) signaling pathway, which mediates protein phosphorylation, is important for sperm motility and male fertility. This process relies on A-kinase anchoring proteins that organize PKA and its signalosomes within specific subcellular compartments. Previously, it was found that the absence of A-kinase anchoring protein 3 (AKAP3) leads to multiple morphological abnormalities in mouse sperm. But how AKAP3 regulates sperm motility is yet to be elucidated. AKAP3 has two amphipathic domains, here named dual and RI, in its N-terminus. These domains are responsible for binding regulatory subunits I alpha (RIα) and II alpha (RIIα) of PKA and for RIα only, respectively. Here, we generated mutant mice lacking the dual and RI domains of AKAP3. It was found that the deletion of these domains caused male mouse infertile, accompanied by mild defects in the fibrous sheath of sperm tails. Additionally, the levels of serine/threonine phosphorylation of PKA substrates and tyrosine phosphorylation decreased in the mutant sperm, which exhibited a defect in hyperactivation under capacitation conditions. The protein levels of PKA subunits remained unchanged. But, interestingly, the regulatory subunit RIα was mis-localized from principal piece to midpiece of sperm tail, whereas this was not observed for RIIα. Further protein-protein interaction assays revealed a preference for AKAP3 to bind RIα over RIIα. Collectively, our findings suggest that AKAP3 is important for sperm hyperactivity by regulating type-I PKA signaling pathway mediated protein phosphorylation via its dual and RI domains.

Platinum based theranostics nanoplatforms for antitumor applications.

Platinum (Pt) based nanoplatforms are biocompatible nanoagents with photothermal antitumor performance, while exhibiting excellent radiotherapy sensitization properties. Pt-nanoplatforms have extensive research prospects in the realm of cancer treatment due to their highly selective and minimally invasive treatment mode with low damage, and integrated diagnosis and treatment with image monitoring and collaborative drug delivery. Platinum based anticancer chemotherapeutic drugs can kill tumor cells by damaging DNA through chemotherapy. Meanwhile, Pt-nanoplatforms also have good electrocatalytic activity, which can mediate novel electrodynamic therapy. Simultaneously, Pt(II) based compounds also have potential as photosensitizers in photodynamic therapy for malignant tumors. Pt-nanoplatforms can also modulate the immunosuppressive environment and synergistically ablate tumor cells in combination with immune checkpoint inhibitors. This article reviews the research progress of platinum based nanoplatforms in new technologies for cancer therapy, starting from widely representative examples of platinum based nanoplatforms in chemotherapy, electrodynamic therapy, photodynamic therapy, photothermal therapy, and immunotherapy. Finally, multimodal imaging techniques of platinum based nanoplatforms for biomedical diagnosis are briefly discussed.

Transplantation of hESCs-Derived Neural Progenitor Cells Alleviates Secondary Damage of Thalamus After Focal Cerebral Infarction in Rats.

Human embryonic stem cells-derived neural progenitor cells (hESCs-NPCs) transplantation holds great potential to treat stroke. We previously reported that delayed secondary degeneration occurs in the ventroposterior nucleus (VPN) of ipsilateral thalamus after distal branch of middle cerebral artery occlusion (dMCAO) in adult male Sprague-Dawley (SD) rats. In this study, we investigate whether hESCs-NPCs would benefit the neural recovery of the secondary damage in the VPN after focal cerebral infarction. Permanent dMCAO was performed with electrocoagulation. Rats were randomized into Sham, dMCAO groups with or without hESCs-NPCs treatment. HESCs-NPCs were engrafted into the peri-infarct regions of rats at 48 h after dMCAO. The transplanted hESCs-NPCs survive and partially differentiate into mature neurons after dMCAO. Notably, hESCs-NPCs transplantation attenuated secondary damage of ipsilateral VPN and improved neurological functions of rats after dMCAO. Moreover, hESCs-NPCs transplantation significantly enhanced the expression of BDNF and TrkB and their interaction in ipsilateral VPN after dMCAO, which was reversed by the knockdown of TrkB. Transplantated hESCs-NPCs reconstituted thalamocortical connection and promoted the formation of synapses in ipsilateral VPN post-dMCAO. These results suggest that hESCs-NPCs transplantation attenuates secondary damage of ipsilateral thalamus after cortical infarction, possibly through activating BDNF/TrkB pathway, enhancing thalamocortical projection, and promoting synaptic formation. It provides a promising therapeutic strategy for secondary degeneration in the ipsilateral thalamus post-dMCAO.

SARS-CoV-2 induces cardiomyocyte apoptosis and inflammation but can be ameliorated by ACE inhibitor Captopril.

Although the clinical manifestation of COVID-19 is mainly respiratory symptoms, approximately 20% of patients suffer from cardiac complications. COVID-19 patients with cardiovascular disease have higher severity of myocardial injury and poor outcomes. The underlying mechanism of myocardial injury caused by SARS-CoV-2 infection remains unclear. Using a non-transgenic mouse model infected with Beta variant (B.1.351), we found that the viral RNA could be detected in lungs and hearts of infected mice. Pathological analysis showed thinner ventricular wall, disorganized and ruptured myocardial fiber, mild inflammatory infiltration, and mild epicardia or interstitial fibrosis in hearts of infected mice. We also found that SARS-CoV-2 could infect cardiomyocytes and produce infectious progeny viruses in human pluripotent stem cell-derived cardiomyocyte-like cells (hPSC-CMs). SARS-CoV-2 infection caused apoptosis, reduction of mitochondrial integrity and quantity, and cessation of beating in hPSC-CMs. In order to dissect the mechanism of myocardial injury caused by SARS-CoV-2 infection, we employed transcriptome sequencing of hPSC-CMs at different time points after viral infection. Transcriptome analysis showed robust induction of inflammatory cytokines and chemokines, up-regulation of MHC class I molecules, activation of apoptosis signaling and cell cycle arresting. These may cause aggravate inflammation, immune cell infiltration, and cell death. Furthermore, we found that Captopril (hypotensive drugs targeting ACE) treatment could alleviate SARS-CoV-2 induced inflammatory response and apoptosis in cardiomyocytes via inactivating TNF signaling pathways, suggesting Captopril may be beneficial for reducing COVID-19 associated cardiomyopathy. These findings preliminarily explain the molecular mechanism of pathological cardiac injury caused by SARS-CoV-2 infection, providing new perspectives for the discovery of antiviral therapeutics.

Decellularised spinal cord matrix manipulates glial niche into repairing phase via serglycin-mediated signalling pathway.

Astrocytes are the most abundant and widespread glial cells in the central nervous system. The heterogeneity of astrocytes plays an essential role in spinal cord injury (SCI) repair. Decellularised spinal cord matrix (DSCM) is advantageous for repairing SCI, but little is known regarding the exact mechanisms and niche alterations. Here, we investigated the DSCM regulatory mechanism of glial niche in the neuro-glial-vascular unit using single-cell RNA sequencing. Our single cell sequencing, molecular and biochemical experiments validated that DSCM facilitated the differentiation of neural progenitor cells through increasing the number of immature astrocytes. Upregulation of mesenchyme-related genes, which maintained astrocyte immaturity, causing insensitivity to inflammatory stimuli. Subsequently, we identified serglycin (SRGN) as a functional component of DSCM, which involves inducing CD44-AKT signalling to trigger human spinal cord-derived primary astrocytes (hspASCs) proliferation and upregulation of genes related to epithelial-mesenchymal transition, thus impeding astrocyte maturation. Finally, we verified that SRGN-COLI and DSCM had similar functions in the human primary cell co-culture system to mimic the glia niche. In conclusion, our work revealed that DSCM reverted astrocyte maturation and altered the glia niche into the repairing phase through the SRGN-mediated signalling pathway.

Concave octopus-like PtCu nanoframe mediated photo-electro Fenton catalysis for fast organic dyestuff elimination.

In this work, a photo-electro Fenton catalytic nanoplatform based on concave octopus-like PtCu nanoframes was fabricated for organic dyestuff degradation. The electrochemical oxidation reaction was performed to generate hydrogen peroxide (H2O2) on the interface of PtCu nanoframes via a promising electro-Fenton process for on-demand aqueous remediation.

Plin2-mediated lipid droplet mobilization accelerates exit from pluripotency by lipidomic remodeling and histone acetylation.

Metabolic switch is critical for cell fate determination through metabolic functions, epigenetic modifications, and gene expression. However, the mechanisms underlying these alterations and their functional roles remain unclear. Here, we show that Plin2-mediated moderate lipid hydrolysis is critical for pluripotency of embryonic stem cells (ESCs). Upon exit from pluripotency, lipid droplet (LD)-associated protein Plin2 is recognized by Hsc70 and degraded via chaperone-mediated autophagy to facilitate LD mobilization. Enhancing lipid hydrolysis by Plin2 knockout promotes pluripotency exit, which is recovered by ATGL inhibition. Mechanistically, excessive lipid hydrolysis induces a dramatic lipidomic remodeling characterized by decreased cardiolipin and phosphatidylethanolamine, which triggers defects in mitochondrial cristae and fatty acid oxidation, resulting in reduced acetyl-CoA and histone acetylation. Our results reveal how LD mobilization is regulated and its critical role in ESC pluripotency, and indicate the mechanism linking LD homeostasis to mitochondrial remodeling and epigenetic regulation, which might shed light on development and diseases.

MYOCD is Required for Cardiomyocyte-like Cells Induction from Human Urine Cells and Fibroblasts Through Remodeling Chromatin.

Despite direct reprogramming of human cardiac fibroblasts into induced cardiomyocytes (iCM) holds great potential for heart regeneration, the mechanisms are poorly understood. Whether other human somatic cells could be reprogrammed into cardiomyocytes is also unknown. Here, we report human urine cells (hUCs) could be converted into CM-like cells from different donors and the related chromatin accessibility dynamics (CAD) by assay for transposase accessible chromatin(ATAC)-seq. hUCs transduced by MEF2C, TBX5, MESP1 and MYOCD but without GATA4 expressed multiple cardiac specific genes, exhibited Ca2+ oscillation potential and sarcomeric structures, and contracted synchronously in coculture with mouse CM. Additionally, we found that MYOCD is required for both closing and opening critical loci, mainly by hindering the opening of loci enriched with motifs for the TEAD and AP1 family and promoting the closing of loci enriched with ETS motifs. These changes differ partially from CAD observed during iCM induction from human fibroblasts. Collectively, our study offers one practical platform for iCM generation and insights into mechanisms for iCM fate determination.

Evaluation of CML TKI Induced Cardiovascular Toxicity and Development of Potential Rescue Strategies in a Zebrafish Model.

Tyrosine kinase inhibitors (TKIs) to BCR-ABL1 have been successfully used to treat chronic myeloid leukemia (CML), however, multiple TKI-associated adverse events have been reported and become an emerging problem in patients. The mechanisms of TKI-induced toxicity are not fully understood and it remains challenging to predict potential cardiovascular toxicity of a compound. In this study, we established a zebrafish model to evaluate potential in vivo cardiovascular toxicity of TKIs. We treated the endothelium labeled Tg(kdrl:EGFP) transgenic zebrafish embryos with TKIs then performed confocal imaging to evaluate their vascular structure and function. We found that among FDA approved CML TKIs, ponatinib (the only approved TKI that is efficacious to T315I mutation) is the most toxic one. We then evaluated safety profiles of several clinical stage kinase inhibitors that can target T315I and found that HQP1351 treatment leads to vasculopathies similar to those induced by ponatinib while the allosteric ABL inhibitor asciminib does not induce noticeable cardiovascular defects, indicating it could be a promising therapeutic reagent for patients with T315I mutation. We then performed proof-of-principle study to rescue those TKI-induced cardiovascular toxicities and found that, among commonly used anti-hypertensive drugs, angiotensin receptor blockers such as azilsartan and valsartan are able to reduce ponatinib or HQP1351 induced cardiovascular toxicities. Together, this study establishes a zebrafish model that can be useful to evaluate cardiovascular toxicity of TKIs as well as to develop strategies to minimize TKI-induced adverse events.

OsEDM2L mediates m6 A of EAT1 transcript for proper alternative splicing and polyadenylation regulating rice tapetal degradation.

N6 -methyladenosine (m6 A) modification affects the post-transcriptional regulation of eukaryotic gene expression, but the underlying mechanisms and their effects in plants remain largely unknown. Here, we report that the N6 -adenine methyltransferase-like domain-containing protein ENHANCED DOWNY MILDEW 2-LIKE (OsEDM2L) is essential for rice (Oryza sativa L.) anther development. The osedm2l knockout mutant showed delayed tapetal programmed cell death (PCD) and defective pollen development. OsEDM2L interacts with the transcription factors basic helix-loop-helix 142 and TAPETUM DEGENERATION RETARDATION to regulate the expression of ETERNAL TAPETUM 1 (EAT1), a positive regulator of tapetal PCD. Mutation of OsEDM2L altered the transcriptomic m6 A landscape, and caused a distinct m6 A modification of the EAT1 transcript leading to dysregulation of its alternative splicing and polyadenylation, followed by suppression of the EAT1 target genes OsAP25 and OsAP37 for tapetal PCD. Therefore, OsEDM2L is indispensable for proper messenger RNA m6 A modification in rice anther development.

Hypoxic postconditioning promotes mitophagy against transient global cerebral ischemia via PINK1/Parkin-induced mitochondrial ubiquitination in adult rats.

Mitophagy alleviates neuronal damage after cerebral ischemia by selectively removing dysfunctional mitochondria. Phosphatase and tensin homolog (PTEN) induced putative kinase 1 (PINK1)/Parkin-mediated mitophagy is the most well-known type of mitophagy. However, little is known about the role of PINK1/Parkin-mediated mitophagy in ischemic tolerance induced by hypoxic postconditioning (HPC) with 8% O2 against transient global cerebral ischemia (tGCI). Hence, we aimed to test the hypothesis that HPC-mediated PINK1/Parkin-induced mitochondrial ubiquitination and promotes mitophagy, thus exerting neuroprotection in the hippocampal CA1 subregion against tGCI. We found that mitochondrial clearance was disturbed at the late phase of reperfusion after tGCI, which was reversed by HPC, as evidenced by the reduction of the translocase of outer mitochondrial membrane 20 homologs (TOMM20), translocase of inner mitochondrial membrane 23 (TIMM23) and heat shock protein 60 (HSP60) in CA1 after HPC. In addition, HPC further increased the ratio of LC3II/I in mitochondrial fraction and promoted the formation of mitophagosomes in CA1 neurons after tGCI. The administration of lysosome inhibitor chloroquine (CQ) intraperitoneally or mitophagy inhibitor (Mdivi-1) intracerebroventricularly abrogated HPC-induced mitochondrial turnover and neuroprotection in CA1 after tGCI. We also found that HPC activated PINK1/Parkin pathway after tGCI, as shown by the augment of mitochondrial PINK1 and Parkin and the promotion of mitochondrial ubiquitination in CA1. In addition, PINK1 or Parkin knockdown with small-interfering RNA (siRNA) suppressed the activation of PINK1/Parkin pathway and hampered mitochondrial clearance and attenuated neuroprotection induced by HPC, whereas PINK1 overexpression promoted PINK1/Parkin-mediated mitophagy and ameliorated neuronal damage in CA1 after tGCI. Taken together, the new finding in this study is that HPC-induced neuroprotection against tGCI through promoting mitophagy mediated by PINK1/Parkin-dependent pathway.

The Dynamics of Metabolic Characterization in iPSC-Derived Kidney Organoid Differentiation via a Comparative Omics Approach.

The use of differentiating human induced pluripotent stem cells (hiPSCs) in mini-tissue organoids provides an invaluable resource for regenerative medicine applications, particularly in the field of disease modeling. However, most studies using a kidney organoid model, focused solely on the transcriptomics and did not explore mechanisms of regulating kidney organoids related to metabolic effects and maturational phenotype. Here, we applied metabolomics coupled with transcriptomics to investigate the metabolic dynamics and function during kidney organoid differentiation. Not only did we validate the dominant metabolic alteration from glycolysis to oxidative phosphorylation in the iPSC differentiation process but we also showed that glycine, serine, and threonine metabolism had a regulatory role during kidney organoid formation and lineage maturation. Notably, serine had a role in regulating S-adenosylmethionine (SAM) to facilitate kidney organoid formation by altering DNA methylation. Our data revealed that analysis of metabolic characterization broadens our ability to understand phenotype regulation. The utilization of this comparative omics approach, in studying kidney organoid formation, can aid in deciphering unique knowledge about the biological and physiological processes involved in organoid-based disease modeling or drug screening.

Understanding the role of tissue-specific decellularized spinal cord matrix hydrogel for neural stem/progenitor cell microenvironment reconstruction and spinal cord injury.

The repair of spinal cord injury (SCI) highly relies on microenvironment remodeling and facilitating the recruitment and neuronal differentiation of endogenous stem/progenitor cells. Decellularized tissue matrices (DTMs) have shown their unique and beneficial characteristics in promoting neural tissue regeneration, especially those derived from the nervous system. Herein, we present a comparative analysis of a DTM hydrogel derived from spinal cord (DSCM-gel) and a decellularized matrix hydrogel derived from peripheral nerves (DNM-gel). The tissue-specificity of DSCM-gel was evaluated both in vitro, using neural stem/progenitor cell (NSPC) culture, and in vivo, using various materials and biological analyses, including transcriptome and proteomics. It was found that DSCM-gel retained an extracellular matrix-like nanofibrous structure but exhibited higher porosity than DNM-gel, which potentiated NSPCs viability, proliferation, and migration in the early stage of 3D culturing, followed by facilitation of the NSPCs differentiation into neurons. Transcriptome analysis indicated that DSCM-gel regulates NSPCs behavior by modulating integrin α2, α9, and ß1 expression profiles along with AKT/ERK related signaling pathways. Proteomics analyses suggest that DSCM specific extracellular matrix proteins, such as the tenascin family (TNC) and some soluble growth factor (FGF2) may contribute to these regulations. Furthermore, in vivo assessments confirmed that DSCM-gel provides a suitable microenvironment for endogenous stem/progenitor cell recruitment and axonal regeneration for bridging the lesion site after a completely transected SCI. Thus, this systematic study provides key insights useful for the development of the tissue-specific DTM biomaterials for translational microenvironment replacement therapies and tissue repair.

TILRR (FREM1 isoform 2) is a prognostic biomarker correlated with immune infiltration in breast cancer.

In atherosclerosis, upregulated TILRR (FREM1 isoform 2) expression increases immune cell infiltration. We hypothesized that TILRR expression is also correlated with cancer progression. By analyzing data from Oncomine and the Tumor Immune Estimation Resource, we found that TILRR mRNA expression was significantly lower in breast cancer tissue than adjacent normal tissue. Kaplan-Meier survival analysis and immunohistochemical staining revealed shortened overall survival and disease-free survival in patients with low TILRR expression. TILRR transcript expression was positively correlated with immune score, immune cell biomarkers and the expression of CXCL10 and CXCL11. TILRR expression was also positively correlated with CD8+ and CD4+ T-cell infiltration. These correlations were verified using the ESTIMATE algorithm, gene set enrichment analysis and Q-PCR. We concluded that impaired TILRR expression is correlated with breast cancer prognosis and immune cell infiltration.

Infectious SARS-CoV-2 in Feces of Patient with Severe COVID-19.

Severe acute respiratory syndrome coronavirus 2 was isolated from feces of a patient in China with coronavirus disease who died. Confirmation of infectious virus in feces affirms the potential for fecal-oral or fecal-respiratory transmission and warrants further study.