Potential biomarker enhancing the activity of tuberculosis, hsa-miR-346.

OBJECTIVES: To determine the usefulness of hsa-miR-346, a potential biomarker enhancing the activity of non-tuberculous mycobacterial diseases, as a biomarker of tuberculosis activity. METHODS: We investigated whether hsa-miR-346 is secreted by human macrophages infected with Mycobacterium tuberculosis (M. tuberculosis) in an in vitro study. In addition, a cross-sectional study was conducted first to evaluate whether serum hsa-miR-346 is elevated in patients with tuberculosis compared with that in healthy individuals. Second, we conducted a retrospective study to evaluate whether anti-tuberculosis treatment reduces serum hsa-miR-346 levels. RESULTS: Log hsa-miR-346 levels were significantly elevated in the supernatant of human macrophages infected with M. tuberculosis in a dose-dependent manner. The mean serum log hsa-miR-346 levels were -15.48 (-15.76 to -15.21) in patients with tuberculosis and -16.12 (-16.29 to -15.95) in healthy volunteers, which significantly differed. In addition, hsa-miR-346 significantly decreased at 2 months from starting an anti-tuberculosis treatment. CONCLUSIONS: We consider hsa-miR-346 as a potential biomarker enhancing the tuberculosis activity.

Prolonged viral shedding of SARS-CoV-2 in an immunocompromised patient.

The duration of viral shedding of SARS-CoV-2 is usually less than 10 days. We experienced a COVID-19 case with prolonged viral shedding for 2 months. His cell mediated immunity has been depressed (CD4+T cell <100/µl) due to advanced malignant lymphoma and chemotherapy which had been completed 4 months prior to the onset of symptoms of COVID-19. We administered several treatments against COVID-19, however the results of Polymerase Chain Reaction (PCR) from nasopharyngeal specimens remained positive to SARS-CoV-2 for 2 months. Moreover, virus isolation assays performed on Day 59 also remained positive. He was finally discharged on Day 69 with two consecutive negative PCR results for SARS-CoV-2. Immunocompromised status may prolong viral shedding and it is therefore important for the clinician to take into account this when assessing such patients.

Eco-Friendly Push-Coated Polymer Solar Cells with No Active Material Wastes Yield Power Conversion Efficiencies over 5.5.

Push-coating is a simple process that can be employed for extremely low-cost polymer electronic device production. Here, we demonstrate its application to the fabrication of poly(2,7-carbazole- alt-dithienylbenzothiadiazole) (PCDTBT):[6,6]-phenyl-C71-butyric acid methyl ester (PC71BM) active layers processed in air, yielding similar photovoltaic performances as thermally annealed spin-coated thin films when used in inverted polymer solar cells (PSCs). During push-coating, the polydimethylsiloxane layer temporarily traps the deposition solvent, resulting in simultaneous film formation and solvent annealing effect. This removes the necessity for a postdeposition thermal annealing step which is required for spin-coated PSCs to produce high photovoltaic performances. Optimized PSC active layers are produced with a push-coating time of 5 min at room temperature with 20 times less hazardous solvent and 40 times less active material than spin-coating. Annealed spin-coated active layers and active layers push-coated for 5 min both produce average power conversion efficiencies (PCEs) of 5.77%, while those push-coated for a shorter time of 1 min yield a slightly lower value of 5.59%. We demonstrate that, despite differences in their donor:acceptor vertical concentration gradients, unencapsulated PCDTBT:PC71BM active layers push-coated for 1 min produce PSCs with similar operational stability and upscaling capacity as thermally annealed spin-coated ones. As fast device fabrication can be achieved with short-time push-coating, we further demonstrate the potential of this deposition technique by manufacturing push-coated PSC-based semitransparent photovoltaic devices with a PCE of 4.23%, relatively neutral colors and an average visible transparency of 40.2%. Our work thus confirms that push-coating is not limited to the widely employed poly(3-hexylthiophene-2,5-diyl) but can also be used with low band gap copolymers and opens the path to low-cost and eco-friendly, yet efficient and stable PSCs.

Projection of invertebrate populations in the headwater streams of a temperate catchment under a changing climate.

Climate change places considerable stress on riverine ecosystems by altering flow regimes and increasing water temperature. This study evaluated how water temperature increases under climate change scenarios will affect stream invertebrates in pristine headwater streams. The studied headwater-stream sites were distributed within a temperate catchment of Japan and had similar hydraulic-geographical conditions, but were subject to varying temperature conditions due to altitudinal differences (100 to 850 m). We adopted eight general circulation models (GCMs) to project air temperature under conservative (RCP2.6), intermediate (RCP4.5), and extreme climate scenarios (RCP8.5) during the near (2031-2050) and far (2081-2100) future. Using the water temperature of headwater streams computed by a distributed hydrological-thermal model as a predictor variable, we projected the population density of stream invertebrates in the future scenarios based on generalized linear models. The mean decrease in the temporally averaged population density of Plecoptera was 61.3% among the GCMs, even under RCP2.6 in the near future, whereas density deteriorated even further (90.7%) under RCP8.5 in the far future. Trichoptera density was also projected to greatly deteriorate under RCP8.5 in the far future. We defined taxa that exhibited temperature-sensitive declines under climate change as cold stenotherms and found that most Plecoptera taxa were cold stenotherms in comparison to other orders. Specifically, the taxonomic families that only distribute in Palearctic realm (e.g., Megarcys ochracea and Scopura longa) were selectively assigned, suggesting that Plecoptera family with its restricted distribution in the Palearctic might be a sensitive indicator of climate change. Plecoptera and Trichoptera populations in the headwaters are expected/anticipated to decrease over the considerable geographical range of the catchment, even under the RCP2.6 in the near future. Given headwater invertebrates play important roles in streams, such as contributing to watershed productivity, our results provide useful information for managing streams at the catchment-level.

Discovery of novel serine palmitoyltransferase inhibitors as cancer therapeutic agents.

We pursued serine palmitoyltransferase (SPT) inhibitors as novel cancer therapeutic agents based on a correlation between SPT inhibition and growth suppression of cancer cells. High-throughput screening and medicinal chemistry efforts led to the identification of structurally diverse SPT inhibitors 4 and 5. Both compounds potently inhibited SPT enzyme and decreased intracellular ceramide content. In addition, they suppressed cell growth of human lung adenocarcinoma HCC4006 and acute promyelocytic leukemia PL-21, and displayed good pharmacokinetic profiles. Reduction of 3-ketodihydrosphingosine, the direct downstream product of SPT, was confirmed under in vivo settings after oral administration of compounds 4 and 5. Their anti-tumor efficacy was observed in a PL-21 xenograft mouse model. These results suggested that SPT inhibitors might have potential to be effective cancer therapeutics.

Discovery of Novel 5-(Piperazine-1-carbonyl)pyridin-2(1H)-one Derivatives as Orally eIF4A3-Selective Inhibitors.

Starting from our previous eIF4A3-selective inhibitor 1a, a novel series of (piperazine-1-carbonyl)pyridin-2(1H)-one derivatives was designed, synthesized, and evaluated for identification of orally bioavailable probe molecules. Compounds 1o and 1q showed improved physicochemical and ADMET profiles, while maintaining potent and subtype-selective eIF4A3 inhibitory potency. In accord with their promising PK profiles and results from initial in vivo PD studies, compounds 1o and 1q showed antitumor efficacy with T/C values of 54% and 29%, respectively, without severe body weight loss. Thus, our novel series of compounds represents promising probe molecules for the in vivo pharmacological study of selective eIF4A3 inhibition.

Parallel fluorescent probe synthesis based on the large-scale preparation of BODIPY FL propionic acid.

We describe a methodology for quick development of fluorescent probes with the desired potency for the target of interest by using a method of parallel synthesis, termed as Parallel Fluorescent Probe Synthesis (Parallel-FPS). BODIPY FL propionic acid 1 is a widely used fluorophore, but it is difficult to prepare a large amount of 1, which hinders its use in parallel synthesis. Optimization of a synthetic scheme enabled us to obtain 50g of 1 in one batch. With this large quantity of 1 in hand, we performed Parallel-FPS of BODIPY FL-labeled ligands for estrogen related receptor-α (ERRα). An initial trial of the parallel synthesis with various linkers provided a potent ligand for ERRα (Reporter IC50=80nM), demonstrating the usefulness of Parallel-FPS.

Orientation Control of Two-Dimensional Perovskites by Incorporating Carboxylic Acid Moieties.

Two-dimensional perovskite compounds, (RNH3)2PbX4, have attracted much attention as quantum confinement materials. To achieve suitable orientation and exciton properties for optical applications, carboxy groups were introduced into the ammonium cations of two-dimensional perovskite compounds, which formed dimer structures based on the hydrogen bonding by the carboxy moieties. This structural organization allowed control of the layer orientation for favorable solar cells and thermal stability of the perovskites, while maintaining quantum confinement effects.