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Spirulina (Arthrospira maxima) hot water extracts such as calcium spirulan (Ca-SP) have demonstrated antiviral effects against herpes simplex virus (HSV), human immunodeficiency virus-1 (HIV-1), and influenza virus infections. There is no prior evidence suggesting the anti-viral activity of the spirulina hot water extract against respiratory syncytial virus (RSV).There are currently no effective antivirals available to treat RSV infection. Therefore, the development of safe and novel anti-RSV drugs is urgent and necessary. The aim of this work was to demonstrate the anti-RSV activity of spirulina hot water extracts and determine the potential mechanism of action.Cytotoxicity and anti-RSV activity of spirulina hot water extracts were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and neutralization assays, respectively. Potential mechanisms and components were assessed using time of addition, attachment, internalization, pull-down assays, and composition analysis.The polysaccharide-enriched high-molecular weight fraction (100 kDa, SHD1) had a high total sugar content, with rhamnose accounting for approximately 60 mol% of total monosaccharides. The main glycosyl linkages included 3-, 4-, and 2,3-rhamnopyranosyl linkages. All spirulina hot water extracts showed no toxicity toward human epithelial type 2 (HEp-2) cells but demonstrated anti-RSV activity. The SHD1 had a half maximal effective concentration (ECSHD1 serves as an effective candidate for novel drug development against RSV infection.

Learning the hidden dynamics from sequence data is crucial. Attention mechanism can be introduced to spotlight on the region of interest for sequential learning. Traditional attention was measured between a query and a sequence based on a discrete-time state trajectory. Such a mechanism could not characterize the irregularly-sampled sequence data. This paper presents an attentive differential network (ADN) where the attention over continuous-time dynamics is developed. The continuous-time attention is performed over the dynamics at all time. The missing information in irregular or sparse samples can be seamlessly compensated and attended. Self attention is computed to find the attended state trajectory. However, the memory cost for attention score between a query and a sequence is demanding since self attention treats all time instants as query points in an ordinary differential equation solver. This issue is tackled by imposing the causality constraint in causal ADN (CADN) where the query is merged up to current time. To enhance the model robustness, this study further explores a latent CADN where the attended dynamics are calculated in an encoder-decoder structure. Experiments on the irregularly-sampled actions, dialogues and bio-signals illustrate the merits of the proposed methods in action recognition, emotion recognition and mortality prediction, respectively.

Influenza A virus mutates rapidly, allowing it to escape natural and vaccine-induced immunity. Neuraminidase (NA) is a surface protein capable of cleaving the glycosidic linkages of neuraminic acids to release newly formed virions from infected cells. Genetic variants within a viral population can influence the emergence of pandemic viruses as well as drug susceptibility and vaccine effectiveness. In the present study, 55 clinical specimens from patients infected with the 2009 pandemic influenza A/H1N1 virus, abbreviated as A(H1N1)pdm09, during the 2015-2016 outbreak season in Taiwan were collected. Whole genomes were obtained through next-generation sequencing. Based on the published sequences from A(H1N1)pdm09 strains worldwide, a mixed population of two distinct variants at NA position 151 was revealed. We initially reasoned that such a mixed population may have emerged during cell culture. However, additional investigations confirmed that these mixed variants were detectable in the specimens of patients. To further investigate the role of the two NA-151 variants in a dynamic population, a reverse genetics system was employed to generate recombinant A(H1N1)pdm09 viruses. It was observed that the mixture of the two distinct variants was characterized by a higher replication rate compared to the recombinant viruses harbouring a single variant. Moreover, an NA inhibition assay revealed that a high frequency of the minor NA-151 variant in A(H1N1)pdm09 was associated with a reduced susceptibility to NA inhibitors. We conclude that two distinct NA-151 variants can be identified in patient specimens and that such variants may increase viral replication and NA activity.

The role of microRNA (miRNA) in influenza A virus (IAV) host species specificity is not well understood as yet. Here, we show that a host miRNA, miR-1290, is induced through the extracellular signal-regulated kinase (ERK) pathway upon IAV infection and is associated with increased viral titers in human cells and ferret animal models. miR-1290 was observed to target and reduce expression of the host vimentin gene. Vimentin binds with the PB2 subunit of influenza A virus ribonucleoprotein (vRNP), and knockdown of vimentin expression significantly increased vRNP nuclear retention and viral polymerase activity. Interestingly, miR-1290 was not detected in either chicken cells or mouse animal models, and the 3′ UTR of the chicken vimentin gene contains no binding site for miR-1290. These findings point to a host species-specific mechanism by which IAV upregulates miR-1290 to disrupt vimentin expression and retain vRNP in the nucleus, thereby enhancing viral polymerase activity and viral replication., Graphical Abstract

The emergence and re-emergence of RNA virus outbreaks highlight the urgent need for the development of broad-spectrum antiviral agents. Arthrospira maxima has be used as a food source for a long time, and the protein or polysaccharide fractions were evidenced to have antiviral activity, therefore we examined the antiviral efficacy of hot water extract from Arthrospira maxima (AHWE), on Enterovirus 71 (EV71), Influenza virus, Herpes simplex virus (HSV), Respiratory syncytial virus (RSV), Ebola virus, and Coronavirus for antiviral spray application. In this study, we demonstrated that the AHWE shown 90 to 100% inhibition rate on the plaque formation of EV71, HSV-1, HSV-2, influenza virus, RSV, 229E and SARS-COV2 at virus attachment stage, and the long-lasting protection study also found while the AHWE was pre-exposed to the open air for more than 4 hours in plaque reduction assay. In addition, AHWE also had inhibitory effect on Ebola virus replication at 500 ug/ml. Finally, AHWE also shown no toxicity and skin sensitivity that imply it could be safe for future clinical use if approved by FDA. In conclusion, this study suggests that AHWE could be developed as a potential broad-spectrum antivirus spray product and therapeutic agent.

Performing measurements for high-weight operators has been a practical problem in quantum computation, especially for quantum codes in the stabilizer formalism. The conventional procedure of measuring a high-weight operator requires multiple pairwise unitary operations, which can be slow and prone to errors. We provide an alternative method to passively detect the value of a high-weight operator using only two-local interactions and single-qubit continuous measurements. This approach involves joint interactions between the system and continuously-monitored ancillary qubits. The measurement outcomes from the monitor qubits reveal information about the value of the operator. This information can be retrieved by using a numerical estimator or by evaluating the time average of the signals. The interaction Hamiltonian can be effectively built using only two-local operators, based on techniques from perturbation theory. We apply this indirect detection scheme to the four-qubit Bacon-Shor code, where the two stabilizers are indirectly monitored using four ancillary qubits. Due to the fact that the four-qubit Bacon-Shor code is an error-detecting code and that the Quantum Zeno Effect can suppress errors, we also study the error suppression under the indirect measurement process. In this example, we show that various types of non-Markovian errors can be suppressed.

Many quantum measurements, such as photodetection, can be destructive. In photodetection, when the detector ``clicks'' a photon has been absorbed and destroyed. Yet the lack of a click also gives information about the presence or absence of a photon. In monitoring the emission of photons from a source, one decomposes the strong measurement into a series of weak measurements, which describe the evolution of the state during the measurement process. Motivated by this example of destructive photon detection, a simple model of destructive weak measurements using qubits was studied in earlier work by the authors. It has shown that the model can achieve any positive-operator-valued measurement (POVM) with commuting POVM elements including projective measurements. In this paper, we use a different approach for decomposing any POVM into a series of weak measurements. The process involves three steps: randomly choose, with certain probabilities, a set of linearly independent POVM elements; perform that POVM by a series of destructive weak measurements; and output the result of the series of weak measurements with certain probabilities. The probabilities of the outcomes from this process agree with those from the original POVM, and hence this model of destructive weak measurements can perform any qubit POVM.

Correction for ‘Superior upconversion fluorescence dopants for highly efficient deep-blue electroluminescent devices’ by Yi-Hsiang Chen et al., Chem. Sci., 2016, DOI: 10.1039/c6sc00100a.

Influenza is one of the most common human respiratory diseases, and represents a serious public health concern. However, the high mutability of influenza viruses has hampered vaccine development, and resistant strains to existing anti-viral drugs have also emerged. Novel anti-influenza therapies are urgently needed, and in this study, we describe the anti-viral properties of a Spirulina (Arthrospira platensis) cold water extract. Anti-viral effects have previously been reported for extracts and specific substances derived from Spirulina, and here we show that this Spirulina cold water extract has low cellular toxicity, and is well-tolerated in animal models at one dose as high as 5,000 mg/kg, or 3,000 mg/kg/day for 14 successive days. Anti-flu efficacy studies revealed that the Spirulina extract inhibited viral plaque formation in a broad range of influenza viruses, including oseltamivir-resistant strains. Spirulina extract was found to act at an early stage of infection to reduce virus yields in cells and improve survival in influenza-infected mice, with inhibition of influenza hemagglutination identified as one of the mechanisms involved. Together, these results suggest that the cold water extract of Spirulina might serve as a safe and effective therapeutic agent to manage influenza outbreaks, and further clinical investigation may be warranted.

The authors describe breast augmentation in a patient with von Willebrand disease (vWD), providing a template for treating such patients. Because there is no single ideal laboratory test predictive of surgical bleeding, preoperative history remains the most important diagnostic tool. A vigilant pursuit of signs of undiagnosed vWD or other coagulopathy in the preoperative patient may prevent unexpected intraoperative or postoperative hemorrhage.

Histone deacetylase (HDAC) inhibitors cause growth arrest and apoptosis of cancer cells by both p21-dependent and independent mechanisms. Decreased expression of growth factor receptors may be a key factor in the p21-independent mechanism, although this has not been directly tested. We have tested the effects of sodium butyrate and trichostatin A on human myeloma cell lines and have observed G1 arrest and apoptosis associated with increased expression of p21WAF1, Bax, Rb dephosphorylation, and decreased IL-6 receptor (IL-6R) expression. Experiments to determine the role of disruption of IL-6 signaling as a result of decreased IL-6 receptor expression in mediating these effects were conducted using a stable transfectant of the OPM-2 line which constitutively expressed the IL-6 receptor. Our results indicated that decreased IL-6R expression was not required for induction of p21WAF1 or apoptosis. Thus, HDAC inhibitors appear to activate multiple cellular pathways, leading to growth arrest and apoptosis, and their use in the treatment of myeloma, particularly in combination with other agents, warrants further investigation. Am. J. Hematol. 68:170–178, 2001. © 2001 Wiley-Liss, Inc.

Highly efficient deep-blue electroluminescent devices are realized via an efficient triplet–triplet annihilation process of styrylpyrene-based emitters., In this study, we revealed a new approach for the development of new triplet–triplet annihilation (TTA) materials with highly efficient deep-blue fluorescence via the incorporation of a styrylpyrene core and an electron-donating group. The resulting deep-blue emitters (PCzSP, DFASP, and DPASP) exhibit intramolecular charge transfer emissions with remarkably high emission quantum yields. The electroluminescent devices based on these three fluorophores as dopants using CBP as a host exhibit very high device efficiencies; in particular, the DPASP-doped device reveals an extremely high EQE of 12%, reaching the limit of a TTA-based device. The EL characteristics of DPASP-doped CBP-based devices at various doping concentrations (0–5%) suggest that the dopant DPASP is responsible for the TTA-type delayed fluorescence in the device; no delayed fluorescence was observed for the device using CBP as the host emitter. Moreover, when using DMPPP with ambipolar characteristics as the host, the deep-blue DPASP-doped device also gives outstanding performance with an EQE of nearly 11% with an extremely small efficiency roll-off, which was ascribed to the excellent charge balance in the emitting layer of the EL device. The TTA process of the SP-based dopants accounts significantly for the superior efficiencies of the EL devices.

Interleukin-6 (IL-6)/IL-6 receptor (IL-6R) plays a major role in autocrine/paracrine growth regulation of myeloma cells. We investigated the effect of dexamethasone and all-trans retinoic acid, previously shown to modulate IL-6/IL-6R, on the in vitro growth of a human myeloma cell line, OPM-2. Both agents inhibited the clonogenic growth and 3H- thymidine incorporation in a concentration-dependent fashion. Isobologram and median effect analysis showed a strong synergy between these two agents with a combination index in the range of 0.2 to 0.6. Both agents decreased the labeling index and the cell fraction in S and G2/M phases, suggesting a block in G1-S phase transition. The clonogenic growth was stimulated by exogenous IL-6 and was inhibited by monoclonal antibody to IL-6, suggesting an autocrine function of IL-6. The effect of dexamethasone but not all-trans retinoic acid was completely reversed by exogenous IL-6. Dexamethasone increased, while all-trans retinoic acid reduced, IL-6R but not gp130 mRNA expression. Their combination caused a net reduction in IL-6R mRNA. Cellular IL-6R density was altered correspondingly without changes in the binding affinity. IL-6 mRNA expression was reduced by dexamethasone and the combination, but was not affected by retinoic acid alone. However, IL-6 secretion into culture supernatant was abolished by both agents. A survey of 4 additional human myeloma cells showed that 1 was sensitive to both, 1 was sensitive to one agent only, and 2 were resistant to both. The study demonstrates the possibility of regulating myeloma cell growth through modulation of IL-6/IL-6R autocrine/paracrine loop and the principle of achieving a synergistic effect by blocking this loop at multiple sites.

Purpose: Hepcidin is a liver-produced peptide implicated in the anemia of inflammation. Because interleukin (IL)-6 is a potent inducer of hepcidin expression and its levels are elevated in multiple myeloma, we studied the role of hepcidin in the anemia of multiple myeloma. Experimental Design: Urinary hepcidin and serum levels of IL-6, ferritin, C-reactive protein, tumor necrosis factor-α, and IL-1β were studied in newly diagnosed myeloma patients. In vitro hepcidin induction assay was assessed by real-time PCR assay. Results: Pretreatment urinary hepcidin levels in 44 patients with stage III multiple myeloma were 3-fold greater than normal controls. In the subset of multiple myeloma patients without renal insufficiency (n = 27), a marked inverse correlation was seen between hemoglobin at diagnosis and urinary hepcidin level (P = 0.014) strongly supporting a causal relationship between up-regulated hepcidin expression and anemia. The urinary hepcidin also significantly (P < 0.05) correlated with serum ferritin and C-reactive protein, whereas its correlation with serum IL-6 levels was of borderline significance (P = 0.06). Sera from 14 multiple myeloma patients, with known elevated urinary hepcidin, significantly induced hepcidin mRNA in the Hep3B cells, whereas normal sera had no effect. For 10 patients, the ability of anti-IL-6 and anti-IL-6 receptor antibodies to prevent the serum-induced hepcidin RNA was tested. In 6 of these patients, hepcidin induction was abrogated by the anti-IL-6 antibodies, but in the other 4 patients, the neutralizing antibodies had no effect. Conclusions: These results indicate hepcidin is up-regulated in multiple myeloma patients by both IL-6-dependent and IL-6-independent mechanisms and may play a role in the anemia of multiple myeloma.

Fetal hemoglobin (HbF) decreases polymerization of sickle hemoglobin (HbS) and improves outcomes in sickle cell disease (SSD). Therefore, a therapeutic goal in SSD is pharmacologic reactivation of HbF. Silencing of the γ-globin (HbF) gene is associated with DNA methylation. The cytosine analog 5-aza-2′-deoxycytidine (decitabine) hypomethylates DNA by inhibiting DNA methyltransferase. We examined if subcutaneous decitabine could increase HbF levels and improve SSD pathophysiology without cytotoxicity. Eight symptomatic SSD patients resistant or intolerant of standard treatment with hydroxyurea received decitabine 0.2 mg/kg subcutaneously 1 to 3 times per week in 2 cycles of 6-week duration. Treatment decreased neutrophils and increased mean HbF (6.5% to 20.4%, P < .0001) and mean total hemoglobin (76 to 96 g/L [7.6 to 9.6 g/dL], P < .001). Features of vaso-occlusive crisis pathophysiology such as red cell adhesion, endothelial damage, and coagulation pathway activity significantly improved. γ-Globin gene promoter methylation decreased, and platelets and the proportion of megakaryocytes and erythroid cells in the marrow increased without a decrease in marrow cellularity, consistent with a DNA hypomethylating, noncytotoxic mechanism of action. Weekly subcutaneous decitabine produces cumulative increases in HbF and total hemoglobin through a noncytotoxic mechanism of action. Chronic dosing and sustained increases in hemoglobin F and total hemoglobin levels may be possible. Further studies in SSD and thalassemia are indicated.

Standard myeloablative conditioning prior to allogeneic hematopoietic stem cell (HSC) transplantation has been associated with significant toxicity in patients older than 45 years of age with myelofibrosis with myeloid metaplasia (MMM). We sought to evaluate the efficacy of a reduced-intensity conditioning regimen for allogeneic HSC transplantation in this setting. A regimen consisting of fludarabine (30 mg/m2 intravenously daily for 5 days) and melphalan (70 mg/m2 intravenously daily for 2 days) followed by transplantation of filgrastim-mobilized peripheral blood cells from HLA-identical siblings was administered to 4 older patients (median age, 56 years; range, 48-58 years) with advanced MMM. All patients achieved prompt neutrophil and platelet engraftment and have experienced a significant regression of splenomegaly and bone marrow fibrosis. All now have normal bone marrow cellularity. With a median follow-up of 13 months (range, 11-19 months), all 4 patients are alive with stable full-donor hematopoietic chimerism. These results support the feasibility and effectiveness of reduced-intensity conditioning prior to allogeneic HSC transplantation for older patients with advanced MMM.

The SHP-1 phosphatase associates with the receptors for erythropoietin, stem cell factor, and interleukin-3, and negatively regulates the mitogenic signals generated during engagement by their respective ligands. The erythroid progenitors of patients with polycythemia vera are hypersensitive to the mitogenic effects of these growth factors despite the fact that the numbers and binding affinities for their receptors are not increased. To determine whether post-receptor signaling defects may account for growth factor-hypersensitivity in polycythemia vera, we determined the expression of SHP-1 in highly purified erythroid progenitors from polycythemia vera patients. Our data demonstrate that in approximately 60% of the patients, expression of SHP-1 in the colony forming unit-erythroid population is diminished. The decreased expression of the protein may result from a transcriptional defect, as suggested by the diminished SHP-1 mRNA expression in the erythroid progenitors of these patients. Studies to determine the level of maturation of polycythemia vera and normal cells indicated that there was no difference between the two at early colony forming unit-erythroid stage of differentiation although polycythemia vera cells showed retarded differentiation kinetics at late colony forming unit-erythroid stage of differentiation. Furthermore, SHP-1 expression in normal colony forming unit-erythroid demonstrated downregulation of mRNA and protein levels during terminal differentiation, suggesting that its function is required for growth control during the early stages of erythropoiesis. These results indicate an important role for SHP-1 in the regulation of normal human erythroid progenitors and suggest that defective expression of the protein may contribute to the pathogenesis of polycythemia vera.

Lymphocyte surface immunoglobulin (SIg) and immunoglobulin (Ig) secretion were studied in 14 patients with chronic lymphocytic leukemia (CLL) and 12 healthy subjects. The determination of SIgM-bearing (SIgM+) cells by immunofluorescent staining and the quantification of SIgM by radioimmunoassay (RIA) permitted the calculation of the SIgM density. In 12 normal subjects the percentage of SIgM+ cells averaged 8% (range 4%-12%) and the SIgM density 10.2 ng antigenic equivalent/10(6) SIgM+ cells (SD 4.3). In 12 patients with CLL the respective figures were 68% (range 35%-90%) and 0.68 ng (SD 0.57). Ig secretion from pokeweed mitogen-stimulated CLL cells was markedly diminished as compared with normal lymphocytes. In coculture experiments CLL cells had no suppressive effect on Ig secretion of normal lymphocytes and normal lymphocytes did not enhance Ig secretion leukemic lymphocytes. These results indicate that the impaired secretory activity of CLL cells results from an intrinsic anomaly of these cells.