Inducing trained immunity in pro-metastatic macrophages to control tumor metastasis.

Metastasis is the leading cause of cancer-related deaths and myeloid cells are critical in the metastatic microenvironment. Here, we explore the implications of reprogramming pre-metastatic niche myeloid cells by inducing trained immunity with whole beta-glucan particle (WGP). WGP-trained macrophages had increased responsiveness not only to lipopolysaccharide but also to tumor-derived factors. WGP in vivo treatment led to a trained immunity phenotype in lung interstitial macrophages, resulting in inhibition of tumor metastasis and survival prolongation in multiple mouse models of metastasis. WGP-induced trained immunity is mediated by the metabolite sphingosine-1-phosphate. Adoptive transfer of WGP-trained bone marrow-derived macrophages reduced tumor lung metastasis. Blockade of sphingosine-1-phosphate synthesis and mitochondrial fission abrogated WGP-induced trained immunity and its inhibition of lung metastases. WGP also induced trained immunity in human monocytes, resulting in antitumor activity. Our study identifies the metabolic sphingolipid-mitochondrial fission pathway for WGP-induced trained immunity and control over metastasis.

Outer Membrane Vesicles Released from Garlic Exosome-like Nanoparticles (GaELNs) Train Gut Bacteria that Reverses Type 2 Diabetes via the Gut-Brain Axis.

Gut microbiota function has numerous effects on humans and the diet humans consume has emerged as a pivotal determinant of gut microbiota function. Here, a new concept that gut microbiota can be trained by diet-derived exosome-like nanoparticles (ELNs) to release healthy outer membrane vesicles (OMVs) is introduced. Specifically, OMVs released from garlic ELN (GaELNs) trained human gut Akkermansia muciniphila (A. muciniphila) can reverse high-fat diet-induced type 2 diabetes (T2DM) in mice. Oral administration of OMVs released from GaELNs trained A. muciniphila can traffick to the brain where they are taken up by microglial cells, resulting in inhibition of high-fat diet-induced brain inflammation. GaELNs treatment increases the levels of OMV Amuc-1100, P9, and phosphatidylcholines. Increasing the levels of Amuc-1100 and P9 leads to increasing the GLP-1 plasma level. Increasing the levels of phosphatidylcholines is required for inhibition of cGas and STING-mediated inflammation and GLP-1R crosstalk with the insulin pathway that leads to increasing expression of Insulin Receptor Substrate (IRS1 and IRS2) on OMV targeted cells. These findings reveal a molecular mechanism whereby OMVs from plant nanoparticle-trained gut bacteria regulate genes expressed in the brain, and have implications for the treatment of brain dysfunction caused by a metabolic syndrome.

Probiotic-derived nanoparticles inhibit ALD through intestinal miR194 suppression and subsequent FXR activation.

BACKGROUND AND AIMS: Intestinal farnesoid X receptor (FXR) plays a critical role in alcohol-associated liver disease (ALD). We aimed to investigate whether alcohol-induced dysbiosis increased intestinal microRNA194 (miR194) that suppressed Fxr transcription and whether Lactobacillus rhamnosus GG-derived exosome-like nanoparticles (LDNPs) protected against ALD through regulation of intestinal miR194-FXR signaling in mice. APPROACH AND RESULTS: Binge-on-chronic alcohol exposure mouse model was utilized. In addition to the decreased ligand-mediated FXR activation, alcohol feeding repressed intestinal Fxr transcription and increased miR194 expression. This transcriptional suppression of Fxr by miR194 was confirmed in intestinal epithelial Caco-2 cells and mouse enteriods. The alcohol feeding-reduced intestinal FXR activation was further demonstrated by the reduced FXR reporter activity in fecal samples and by the decreased fibroblast growth factor 15 (Fgf15) messenger RNA (mRNA) in intestine and protein levels in the serum, which caused an increased hepatic bile acid synthesis and lipogeneses. We further demonstrated that alcohol feeding increased-miR194 expression was mediated by taurine-upregulated gene 1 (Tug1) through gut microbiota regulation of taurine metabolism. Importantly, 3-day oral administration of LDNPs increased bile salt hydrolase (BSH)-harboring bacteria that decreased conjugated bile acids and increased gut taurine concentration, which upregulated Tug1, leading to a suppression of intestinal miR194 expression and recovery of FXR activation. Activated FXR upregulated FGF15 signaling and subsequently reduced hepatic bile acid synthesis and lipogenesis and attenuated ALD. These protective effects of LDNPs were eliminated in intestinal FxrΔIEC and Fgf15-/- mice. We further showed that miR194 was upregulated, whereas BSH activity and taurine levels were decreased in fecal samples of patients with ALD. CONCLUSIONS: Our results demonstrated that gut microbiota-mediated miR194 regulation contributes to ALD pathogenesis and to the protective effects of LDNPs through modulating intestinal FXR signaling.

Regulation of BTB (POZ) Structural Domain 6b by MicroRNA-222b in Zebrafish Embryos after Exposure to Di(2-ethylhexyl)phthalate at Low Concentrations.

Di-(2-ethylhexyl) phthalate (DEHP) is a sort of endocrine disruptor that induces abnormal physiological and biochemical activities such as epigenetic alterations, apoptosis, and oxidative stress. MicroRNAs (miRNAs) are a class of short noncoding RNAs that may regulate the expression of many protein-coding genes when organisms are exposed to environmental chemicals. miR-222b is a differentially expressed miRNA after DEHP exposure. miRNA-mRNA prediction suggested that BTB (POZ) structural domain 6b (BTBD6B) might be a target mRNA of miR-222b, and DEHP exposure altered its expression. However, the correlation between miR-222b and BTBD6B has not been experimentally confirmed. The aim of this study was to investigate the regulation of BTBD6B by miR-222b in zebrafish embryos under the effect of low concentration of DEHP. Dual fluorescent protein assays and dual luciferase reporter gene assays confirmed the interaction between miR-222b and the 3'-untranslated region (3'-UTR) of BTBD6B. Ectopic expression assays showed that miR-222b could negatively regulate BTBD6B in ZF4 cells. However, the relative expression of miR-222b and BTBD6B was significantly higher at both transcriptional and post-transcriptional levels in zebrafish embryos exposed to low concentrations of DEHP. The results of this study improved our understanding of the molecular mechanism of DEHP exposure toxicity. It identified that the aberrant expression of miR-222b/BTBD6B may be one of the mechanisms of DEHP toxicity, which can provide a theoretical reference and scientific basis for environmental management and biological health risk assessment.

Exosome-like nanoparticles from Mulberry bark prevent DSS-induced colitis via the AhR/COPS8 pathway.

Bark protects the tree against environmental insults. Here, we analyzed whether this defensive strategy could be utilized to broadly enhance protection against colitis. As a proof of concept, we show that exosome-like nanoparticles (MBELNs) derived from edible mulberry bark confer protection against colitis in a mouse model by promoting heat shock protein family A (Hsp70) member 8 (HSPA8)-mediated activation of the AhR signaling pathway. Activation of this pathway in intestinal epithelial cells leads to the induction of COP9 Constitutive Photomorphogenic Homolog Subunit 8 (COPS8). Utilizing a gut epithelium-specific knockout of COPS8, we demonstrate that COPS8 acts downstream of the AhR pathway and is required for the protective effect of MBELNs by inducing an array of anti-microbial peptides. Our results indicate that MBELNs represent an undescribed mode of inter-kingdom communication in the mammalian intestine through an AhR-COPS8-mediated anti-inflammatory pathway. These data suggest that inflammatory pathways in a microbiota-enriched intestinal environment are regulated by COPS8 and that edible plant-derived ELNs may hold the potential as new agents for the prevention and treatment of gut-related inflammatory disease.

Discovery of a novel BTK inhibitor S-016 and identification of a new strategy for the treatment of lymphomas including BTK inhibitor-resistant lymphomas.

Bruton's tyrosine kinase (BTK) has emerged as a therapeutic target for B-cell malignancies, which is substantiated by the efficacy of various irreversible or reversible BTK inhibitors. However, on-target BTK mutations facilitating evasion from BTK inhibition lead to resistance that limits the therapeutic efficacy of BTK inhibitors. In this study we employed structure-based drug design strategies based on established BTK inhibitors and yielded a series of BTK targeting compounds. Among them, compound S-016 bearing a unique tricyclic structure exhibited potent BTK kinase inhibitory activity with an IC50 value of 0.5 nM, comparable to a commercially available BTK inhibitor ibrutinib (IC50 = 0.4 nM). S-016, as a novel irreversible BTK inhibitor, displayed superior kinase selectivity compared to ibrutinib and significant therapeutic effects against B-cell lymphoma both in vitro and in vivo. Furthermore, we generated BTK inhibitor-resistant lymphoma cells harboring BTK C481F or A428D to explore strategies for overcoming resistance. Co-culture of these DLBCL cells with M0 macrophages led to the polarization of M0 macrophages toward the M2 phenotype, a process known to support tumor progression. Intriguingly, we demonstrated that SYHA1813, a compound targeting both VEGFR and CSF1R, effectively reshaped the tumor microenvironment (TME) and significantly overcame the acquired resistance to BTK inhibitors in both BTK-mutated and wild-type BTK DLBCL models by inhibiting angiogenesis and modulating macrophage polarization. Overall, this study not only promotes the development of new BTK inhibitors but also offers innovative treatment strategies for B-cell lymphomas, including those with BTK mutations.

Multifunctional nano-in-micro delivery systems for targeted therapy in fundus neovascularization diseases.

Fundus neovascularization diseases are a series of blinding eye diseases that seriously impair vision worldwide. Currently, the means of treating these diseases in clinical practice are continuously evolving and have rapidly revolutionized treatment opinions. However, key issues such as inadequate treatment effectiveness, high rates of recurrence, and poor patient compliance still need to be urgently addressed. Multifunctional nanomedicine can specifically respond to both endogenous and exogenous microenvironments, effectively deliver drugs to specific targets and participate in activities such as biological imaging and the detection of small molecules. Nano-in-micro (NIM) delivery systems such as metal, metal oxide and up-conversion nanoparticles (NPs), quantum dots, and carbon materials, have shown certain advantages in overcoming the presence of physiological barriers within the eyeball and are widely used in the treatment of ophthalmic diseases. Few studies, however, have evaluated the efficacy of NIM delivery systems in treating fundus neovascular diseases (FNDs). The present study describes the main clinical treatment strategies and the adverse events associated with the treatment of FNDs with NIM delivery systems and summarizes the anatomical obstacles that must be overcome. In this review, we wish to highlight the principle of intraocular microenvironment normalization, aiming to provide a more rational approach for designing new NIM delivery systems to treat specific FNDs.

Activation of PTH1R alleviates epididymitis and orchitis through Gq and ß-arrestin-1 pathways.

Inflammation in the epididymis and testis contributes significantly to male infertility. Alternative therapeutic avenues treating epididymitis and orchitis are expected since current therapies using antibiotics have limitations associated to side effects and are commonly ineffective for inflammation due to nonbacterial causes. Here, we demonstrated that type 1 parathyroid hormone receptor (PTH1R) and its endogenous agonists, parathyroid hormone (PTH) and PTH-related protein (PTHrP), were mainly expressed in the Leydig cells of testis as well as epididymal epithelial cells. Screening the secretin family G protein-coupled receptor identified that PTH1R in the epididymis and testis was down-regulated in mumps virus (MuV)- or lipopolysaccharide (LPS)-induced inflammation. Remarkably, activation of PTH1R by abaloparatide (ABL), a Food and Drug Administration-approved treatment for postmenopausal osteoporosis, alleviated MuV- or LPS-induced inflammatory responses in both testis and epididymis and significantly improved sperm functions in both mouse model and human samples. The anti-inflammatory effects of ABL were shown to be regulated mainly through the Gq and ß-arrestin-1 pathway downstream of PTH1R as supported by the application of ABL in Gnaq± and Arrb1-/- mouse models. Taken together, our results identified an important immunoregulatory role for PTH1R signaling in the epididymis and testis. Targeting to PTH1R might have a therapeutic effect for the treatment of epididymitis and orchitis or other inflammatory disease in the male reproductive system.

MicroRNA-375 Mediated Regulation on Pre-mRNA Processing Factor 3 in Zebrafish Embryos Exposed to Di-(2-ethylhexyl)phthalate at Low Concentrations.

Di-(2-ethylhexyl)phthalate (DEHP) is an endocrine-disrupting chemical (EDC) that induces epigenetic alterations, apoptosis, and oxidative stress after biological exposure. MicroRNAs (miRNAs) are a class of small noncoding RNAs with many regulatory functions and play a role in organisms exposed to environmental chemicals. miRNA-mRNA prediction indicated that pre-mRNA processing factor 3 (PRPF3) is a likely target mRNA for miR-375 whose expression is altered by DEHP exposure. However, the interrelation between miR-375 and PRPF3 has not yet been confirmed experimentally. This study aimed to investigate the effects of DEHP on miR-375 and PRPF3 in zebrafish. The expression of miR-375 was downregulated, whereas PRPF3 was upregulated at both transcriptional and post-transcriptional levels upon stimulation with DEHP. The interaction between miR-375 and the 3'-untranslated region (3'-UTR) of PRPF3 was confirmed by a dual fluorescent protein assay and a dual luciferase reporter gene assay. The expression of PRPF3 at both transcriptional and post-transcriptional levels was reduced in ZF4 cells when transfected with a miR-375 mimic but increased when transfected with a miR-375 inhibitor. The results improved our understanding of molecular mechanisms of toxicity upon DEHP exposure and presented miR-375 as a potential novel toxicological biomarker for chemical exposure.

Emerging role of toll-like receptors signaling and its regulators in preterm birth: a narrative review.

INTRODUCTION: Despite intensive research, preterm birth (PTB) rates have not decreased significantly in recent years due to a lack of understanding of the underlying causes and insufficient treatment options for PTB. We are committed to finding promising biomarkers for the treatment of PTB. METHODS: An extensive search of the literature was conducted with MEDLINE/PubMed, and in total, 151 studies were included and summarized in the present review. RESULTS: Substantial evidence supports that the infection and/or inflammatory cascade associated with infection is an early event in PTB. Toll-like receptor (TLR) is a prominent pattern recognition receptor (PRR) found on both immune and non-immune cells, including fetal membrane cells. The activation of TLR downstream molecules, followed by TLR binding to its ligand, is critical for infection and inflammation, leading to the involvement of the TLR signaling pathway in PTB. TLR ligands are derived from microbial components and molecules released by damaged and dead cells. Particularly, TLR4 is an essential TLR because of its ability to recognize lipopolysaccharide (LPS). In this comprehensive overview, we discuss the role of TLR signaling in PTB, focus on numerous host-derived genetic and epigenetic regulators of the TLR signaling pathway, and cover ongoing research and prospective therapeutic options for treating PTB by inhibiting TLR signaling. CONCLUSION: This is a critical topic because TLR-related molecules and mechanisms may enable obstetricians to better understand the physiological changes in PTB and develop new treatment and prevention strategies.

Restoring Oat Nanoparticles Mediated Brain Memory Function of Mice Fed Alcohol by Sorting Inflammatory Dectin-1 Complex Into Microglial Exosomes.

Microglia modulate pro-inflammatory and neurotoxic activities. Edible plant-derived factors improve brain function. Current knowledge of the molecular interactions between edible plant-derived factors and the microglial cell is limited. Here an alcohol-induced chronic brain inflammation model is used to identify that the microglial cell is the novel target of oat nanoparticles (oatN). Oral administration of oatN inhibits brain inflammation and improves brain memory function of mice that are fed alcohol. Mechanistically, ethanol activates dectin-1 mediated inflammatory pathway. OatN is taken up by microglial cells via ß-glucan mediated binding to microglial hippocalcin (HPCA) whereas oatN digalactosyldiacylglycerol (DGDG) prevents assess of oatN ß-glucan to dectin-1. Subsequently endocytosed ß-glucan/HPCA is recruited in an endosomal recycling compartment (ERC) via interaction with Rab11a. This complex then sequesters the dectin-1 in the ERC in an oatN ß-glucan dependent manner and alters the location of dectin-1 from Golgi to early endosomes and lysosomes and increases exportation of dectin-1 into exosomes in an Rab11a dependent manner. Collectively, these cascading actions lead to preventing the activation of the alcoholic induced brain inflammation signing pathway(s). This coordinated assembling of the HPCA/Rab11a/dectin-1 complex by oral administration of oatN may contribute to the prevention of brain inflammation.

Plant-derived exosomal microRNAs inhibit lung inflammation induced by exosomes SARS-CoV-2 Nsp12.

Lung inflammation is a hallmark of coronavirus disease 2019 (COVID-19). In this study, we show that mice develop inflamed lung tissue after being administered exosomes released from the lung epithelial cells exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Nsp12 and Nsp13 (exosomesNsp12Nsp13). Mechanistically, we show that exosomesNsp12Nsp13 are taken up by lung macrophages, leading to activation of nuclear factor κB (NF-κB) and the subsequent induction of an array of inflammatory cytokines. Induction of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß from exosomesNsp12Nsp13-activated lung macrophages contributes to inducing apoptosis in lung epithelial cells. Induction of exosomesNsp12Nsp13-mediated lung inflammation was abolished with ginger exosome-like nanoparticle (GELN) microRNA (miRNA aly-miR396a-5p. The role of GELNs in inhibition of the SARS-CoV-2-induced cytopathic effect (CPE) was further demonstrated via GELN aly-miR396a-5p- and rlcv-miR-rL1-28-3p-mediated inhibition of expression of Nsp12 and spike genes, respectively. Taken together, our results reveal exosomesNsp12Nsp13 as potentially important contributors to the development of lung inflammation, and GELNs are a potential therapeutic agent to treat COVID-19.

Regulation of TRAF6 by MicroRNA-146a in Zebrafish Embryos after Exposure to Di(2-Ethylhexyl) Phthalate at Different Concentrations.

As an endocrine disruptor, di(2-ethylhexyl) phthalate (DEHP) is ubiquitous in multiple environmental media, causing long-term toxic effects on organisms. MicroRNAs are a class of noncoding RNAs with only 20-24 nucleotides in length, which regulate the expression of many protein-coding genes when organisms are exposed to environmental chemicals. MiR-146a, a differentially expressed miRNA after DEHP exposure, was screened by miRNA sequencing. As its target, TRAF6 was predicted and identified by double fluorescent protein assay and double fluorescent gene reporting assay. It shows the contrary expression pattern with miR-146a when mimics and inhibitors were transfected into ZF4 cells. MiR-146a and TRAF6 were downregulated and upregulated, respectively, in zebrafish embryos exposed to a low-dose concentration gradient of DEHP. These results deepen our understanding of the molecular mechanisms of DEHP toxicity and suggest that miR-146a can serve as a potential biomarker for DEHP exposure.

Tumor Microenvironment Modulates Immunological Outcomes of Myeloid Cells with mTORC1 Disruption.

The role of the mTOR signaling pathway in different myeloid cell subsets is poorly understood in the context of tumor development. In this study, myeloid cell-specific Raptor knockout (KO) mice were used to determine the roles of mechanistic target of rapamycin complex 1 (mTORC1) in regulating macrophage function from Lewis lung carcinoma (LLC) s.c. tumors and lung tumor metastasis. We found no difference in tumor growth between conditional Raptor KO and control mice in the s.c. tumor models, although depletion of mTORC1 decreased the immunosuppressive function of tumor-associated macrophages (TAM). Despite the decreased immunosuppressive activity of TAM, M1-like TAM differentiation was impaired in the s.c. tumor microenvironment of mTORC1 conditional Raptor KO mice due to downregulated CD115 expression on macrophages. In addition, TNF-α production by mTORC1-deficient myeloid cells was also decreased in the s.c. LLC tumors. On the contrary, disruption of mTORC1 in myeloid cells promoted lung cancer metastasis. Accordingly, immunosuppressive interstitial macrophages/metastasis-associated macrophages (CD11b+F4/80high) were accumulated in the lungs of Raptor KO mice in the LLC lung metastasis model, leading to decreased Th1 responses. Taken together, our results demonstrate that differential tumor microenvironment dictates the immunological outcomes of myeloid cells, with mTORC1 disruption leading to different tumor growth phenotypes.

Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation.

Interleukin-23 (IL-23) and CD4(+) T helper 17 (Th17) cells are thought to be critical in psoriasis pathogenesis. Here, we report that IL-23 predominantly stimulated dermal γδ T cells to produce IL-17 that led to disease progression. Dermal γδ T cells constitutively expressed the IL-23 receptor (IL-23R) and transcriptional factor RORγt. IL-17 production from dermal γδ T cells was independent of αß T cells. The epidermal hyperplasia and inflammation induced by IL-23 were significantly decreased in T cell receptor δ-deficient (Tcrd(-/-)) and IL-17 receptor-deficient (Il17ra(-/-)) mice but occurred normally in Tcra(-/-) mice. Imiquimod-induced skin pathology was also significantly decreased in Tcrd(-/-) mice. Perhaps further promoting disease progression, IL-23 stimulated dermal γδ T cell expansion. In psoriasis patients, γδ T cells were greatly increased in affected skin and produced large amounts of IL-17. Thus, IL-23-responsive dermal γδ T cells are the major IL-17 producers in the skin and may represent a novel target for the treatment of psoriasis.

Impact of pharmaceutical care in the orthopaedic department.

WHAT IS KNOWN AND OBJECTIVE: In the mid-1960s, clinical pharmacy developed in the USA, and as the demand for pharmaceutical services continued to grow, their impact began to be taken seriously. However, the participation of clinical pharmacists as members of the multidisciplinary team in the orthopaedic department is still in its infancy, although its role in orthopaedics has not been defined. The object of this study was to identify and discuss the impact of pharmaceutical care in the orthopaedic department. METHODS: A literature search was conducted on MEDLINE, PubMed, Web of Science, the Cochrane Library and CNKI (China National Knowledge Infrastructure) for papers published between 1998 and 2019, using the keywords pharmacy, pharmacist, and medication or drug combined with orthopaedic. Other available resources were also used to identify relevant articles. RESULTS AND DISCUSSION: Based on the available evidence in 74 articles, it was found that clinical pharmacists play an important role in all aspects of rational use of medications, medication review and reconciliation, monitoring adverse drug events, risk assessment, and medication education and counselling. In addition, clinical pharmacy services were developed to minimize medication errors, adverse drug events and medical costs, but clinical pharmacy is still in its early stages in orthopaedics. WHAT IS NEW AND CONCLUSION: A multidisciplinary approach should be adopted in the orthopaedic department, as pharmacist interventions can be vital for promoting the safety, effectiveness and cost-effectiveness of pharmacotherapy. Although pharmacists' contributions to orthopaedics are not yet fully recognized, pharmaceutical services can undoubtedly contribute to both clinical and societal outcomes.

Endovascular Treatment for Cavernous Carotid Aneurysms: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Coiling and flow diversion are established endovascular techniques for treatment of cavernous carotid aneurysms (CCAs). We performed a systematic review of published series on endovascular treatment of CCAs in order to assess the efficacy and safety between coiling and flow diversion. METHODS: We conducted a computerized search of PubMed, MEDLINE, and Web of Science electronic databases for reports on endovascular treatment of CCAs from 1990 to 2019. Comparisons were made in complete occlusion rate, improvement of symptoms rate and intraoperative complication rate between coiling and flow diversion. RESULTS: Fourteen studies with 736 patients were included in this systematic review. Five hundred ninety-4 patients underwent coiling, 142 patients underwent flow diversion. The complete occlusion rate in the coiling group was significantly lower than that in the flow division group (odds ratio .37, 95%CI .16-.83, P < .00001), a forest plot did not reveal any significant differences in the improvement of symptoms rate or intraoperative complication rate following coiling and flow diversion. Complete occlusion rate was significantly lower in the coiling group (53%, 95%CI .40-.67) compared with the flow diversion group (74%, 95%CI .55-.94). Improvement of symptoms was significantly lower in the coiling group (54%, 95%CI .46-.63) compared with the flow diversion group (92%, 95%CI .85-.99). Coiling group had lower intraoperative complication rate (9%, 95%CI .06-.12) compared with flow division group (36%, 95%CI .25-.47). CONCLUSIONS: Compared with coiling, the use of flow diversion for the treatment of CCAs may increase complete occlusion rate, and improvement of symptoms rate, but it also raised intraoperative complication rate. Due to the lack of high quality control research, further randomized controlled trials are needed to verify our conclusions.

A Comparison of Two Isoreticular Metal-Organic Frameworks with Cationic and Neutral Skeletons: Stability, Mechanism, and Catalytic Activity.

Although many ionic metal-organic frameworks (MOFs) have been reported, little is known about how the charge of the skeleton affects the properties of the MOF materials. Herein we report how the chemical stability of MOFs can be substantially improved through embedding electrostatic interactions in structure. A MOF with a cationic skeleton is impervious to extremely acidic, oxidative, reductive, and high ionic strength conditions, such as 12 m HCl (301 days), aqua regia (86 days), H2 O2 (30 days), and seawater (30 days), which is unprecedented for MOFs. DFT calculations suggested that steric hinderance and the repulsive interaction of the cationic framework toward positively charged species in microenvironments protects the vulnerable bonds in the structure. Diverse functionalities can be bestowed by substituting the counterions of the charged framework with identically charged functional species, which broadens the horizon in the design of MOFs adaptable to a demanding environment with specific functionalities.

Neural Correlate of Visual Familiarity in Macaque Area V2.

Neurons in macaque inferotemporal cortex (ITC) respond less strongly to familiar than to novel images. It is commonly assumed that this effect arises within ITC because its neurons respond selectively to complex images and thus encode in an explicit form information sufficient for identifying a particular image as familiar. However, no prior study has examined whether neurons in low-order visual areas selective for local features also exhibit familiarity suppression. To address this issue, we recorded from neurons in macaque area V2 with semichronic microelectrode arrays while monkeys repeatedly viewed a set of large complex natural images. We report here that V2 neurons exhibit familiarity suppression. The effect develops over several days with a trajectory well fitted by an exponential function with a rate constant of ∼100 exposures. Suppression occurs in V2 at a latency following image onset shorter than its reported latency in ITC.SIGNIFICANCE STATEMENT Familiarity suppression, the tendency for neurons to respond less strongly to familiar than novel images, is well known in monkey inferotemporal cortex. Suppression has been thought to arise in inferotemporal cortex because its neurons respond selectively to large complex images and thus explicitly to encode information sufficient for identifying a particular image as familiar. No previous study has explored the possibility that familiarity suppression occurs even in early-stage visual areas where neurons are selective for simple features in confined receptive fields. We now report that neurons in area V2 exhibit familiarity suppression. This finding challenges our current understanding of information processing in V2 as well as our understanding of the mechanisms that underlie familiarity suppression.

A seven-long noncoding RNA signature predicts relapse in patients with early-stage lung adenocarcinoma.

BACKGROUND: Long noncoding RNA (lncRNA) has been increasingly reported to play crucial roles in cancer development. In this study, we aim to develop a lncRNA-based signature to predict the relapse of early-stage (stage I-II) lung adenocarcinoma (LUAD). METHODS: With a lncRNA-mining strategy, lncRNA expression profiles of three LUAD cohorts were obtained from the Gene Expression Omnibus database. A risk score model was established based on the lncRNAs expression from training set (GSE31210, n = 204) and further validated in two independent testing sets (GSE50081, n = 124; and GSE30219, n = 84). The potential signaling pathways modulated by the prognostic lncRNAs were explored using bioinformatics analysis. RESULTS: In the training set, seven lncRNAs were identified to be significantly correlated with the relapse-free survival (RFS) of early-stage LUAD, and were then aggregated to form a seven-lncRNA prognostic signature to classify patients into high-risk and low-risk groups. Individuals of training set in the high-risk group exhibited a poorer RFS than those in the low-risk group (HR: 7.574, 95% CI: 4.165-13.775; P < 0.001). The similar prognostic powers of the seven-lncRNA signature were also achieved in the two independent testing sets and in stratified analysis. Multivariate Cox regression indicated that the prognostic value of seven-lncRNA signature was independent of other clinical features. Functional enrichment analysis found that the seven-lncRNA signature may be involved in biological pathways such as cell cycle, DNA replication, and p53 signaling pathway. CONCLUSION: Our results indicate that the seven-lncRNA signature may be an innovative biomarker to predict the relapse of early-stage LUAD.