Synthesis and Evaluation of [18F]AlF-NOTA-c-DVAP: A Novel PET Probe for Imaging GRP78 in Cancer.

GRP78, a member of the HSP70 superfamily, is an endoplasmic reticulum chaperone protein overexpressed in various cancers, making it a promising target for cancer imaging and therapy. Positron emission tomography (PET) imaging offers unique advantages in real time, noninvasive tumor imaging, rendering it a suitable tool for targeting GRP78 in tumor imaging to guide targeted therapy. Several studies have reported successful tumor imaging using PET probes targeting GRP78. However, existing PET probes face challenges such as low tumor uptake, inadequate in vivo distribution, and high abdominal background signal. Therefore, this study introduces a novel peptide PET probe, [18F]AlF-NOTA-c-DVAP, for targeted tumor imaging of GRP78. [18F]AlF-NOTA-c-DVAP was radiolabeled with fluoride-18 using the aluminum-[18F]fluoride ([18F]AlF) method. The study assessed the partition coefficients, stability in vitro, and metabolic stability of [18F]AlF-NOTA-c-DVAP. Micro-PET imaging, pharmacokinetic analysis, and biodistribution studies were carried out in tumor-bearing mice to evaluate the probe's performance. Docking studies and pharmacokinetic analyses of [18F]AlF-NOTA-c-DVAP were also performed. Immunohistochemical and immunofluorescence analyses were conducted to confirm GRP78 expression in tumor tissues. The probe's binding affinity to GRP78 was analyzed by molecular docking simulation. [18F]AlF-NOTA-c-DVAP was radiolabeled in just 25 min with a high yield of 51 ± 16%, a radiochemical purity of 99%, and molar activity within the range of 20-50 GBq/µmol. [18F]AlF-NOTA-c-DVAP demonstrated high stability in vitro and in vivo, with a logD value of -3.41 ± 0.03. Dynamic PET imaging of [18F]AlF-NOTA-c-DVAP in tumors showed rapid uptake and sustained retention, with minimal background uptake. Biodistribution studies revealed rapid blood clearance and excretion through the kidneys following a single-compartment reversible metabolic model. In PET imaging, the T/M ratios for A549 tumors (high GRP78 expression), MDA-MB-231 tumors (medium expression), and HepG2 tumors (low expression) at 60 min postintravenous injection were 10.48 ± 1.39, 6.25 ± 0.47, and 3.15 ± 1.15% ID/g, respectively, indicating a positive correlation with GRP78 expression. This study demonstrates the feasibility of using [18F]AlF-NOTA-c-DVAP as a PET tracer for imaging GRP78 in tumors. The probe shows promising results in terms of stability, specificity, and tumor targeting. Further research may explore the clinical utility and potential therapeutic applications of this PET tracer for cancer diagnosis.

A genome-wide CRISPR screening uncovers that TOB1 acts as a key host factor for FMDV infection via both IFN and EGFR mediated pathways.

The interaction between foot-and-mouth disease virus (FMDV) and the host is extremely important for virus infection, but there are few researches on it, which is not conducive to vaccine development and FMD control. In this study, we designed a porcine genome-scale CRISPR/Cas9 knockout library containing 93,859 single guide RNAs targeting 16,886 protein-coding genes, 25 long ncRNAs, and 463 microRNAs. Using this library, several previously unreported genes required for FMDV infection are highly enriched post-FMDV selection in IBRS-2 cells. Follow-up studies confirmed the dependency of FMDV on these genes, and we identified a functional role for one of the FMDV-related host genes: TOB1 (Transducer of ERBB2.1). TOB1-knockout significantly inhibits FMDV infection by positively regulating the expression of RIG-I and MDA5. We further found that TOB1-knockout led to more accumulation of mRNA transcripts of transcription factor CEBPA, and thus its protein, which further enhanced transcription of RIG-I and MDA5 genes. In addition, TOB1-knockout was shown to inhibit FMDV adsorption and internalization mediated by EGFR/ERBB2 pathway. Finally, the FMDV lethal challenge on TOB1-knockout mice confirmed that the deletion of TOB1 inhibited FMDV infection in vivo. These results identify TOB1 as a key host factor involved in FMDV infection in pigs.

Construction of Imidazole-Fused-Ring Systems by Iron-Catalyzed C(sp3)-H Amination-Cyclization under Aerobic Conditions.

An iron-catalyzed efficient C-H amination for the construction of imidazole-fused-ring systems was developed under aerobic conditions. Compared to previous studies, this work exhibited green features. The reaction was conducted in the green solvent anisole, with water as the only byproduct. Four C(sp3)-H bonds were cleaved and three C-N bonds were formed in this transformation. Imidazo[1,5-a]pyridine-, imidazo[5,1-b]oxazole-, imidazo[5,1-b]thiazole-, imidazo[1,5-a]pyrazine-, and imidazo[1,5-a]imidazole-related N-heterocycles were obtained in acceptable-to-excellent yield.

One-Step Automatic Radiosynthesis and Evaluation of [18F]TM-30089 as GPR44 Radiotracer.

Recently, a G-protein coupled receptor 44 (GPR44) was discovered to play a significant role in the process of inflammation-related diseases, including cancer and diabetes. However, the precise role of GPR44 has yet to be fully elucidated. Currently, there is a strong and urgent need for the development of GPR44 radiotracers as a non-invasive methodology to explore the exact mechanism of GPR44 on inflammation-related diseases and monitor the progress of therapy. TM-30089 is a potent GPR44 antagonist that exhibits a high specificity and selectivity for GPR44. Its structure contains a fluorine nuclide, which could potentially be replaced with 18F. In the present study, we successfully took a highly effective synthesis strategy that pretreated the unprotected carboxylic acid group of the precursor and developed a feasible one-step automatic radiosynthesis strategy for [18F]TM-30089 with a high radiochemical purity and a good radiochemical yield. We further evaluated this radiotracer using mice models implanted with 1.1 B4 cell lines (GPR44-enriched cell lines) and human islets (high GPR44 expression), respectively. The results revealed the persistent and specific uptake of [18F]TM-30089 in GPR44 region, indicating that [18F]TM-30089 is a promising candidate for targeting GPR44. Further evaluation is ongoing.

Functional characterization of African swine fever virus I329L gene by transcriptome analysis.

African swine fever (ASF) is an acute, severe, and highly contagious disease caused by the African swine fever virus (ASFV), which infects domestic pigs and wild boars. The incidence and mortality rates of swine infected with virulent strains of ASFV can reach up to 100%. The large genome, its complex structure, multiple genotypes, and a lack of understanding regarding ASFV gene function are serious obstacles to the development of safe and effective vaccines. Here, ASFV I329L was identified as a relatively conserved gene that is expressed during the late stage of infection. A recombinant virus with I329L gene deletion (ASFV CN/GS/2018-ΔI329L) was produced by replacing I329L with an enhanced green fluorescent protein (EGFP) cassette. In order to explore the function of the ASFV I329L gene, transcriptome sequencing (RNA-seq) was performed on porcine alveolar macrophages (PAMs) infected with ASFV CN/GS/2018 and ASFV CN/GS/2018-ΔI329L. GO functional and KEGG pathway analyses were performed to analyze differentially expressed genes, and different alternative splicing (AS) events were also analyzed. We compared the sequencing data for each sample with the ASFV CN/GS/2018 reference sequence. Interestingly, we found 3 and 1 up-regulated genes and 12 and 19 down-regulated genes at 12 and 24 h post-infection, respectively. In addition, we verified the expression of 5 up-regulated and 5 down-regulated genes by RT-qPCR, and the results were consistent with those obtained based on RNA-seq. In summary, the results obtained in this study provide new insights for further elucidation of ASFV proteins and ASFV-host interactions. These findings will contribute to implementing a comprehensive strategy for controlling the spread of ASF.

Design, Synthesis, Computational and Biological Evaluation of Novel Structure Fragments Based on Lithocholic Acid (LCA).

The regulation of bile acid pathways has become a particularly promising therapeutic strategy for a variety of metabolic disorders, cancers, and diseases. However, the hydrophobicity of bile acids has been an obstacle to clinical efficacy due to off-target effects from rapid drug absorption. In this report, we explored a novel strategy to design new structure fragments based on lithocholic acid (LCA) with improved hydrophilicity by introducing a polar "oxygen atom" into the side chain of LCA, then (i) either retaining the carboxylic acid group or replacing the carboxylic acid group with (ii) a diol group or (iii) a vinyl group. These novel fragments were evaluated using luciferase-based reporter assays and the MTS assay. Compared to LCA, the result revealed that the two lead compounds 1a-1b were well tolerated in vitro, maintaining similar potency and efficacy to LCA. The MTS assay results indicated that cell viability was not affected by dose dependence (under 25 µM). Additionally, computational model analysis demonstrated that compounds 1a-1b formed more extensive hydrogen bond networks with Takeda G protein-coupled receptor 5 (TGR5) than LCA. This strategy displayed a potential approach to explore the development of novel endogenous bile acids fragments. Further evaluation on the biological activities of the two lead compounds is ongoing.

African swine fever virus MGF-360-10L is a novel and crucial virulence factor that mediates ubiquitination and degradation of JAK1 by recruiting the E3 ubiquitin ligase HERC5.

African swine fever virus (ASFV) causes acute hemorrhagic infectious disease in pigs. The ASFV genome encodes various proteins that enable the virus to escape innate immunity; however, the underlying mechanisms are poorly understood. The present study found that ASFV MGF-360-10L significantly inhibits interferon (IFN)-ß-triggered STAT1/2 promoter activation and the production of downstream IFN-stimulated genes (ISGs). ASFV MGF-360-10L deletion (ASFV-Δ10L) replication was impaired compared with the parental ASFV CN/GS/2018 strain, and more ISGs were induced by the ASFV-Δ10L in porcine alveolar macrophages in vitro. We found that MGF-360-10L mainly targets JAK1 and mediates its degradation in a dose-dependent manner. Meanwhile, MGF-360-10L also mediates the K48-linked ubiquitination of JAK1 at lysine residues 245 and 269 by recruiting the E3 ubiquitin ligase HERC5 (HECT and RLD domain-containing E3 ubiquitin protein ligase 5). The virulence of ASFV-Δ10L was significantly lower than that of the parental strain in vivo, which indicates that MGF-360-10L is a novel virulence factor of ASFV. Our findings elaborate the novel mechanism of MGF-360-10L on the STAT1/2 signaling pathway, expanding our understanding of the inhibition of host innate immunity by ASFV-encoded proteins and providing novel insights that could contribute to the development of African swine fever vaccines. IMPORTANCE African swine fever outbreaks remain a concern in some areas. There is no effective drug or commercial vaccine to prevent African swine fever virus (ASFV) infection. In the present study, we found that overexpression of MGF-360-10L strongly inhibited the interferon (IFN)-ß-induced STAT1/2 signaling pathway and the production of IFN-stimulated genes (ISGs). Furthermore, we demonstrated that MGF-360-10L mediates the degradation and K48-linked ubiquitination of JAK1 by recruiting the E3 ubiquitin ligase HERC5. The virulence of ASFV with MGF-360-10L deletion was significantly less than parental ASFV CN/GS/2018. Our study identified a new virulence factor and revealed a novel mechanism by which MGF-360-10L inhibits the immune response, thus providing new insights into the vaccination strategies against ASFV.

Deletions of MGF110-9L and MGF360-9L from African swine fever virus are highly attenuated in swine and confer protection against homologous challenge.

African swine fever, caused by a large icosahedral DNA virus (African swine fever virus, ASFV), is a highly contagious disease in domestic and feral swine, thus posing a significant economic threat to the global swine industry. Currently, there are no effective vaccines or the available methods to control ASFV infection. Attenuated live viruses with deleted virulence factors are considered to be the most promising vaccine candidates; however, the mechanism by which these attenuated viruses confer protection is unclear. Here, we used the Chinese ASFV CN/GS/2018 as a backbone and used homologous recombination to generate a virus in which MGF110-9L and MGF360-9L, two genes antagonize host innate antiviral immune response, were deleted (ASFV-ΔMGF110/360-9L). This genetically modified virus was highly attenuated in pigs and provided effective protection of pigs against parental ASFV challenge. Importantly, we found ASFV-ΔMGF110/360-9L infection induced higher expression of Toll-like receptor 2 (TLR2) mRNA compared with parental ASFV as determined by RNA-Seq and RT-PCR analysis. Further immunoblotting results showed that parental ASFV and ASFV-ΔMGF110/360-9L infection inhibited Pam3CSK4-triggered activating phosphorylation of proinflammatory transcription factor NF-κB subunit p65 and phosphorylation of NF-κB inhibitor IκBα levels, although NF-κB activation was higher in ASFV-ΔMGF110/360-9L-infected cells compared with parental ASFV-infected cells. Additionally, we show overexpression of TLR2 inhibited ASFV replication and the expression of ASFV p72 protein, whereas knockdown of TLR2 had the opposite effect. Our findings suggest that the attenuated virulence of ASFV-ΔMGF110/360-9L might be mediated by increased NF-κB and TLR2 signaling.

African Swine Fever Virus Cysteine Protease pS273R Inhibits Type I Interferon Signaling by Mediating STAT2 Degradation.

African swine fever virus (ASFV) is a large DNA virus that causes African swine fever (ASF), an acute and hemorrhagic disease in pigs with lethality rates of up to 100%. To date, how ASFV efficiently suppress the innate immune response remains enigmatic. In this study, we identified ASFV cysteine protease pS273R as an antagonist of type I interferon (IFN). Overexpression of pS273R inhibited JAK-STAT signaling triggered by type I IFNs. Mechanistically, pS273R interacted with STAT2 and recruited the E3 ubiquitin ligase DCST1, resulting in K48-linked polyubiquitination at K55 of STAT2 and subsequent proteasome-dependent degradation of STAT2. Furthermore, such a function of pS273R in JAK-STAT signaling is not dependent on its protease activity. These findings suggest that ASFV pS273R is important to evade host innate immunity. IMPORTANCE ASF is an acute disease in domestic pigs caused by infection with ASFV. ASF has become a global threat with devastating economic and ecological consequences. To date, there are no commercially available, safe, and efficacious vaccines to prevent ASFV infection. ASFV has evolved a series of strategies to evade host immune responses, facilitating its replication and transmission. Therefore, understanding the immune evasion mechanism of ASFV is helpful for the development of prevention and control measures for ASF. Here, we identified ASFV cysteine protease pS273R as an antagonist of type I IFNs. ASFV pS273R interacted with STAT2 and mediated degradation of STAT2, a transcription factor downstream of type I IFNs that is responsible for induction of various IFN-stimulated genes. pS273R recruited the E3 ubiquitin ligase DCST1 to enhance K48-linked polyubiquitination of STAT2 at K55 in a manner independent of its protease activity. These findings suggest that pS273R is important for ASFV to escape host innate immunity, which sheds new light on the mechanisms of ASFV immune evasion.

Heart Uptake of [18F]Fluoro-4-Thia-Oleate in a Non-Alcoholic Fatty Liver Disease Mouse Model.

The world-wide high incidence of non-alcoholic fatty liver disease (NAFLD) is of concern for its progression to insulin resistance, steatohepatitis and cardiovascular disease (CVD). The increased uptake of fatty acids in critical organs plays a major role in NAFLD progression. Male Ceacam1−/− mice that develop NAFLD, insulin resistance and CVD on normal chow are a potential model for studying the dysregulation of fatty acid uptake. [18F]fluoro-4-thia-oleate ([18F]FTO) was chosen as a fatty acid reporter because of its higher uptake and retention in the heart in an animal model of CVD. Male wild-type (WT) or Ceacam1−/− mice fasted 4−6 h were administered [18F]FTO i.v., and dynamic PET scans were conducted in an MR/PET small animal imaging system along with terminal tissue biodistributions. Quantitative heart image analysis revealed significantly higher uptake at 35 min in Ceacam1−/− (6.0 ± 1.0% ID/cc) vs. WT (3.9 ± 0.6% ID/cc) mice (p = 0.006). Ex vivo heart uptake/retention (% ID/organ) was 2.82 ± 0.45 for Ceacam1−/− mice vs. 1.66 ± 0.45 for WT mice (p < 0.01). Higher kidney and pancreas uptake/retention in Ceacam1−/− was also evident, and the excretion of [18F]FTO into the duodenum was observed for both WT and Ceacam1−/− mice starting at 10 min. This study suggests that the administration of [18F]FTO as a marker of fatty acid uptake and retention may be an important tool in analyzing the effect of NAFLD on lipid dysregulation in the heart.

Glu-Urea-Lys Scaffold Functionalized Superparamagnetic Iron Oxide Nanoparticles Targeting PSMA for In Vivo Molecular MRI of Prostate Cancer.

The prostate specific membrane antigen (PSMA), extensively overexpressed on prostate cancer (PCa) cell surface, has been validated as a diagnostic biomarker for PCa. However, insufficient attention has been paid to the development of PSMA-specific probes loaded with small chemical molecules for the in vivo molecular imaging of PCa. In this study, we innovatively labelled superparamagnetic iron oxide nanoparticles with a PSMA-targeting Glu-Urea-Lys scaffold. An optimized synthetic route was developed to offer a physiochemically stable probe. The probe demonstrated high binding affinity (0.38 ± 0.08 µg(Fe)/mL) and binding specificity to PSMA expressed on prostate cancer cell surface in vitro. In a xenograft PCa mouse model, significant negative contrast of the implanted prostate cancer xenograft could be specifically observed by MRI 6 h after tail vein injection of the tracer (Fe, 20 mg/kg), exhibiting its potential to exclusively enhance magnetic resonance detection of PCa.

Biodistribution of Intra-Arterial and Intravenous Delivery of Human Umbilical Cord Mesenchymal Stem Cell-Derived Extracellular Vesicles in a Rat Model to Guide Delivery Strategies for Diabetes Therapies.

Umbilical cord mesenchymal stem cell-derived extracellular vesicles (UC-MSC-EVs) have become an emerging strategy for treating various autoimmune and metabolic disorders, particularly diabetes. Delivery of UC-MSC-EVs is essential to ensure optimal efficacy of UC-MSC-EVs. To develop safe and superior EVs-based delivery strategies, we explored nuclear techniques including positron emission tomography (PET) to evaluate the delivery of UC-MSC-EVs in vivo. In this study, human UC-MSC-EVs were first successfully tagged with I-124 to permit PET determination. Intravenous (I.V.) and intra-arterial (I.A.) administration routes of [124I]I-UC-MSC-EVs were compared and evaluated by in vivo PET-CT imaging and ex vivo biodistribution in a non-diabetic Lewis (LEW) rat model. For I.A. administration, [124I]I-UC-MSC-EVs were directly infused into the pancreatic parenchyma via the celiac artery. PET imaging revealed that the predominant uptake occurred in the liver for both injection routes, and further imaging characterized clearance patterns of [124I]I-UC-MSC-EVs. For biodistribution, the uptake (%ID/gram) in the spleen was significantly higher for I.V. administration compared to I.A. administration (1.95 ± 0.03 and 0.43 ± 0.07, respectively). Importantly, the pancreas displayed similar uptake levels between the two modalities (0.20 ± 0.06 for I.V. and 0.24 ± 0.03 for I.A.). Therefore, our initial data revealed that both routes had similar delivery efficiency for [124I]I-UC-MSC-EVs except in the spleen and liver, considering that higher spleen uptake could enhance immunomodulatory application of UC-MSC-EVs. These findings could guide the development of safe and efficacious delivery strategies for UC-MSC-EVs in diabetes therapies, in which a minimally invasive I.V. approach would serve as a better delivery strategy. Further confirmation studies are ongoing.

Design, Synthesis and Biological Evaluation of Prodrugs of 666-15 as Inhibitors of CREB-Mediated Gene Transcription.

cAMP-response element binding protein (CREB) is a transcription factor involved in multiple cancers. Chemical inhibitors of CREB represent potential anticancer agents. We previously identified 666-15 as a potent CREB inhibitor. While 666-15 showed efficacious anticancer activity in vivo through intraperitoneal (IP) injection, its oral bioavailability is limited. To increase its oral bioavailability, we describe synthesis and evaluation of prodrugs based on 666-15. The amino acid esters were attempted, but they were not stable for detailed characterization. The corresponding sulfate and phosphates were prepared. The sulfate of 666-15 was too stable to release 666-15 while the phosphates were converted into 666-15 with half-lives of ∼2 h. Phosphate 3 was also a potent CREB inhibitor with anti-breast cancer activity. Furthermore, compound 3 showed much improved oral bioavailability at 38%. These studies support that 3 can be used as an oral CREB inhibitor while IP administration of 666-15 is preferred for in vivo applications.

A narrative review of molecular mechanism and therapeutic effect of cannabidiol (CBD).

Cannabidiol (CBD) is an abundant non-psychoactive phytocannabinoid in cannabis extracts which has high affinity on a series of receptors, including Type 1 cannabinoid receptor (CB1), Type 2 cannabinoid receptor (CB2), GPR55, transient receptor potential vanilloid (TRPV) and peroxisome proliferator-activated receptor gamma (PPARγ). By modulating the activities of these receptors, CBD exhibits multiple therapeutic effects, including neuroprotective, antiepileptic, anxiolytic, antipsychotic, anti-inflammatory, analgesic and anticancer properties. CBD could also be applied to treat or prevent COVID-19 and its complications. Here, we provide a narrative review of CBD's applications in human diseases: from mechanism of action to clinical trials.

Bile Acid-Mediated Activation of Brown Fat Protects From Alcohol-Induced Steatosis and Liver Injury in Mice.

BACKGROUND & AIMS: Alcohol-associated liver disease (AALD) is one of the most common causes of liver injury and failure. Limited knowledge of the mechanisms underlying AALD impedes the development of efficacious therapies. Bile acid (BA) signaling was shown to participate in the progression of AALD. However, the mechanisms remain poorly understood. METHODS: C57BL/6J wild-type (WT), Takeda G-protein-coupled bile acid receptor 5 (TGR5) knockout (KO) and brown adipose tissue (BAT)-specific TGR5 knockdown mice were subjected to ethanol feeding-induced AALD. Liver samples from alcoholic hepatitis patients were used to examine the BA circulation signaling. Human Embryonic Kidney Cells 293 were used for the TGR5 reporter assay. 23(S)-methyl-lithocholic acid was used as a molecular tool to confirm the regulatory functions of BAT in the AALD mouse model. RESULTS: Ethanol feeding increased the expression of the thermogenesis genes downstream of TGR5 in BAT of WT, but not TGR5 KO, mice. TGR5 deficiency significantly blocked BAT activity and energy expenditure in mice after ethanol feeding. Alcohol increased serum BA levels in mice and human beings through altering BA transportation, and the altered BAs activated TGR5 signaling to regulate metabolism. Compared with ethanol-fed WT mice, ethanol-fed TGR5 KO mice showed less free fatty acid (FFA) ß-oxidation in BAT, leading to higher levels of FFA in the circulation, increased liver uptake of FFAs, and exacerbated AALD. BAT-specific TGR5 knockdown mice showed similar results with TGR5 KO mice in AALD. Agonist treatment significantly activated TGR5 signaling in BAT, increased thermogenesis, reduced serum FFA level, and ameliorated hepatic steatosis and injury in AALD mice, while these effects were lost in TGR5 KO mice. CONCLUSIONS: BA signaling plays a protective role in AALD by enhancing BAT thermogenesis. Targeting TGR5 in BAT may be a promising approach for the treatment of AALD.

Degradation of Host Proteins and Apoptosis Induced by Foot-and-Mouth Disease Virus 3C Protease.

Foot-and-mouth disease (FMD), induced by the foot-and-mouth disease virus (FMDV), is a highly contagious disease of cloven-hoofed animals. Previous studies have reported that FMDV 3C protease could degrade multiple host proteins; however, the degradation mechanism mediated by FMDV 3C is still unclear. Here, we found that transient expression of FMDV 3C degraded various molecules in NF-κB signaling in a dose-dependent manner, and the proteolytic activity of FMDV 3C is important for inducing degradation. Additionally, 3C-overexpression was associated with the induction of apoptosis. In this study, we showed that an apoptosis inhibitor CrmA abolished the ability of 3C to degrade molecules in NF-κB signaling. Further experiments using specific caspase inhibitors confirmed the irrelevance of caspase3, caspase8, and caspase9 activity for degradation induced by 3C. Altogether, these results suggest that FMDV 3C induces the widespread degradation of host proteins through its proteolytic activity and that the apoptosis pathway might be an important strategy to mediate this process. Further exploration of the relationship between apoptosis and degradation induced by 3C could provide novel insights into the pathogenic mechanisms of FMDV.

Picornavirus 3C - a protease ensuring virus replication and subverting host responses.

The protease 3C is encoded by all known picornaviruses, and the structural features related to its protease and RNA-binding activities are conserved; these contribute to the cleavage of viral polyproteins and the assembly of the viral RNA replication complex during virus replication. Furthermore, 3C performs functions in the host cell through its interaction with host proteins. For instance, 3C has been shown to selectively 'hijack' host factors involved in gene expression, promoting picornavirus replication, and to inactivate key factors in innate immunity signaling pathways, inhibiting the production of interferon and inflammatory cytokines. Importantly, 3C maintains virus infection by subtly subverting host cell death and modifying critical molecules in host organelles. This Review focuses on the molecular mechanisms through which 3C mediates physiological processes involved in virus-host interaction, thus highlighting the picornavirus-mediated pathogenesis caused by 3C.

Advances in Foot-and-Mouth Disease Virus Proteins Regulating Host Innate Immunity.

Foot-and-mouth disease (FMD) is a highly contagious disease that affects cloven-hoofed animals such as pigs, cattle, and sheep. The disease is caused by the foot-and-mouth disease virus (FMDV) which has a non-enveloped virion with icosahedral symmetry that encapsulates a positive-sense, single-stranded RNA genome of ∼8.4 kb. FMDV infection causes obvious immunosuppressive effects on the host. In recent years, studies on the immunosuppressive mechanism of FMDV have become a popular topic. In addition, studies have shown that many FMDV proteins are involved in the regulation of host innate immunity and have revealed mechanisms by which FMDV proteins mediate host innate immunity. In this review, advances in studies on the mechanisms of interaction between FMDV proteins and host innate immunity are summarized to provide a comprehensive understanding of FMDV pathogenesis and the theoretical basis for FMD prevention and control.

Synthesis and evaluation of 18F-PTTCO-Cys40-Exendin-4 for PET imaging of ectopic insulinomas in rodents.

A major limitation in the development of radiolabeled Exendin-4 analogues (short half-life isotopes) is an inability to efficiently and rapidly separate final products from precursors. This is important as lack of purity in the final product decreases probe efficiency. The purpose of this study was to develop a method to prepare the high-purity imaging reagent [18F] PTTCO-Cys40-Exendin-4. To accomplish this, magnetic TCO-beads were incubated with the crude product to remove unlabeled Exendin-4. In rodents pre-treatment with purified [18F] PTTCO-Cys40-Exendin-4 (~1.85 MBq) allowed precise microPET imaging of ectopic insulinomas. Moreover, analogue uptake was successfully blocked by administering non-labelled "cold" Exendin-4. Biodistribution data revealed that [18F] PTTCO-Cys40-Exendin-4 accumulated specifically in GLP-1R-enriched insulinomas in mice, confirming results obtained using miroPET. Investigation of [18F] PTTCO-Cys40-Exendin-4 as a tracer to image portal vein-transplanted pancreatic islets is proceeding in animals.

Cu/Fe-cocatalyzed Meyer-Schuster-like rearrangement of propargylic amines: direct access to E-ß-aminoacryaldehydes.

A simple and efficient method for the synthesis of ß-aminoacryaldehydes via Cu(OAc)2·H2O and FeCl3 cocatalyzed Meyer-Schuster-Like rearrangement of propargylic amines was developed. The reactions proceed selectively as the E-isomers in generally good yields under aerobic conditions, and are compatible with a broad range of functional groups. This method combines C-N bond cleavage as well as the N-aryl group migration and provides a practical and mild synthetic approach to α,ß-unsaturated carbonyl compounds, which are useful precursors in a variety of functional group transformations.