A Novel Prodrug Strategy Based on Reversibly Degradable Guanidine Imides for High Oral Bioavailability and Prolonged Pharmacokinetics of Broad-Spectrum Anti-influenza Agents.

We present orally administrable prodrugs (s) of guanidino oseltamivir carboxylate () based on guanidine cyclic diimide (GCDI) to treat influenza viruses. By concealing the guanidine group, which significantly limits the intestinal absorption, its prodrugs s demonstrate dramatic improvement of oral bioavailability. The most promising antiviral substance readily forms covalent adducts with serum proteins via a degradable linker after the intestinal absorption.

Inhibition of IRP2-dependent reprogramming of iron metabolism suppresses tumor growth in colorectal cancer.

Background: Dysregulation of iron metabolism is implicated in malignant transformation, cancer progression, and therapeutic resistance. Here, we demonstrate that iron regulatory protein 2 (IRP2) preferentially regulates iron metabolism and promotes tumor growth in colorectal cancer (CRC).

Methods: IRP2 knockdown and knockout cells were generated using RNA interference and clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 methodologies, respectively.

A dual inhibitor of PIP5K1C and PIKfyve prevents SARS-CoV-2 entry into cells.

The SARS-CoV-2 pandemic has had an unprecedented impact on global public health and the economy. Although vaccines and antivirals have provided effective protection and treatment, the development of new small molecule-based antiviral candidates is imperative to improve clinical outcomes against SARS-CoV-2. In this study, we identified UNI418, a dual PIKfyve and PIP5K1C inhibitor, as a new chemical agent that inhibits SARS-CoV-2 entry into host cells.

3D-printed airway model as a platform for SARS-CoV-2 infection and antiviral drug testing.

We present a bioprinted three-layered airway model with a physiologically relevant microstructure for the study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection dynamics. This model exhibited clear cell-cell junctions and mucus secretion with an efficient expression of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Having infected air-exposed epithelial cells in the upper layer with a minimum multiplicity of infection of 0.

ELAVL1 primarily couples mRNA stability with the 3' UTRs of interferon-stimulated genes.

Upon pathogen detection, the innate immune system triggers signaling events leading to upregulation of pro-inflammatory and anti-microbial mRNA transcripts. RNA-binding proteins (RBPs) interact with these critical mRNAs and regulate their fates at the post-transcriptional level. One such RBP is ELAVL1.

Viral crosslinking and solid-phase purification enables discovery of ribonucleoprotein complexes on incoming RNA virus genomes.

The initial interactions between incoming, pre-replicated virion RNA and host protein factors are important in infection and immunity. Yet currently there are no methods to study these crucial events. We established VIR-CLASP (VIRal Cross-Linking And Solid-phase Purification) to identify the primary viral RNA-host protein interactions.

Discovery of Widespread Host Protein Interactions with the Pre-replicated Genome of CHIKV Using VIR-CLASP.

The primary interactions between incoming viral RNA genomes and host proteins are crucial to infection and immunity. Until now, the ability to study these events was lacking. We developed viral cross-linking and solid-phase purification (VIR-CLASP) to characterize the earliest interactions between viral RNA and cellular proteins.

Small molecule inhibition of human cGAS reduces total cGAMP output and cytokine expression in cells.

The cGAS-STING pathway is a major mechanism that mammalian cells utilize to detect cytoplasmic dsDNA from incoming viruses, bacteria, or self. CYCLIC GMP-AMP SYNTHASE (cGAS) is the sensor protein that directly binds dsDNAs. cGAS synthesizes cyclic GMP-AMP (cGAMP), which binds to the adaptor STIMULATOR OF INTERFERON GENES (STING), activating an INTERFERON REGULATORY FACTOR 3 (IRF3)-mediated immune response.

Dual roles for the ER membrane protein complex in flavivirus infection: viral entry and protein biogenesis.

Hundreds of cellular host factors are required to support dengue virus infection, but their identity and roles are incompletely characterized. Here, we identify human host dependency factors required for efficient dengue virus-2 (DENV2) infection of human cells. We focused on two, TTC35 and TMEM111, which we previously demonstrated to be required for yellow fever virus (YFV) infection and others subsequently showed were also required by other flaviviruses.

Design of High Corrosion Resistant Ni Alloy Using Electronic State Calculation.

Ni alloys are used as the prominent industrial material for heat-resistance and corrosion-resistance. Out of them, Inconel has excellent properties for high-temperature heat-resistant equipment as an excellent material for equipment such as ultrahigh-temperature electric furnace and or boiler. However, Ni alloys used in various areas contain high-priced metals such as Ta, Nb, or Re and their use have been limited to industrial sector so far due to the price incompetence.

Cutting Edge: The Histone Methyltransferase G9a Is Required for Silencing of Helper T Lineage-Associated Genes in Proliferating CD8 T Cells.

Helper versus cytotoxic T lineage decision in the thymus has been studied as a model for silencing of alternative lineage genes. Although the transcription factor RUNX3 is required for the initiation of silencing in developing CD8 T cells, it is unknown how silencing of and other helper T lineage genes is maintained. We show that the histone methyltransferase G9a is necessary for silencing helper T lineage genes in proliferating mouse CD8 T cells.

Development of a disposable kit with fully automatic self-shielding reactor for [F]FDG synthesis.

A self-shielding device for the synthesis of radiopharmaceuticals was developed and fabricated in this study. Radiation exposure was minimized by the self-shielding of the kit, installation of the disposable kit in the auxiliary chamber while in a shielded state, and discharge of the kit into a radioactive waste container upon completion of the synthesis process. The developed self-shielding synthesis kit was tested by synthesizing 2-[F]fluoro-2-deoxy-D-glucose ([F]FDG) in order to verify its performance.

Restriction of Nonpermissive RUNX3 Protein Expression in T Lymphocytes by the Kozak Sequence.

The transcription factor Runx3 promotes differentiation of naive CD4(+) T cells into type-1 effector T (TH1) cells at the expense of TH2. TH1 cells as well as CD8(+) T cells express a subset-specific Runx3 transcript from a distal promoter, which is necessary for high protein expression. However, all T cell subsets, including naive CD4(+) T cells and TH2 cells, express a distinct transcript of Runx3 that is derived from a proximal promoter and that produces functional protein in neurons.

Production of α-particle emitting ²¹¹At using 45 MeV α-beam.

Among the α-particle emitting radionuclides, (211)At is considered to be a promising radionuclide for targeted cancer therapy due to its decay properties. The range of alpha particles produced by the decay of (211)At are less than 70 µm in water with a linear energy transfer between 100 and 130 keV µm(-1), which are about the maximum relative biological effectiveness for heavy ions. It is important to note that at the present time, only a few of cyclotrons routinely produce (211)At.

Genome-wide profiling of in vivo LPS-responsive genes in splenic myeloid cells.

Lipopolysaccharide (LPS), the major causative agent of bacterial sepsis, has been used by many laboratories in genome-wide expression profiling of the LPS response. However, these studies have predominantly used in vitro cultured macrophages (Macs), which may not accurately reflect the LPS response of these innate immune cells in vivo. To overcome this limitation and to identify inflammatory genes in vivo, we have profiled genome-wide expression patterns in non-lymphoid, splenic myeloid cells extracted directly from LPS-treated mice.

OASL1 inhibits translation of the type I interferon-regulating transcription factor IRF7.

The production of type I interferon is essential for viral clearance but is kept under tight control to avoid unnecessary tissue damage from hyperinflammatory responses. Here we found that OASL1 inhibited translation of IRF7, the master transcription factor for type I interferon, and thus negatively regulated the robust production of type I interferon during viral infection. OASL1 inhibited the translation of IRF7 mRNA by binding to the 5' untranslated region (UTR) of IRF7 and possibly by inhibiting scanning of the 43S preinitiation complex along the message.

Effect of polymer molecular weight on the fiber morphology of electrospun mats.

In this work, different fractions of solvent-induced polymer degraded solution were mixed with freshly prepared solution of same polymer, and its effect on fiber morphology of electrospun mats was investigated. Nylon-6 solution in formic acid was allowed to degrade for 3 weeks and different fractions of it were mixed with freshly prepared nylon-6 solution to get the electrospun mats. FE-SEM images of the mats indicated that the a large amount of sub-nanofibers (<50 nm in diameter) in the form of spider-net like structures were achieved by tailoring the amount of solvent degraded polymer solution in the freshly prepared nylon-6 solution.

Effect of bisphosphonates on anodized and heat-treated titanium surfaces: an animal experimental study.

Background: Recent investigations reported that osseointegration of titanium implants can be significantly reinforced with a nanostructure treated with anodic oxidation and heat treatment. This experimental study investigates the effect of bisphosphonates on the nanotubular implant surface in rats.

Methods: Thirty-six titanium implants were divided into three groups: 1) machine-turned (MT), 2) anodized and heat-treated (AH), and 3) anodized and heat- and bisphosphonate-treated (AHB) groups.

Requirement of Split ends for epigenetic regulation of Notch signal-dependent genes during infection-induced hemocyte differentiation.

Drosophila producing a mutant form of the putative transcription coregulator, Split ends (Spen), originally identified in the analysis of neuronal development, display diverse immune defects. In order to understand the role of Spen in the innate immune response, we analyzed the transcriptional defects associated with spen mutant hemocytes and their relationship to the Notch signaling pathways. Spen is regulated by the Notch pathway in the lymph glands and is required for Notch-dependent activation of a large number of genes involved in energy metabolism and differentiation.

[Roles of F-18 FDG PET or PET/CT for the evaluation of gastrointestinal malignancies].

18F-FDG PET scan is an useful functional whole body imaging modality that images various types of malignancies with relative high sensitivity and specificity in a reasonably rapid time. It depicts a lesion based on abnormal glucose metabolism whereas CT detects malignant process mostly based on altered anatomy. In patients with gastric cancers, PET scan detects only less than 50% of early cancers and 62-98% of advanced cancers.