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Influenza is an acute respiratory infectious disease caused by the influenza virus, affecting people globally and causing significant social and economic losses. Due to the inevitable limitations of vaccines and approved drugs, there is an urgent need to discover new anti-influenza drugs with different mechanisms. The viral ribonucleoprotein complex (vRNP) plays an essential role in the life cycle of influenza viruses, representing an attractive target for drug design. In recent years, the functional area of constituent proteins in vRNP are widely used as targets for drug discovery, especially the PA endonuclease active site, the RNA-binding site of PB1, the cap-binding site of PB2 and the nuclear export signal of NP protein. Encouragingly, the PA inhibitor baloxavir has been marketed in Japan and the United States, and several drug candidates have also entered clinical trials, such as favipiravir. This article reviews the compositions and functions of the influenza virus vRNP and the research progress on vRNP inhibitors, and discusses the representative drug discovery and optimization strategies pursued.

To address drug resistance to influenza virus neuraminidase inhibitors (NAIs), a series of novel boron-containing N-substituted oseltamivir derivatives were designed and synthesized to target the 150-cavity of neuraminidase (NA). In NA inhibitory assays, it was found that most of the new compounds exhibited moderate inhibitory potency against the wild-type NAs. Among them, compound 2c bearing 4-(3-boronic acid benzyloxy)benzyl group displayed weaker or slightly improved activities against group-1 NAs (H1N1, H5N1, H5N8 and H5N1-H274Y) compared to that of oseltamivir carboxylate (OSC). Encouragingly, 2c showed 4.6 times greater activity than OSC toward H5N1-H274Y NA. Moreover, 2c exerted equivalent or more potent antiviral activities than OSC against H1N1, H5N1 and H5N8. Additionally, 2c demonstrated low cytotoxicity in vitro and no acute toxicity at the dose of 1000 mg/kg in mice. Molecular docking of 2c was employed to provide a possible explanation for the improved anti-H274Y NA activity, which may be due to the formation of key additional hydrogen bonds with surrounding amino acid residues, such as Arg152, Gln136 and Val149. Taken together, 2c appeared to be a promising lead compound for further optimization.

Nano differential scanning fluorimetry (nanoDSF) is a high-throughput protein stability screening technique that simultaneously monitors protein unfolding and aggregation properties. The thermal stability of immunoglobulin G (IgG) was investigated in three different buffers (sodium acetate, sodium citrate, and sodium phosphate) ranging from pH 4 to 8. In all three buffers, the midpoint temperature of thermal unfolding (Tm) showed a tendency to increase as the pH increased, but the aggregation propensity was different depending on the buffer species. The best stability against aggregation was obtained in the sodium acetate buffers below pH 4.6. On the other hand, IgG in the sodium citrate buffer had higher aggregation and viscosity than in the sodium acetate buffer at the same pH. Difference of aggregation between acetate and citrate buffers at the same pH could be explained by a protein–protein interaction study, performed with dynamic light scattering, which suggested that intermolecular interaction is attractive in citrate buffer but repulsive in acetate buffer. In conclusion, this study indicates that the sodium acetate buffer at pH 4.6 is suitable for IgG formulation, and the nanoDSF method is a powerful tool for thermal stability screening and optimal buffer selection in antibody formulations.

Let X be a complex Banach space and Cb(Ω:X) be the Banach space of all bounded continuous functions from a Hausdorff space Ω to X, equipped with sup norm. A closed subspace A of Cb(Ω:X) is said to be an X-valued function algebra if it satisfies the following three conditions: (i) A≔{x⁎∘f:f∈A, x⁎∈X⁎} is a closed subalgebra of Cb(Ω), the Banach space of all bounded complex-valued continuous functions; (ii) ϕ⊗x∈A for all ϕ∈A and x∈X; and (iii) ϕf∈A for every ϕ∈A and for every f∈A. It is shown that k-homogeneous polynomial and analytic numerical index of certain X-valued function algebras are the same as those of X.

The solution-phase self-assembly of bidentate 16-[3,5-bis(mercapto-methyl)phenoxy]hexadecanoic acid (BMPHA) on Au(111) was studied using nano-fabrication protocols with scanning probe nanolithography and immersion particle lithography. Molecularly thin films of BMPHA prepared by surface self-assembly have potential application as spatially selective layers in sensor designs. Either monolayer or bilayer films of BMPHA can be formed under ambient conditions, depending on the parameters of concentration and immersion intervals. Experiments with scanning probe-based lithography (nanoshaving and nanografting) were applied to measure the thickness of BMPHA films. The thickness of a monolayer and bilayer film of BMPHA on Au(111) were measured in situ with atomic force microscopy using n-octadecanethiol as an internal reference. Scanning probe-based nanofabrication provides a way to insert nanopatterns of a reference molecule of known dimensions within a matrix film of unknown thickness to enable a direct comparison of heights and surface morphology. Immersion particle lithography was used to prepare a periodic arrangement of nanoholes within films of BMPHA. The nanoholes could be backfilled by immersion in a SAM solution to produce nanodots of n-octadecanethiol surrounded by a film of BMPHA. Test platforms prepared by immersion particle lithography enables control of the dimensions of surface sites to construct supramolecular assemblies.

This study investigates the effects of FigureNotes on sensory processing abilities and the learning behaviors of young children. The settings for this research were a non-profit early-intervention center and a private preschool in the metropolitan, where one hundred and twenty private preschool children and 32 children with Autism Spectrum Disorder, aged 40-63 months, were selected as the research participants by purposive sampling. The research design incorporated HMEAYC with FigureNotes. Each participant participated in one 40-minute session per week for 16 weeks. The research results showed the positive effects of FigureNotes on the children's sensory processing abilities and learning behaviors. The research illustrated FigureNotes not only enhanced visual processing and learning habits in young children, but also enhanced tactile processing in children with Autism Spectrum Disorder (ASD). In this first of its kind, research in Taiwan we propose to prove that FigureNotes can improve young children's visual processing and positive learning habits, and it can enhance the tactile processing of children with ASD. Therefore, we highlight the benefits to promote the use of FigureNotes to assist and support the effective development of young children at different developmental levels.

We study the Bishop-Phelps-Bollobás property for numerical radius (in short, BPBp-nu) and find sufficient conditions for Banach spaces to ensure the BPBp-nu. Among other results, we show that L1μ-spaces have this property for every measure μ. On the other hand, we show that every infinite-dimensional separable Banach space can be renormed to fail the BPBp-nu. In particular, this shows that the Radon-Nikodým property (even reflexivity) is not enough to get BPBp-nu.

The Banach-Saks index of an Orlicz-Lorentz space Λφ,w(I) for both function and sequence case, is computed with respect to its Matuszewska-Orlicz indices of φ. It is also shown that an Orlicz-Lorentz function space has weak Banach-Saks (resp., Banach-Saks) property if and only if it is separable (resp., reflexive).

The generalized numerical index of a Banach space is introduced, and its properties on certain Banach spaces are studied. Ed-dari's theorem on the numerical index is extended to the generalized index and polynomial numerical index of a Banach space. The denseness of numerical strong peak holomorphic functions is also studied.

We study the density of numerical radius attaining holomorphic functions on certain Banach spaces using the Lindenstrauss method. In particular, it is shown that if a complex Banach space X is locally uniformly convex, then the set of all numerical attaining elements of A(BX:X) is dense in A(BX:X).

Abstract Background Osteosarcoma is a malignant tumor with high ability to form invasion and metastasis. Identifying prognostic factor in osteosarcoma is helpful to select those patients for more aggressive management. Our study evaluated serum alkaline phosphatase (ALP) cooperating with matrix metalloproteinase-9 (MMP-9) as an important prognostic predictor for local recurrence and distant metastasis of osteosarcoma. Methods 177 cases were included from the osteosarcoma patients treated at 1st Affiliated Hospital of Sun Yat-sen University (1999-2008). Pre-chemotherapy serum ALP (pre-ALP) were studied and correlated with tumor recurrence, lung metastasis and patient survival. MMP-9 protein in tumor tissues was detected by immunohistochemistry and correlated with pre-ALP level. Results Pre-ALP were partitioned into normal, high, and very high groups, in each group the incidence of metastases was 12.2%, 21.2% and 34.6%, respectively (p = 0.007). In the three groups the mean disease-free survival (DFS) was 57 ± 3.15, 28 ± 3.57 and 14 ± 3.35 months, respectively (p < 0.001); overall survival (OS) was 92 ± 26.89, 39 ± 8.61 and 17 ± 5.07 months, respectively (p < 0.001). By multivariate analysis, elevated serum pre-ALP were associated with shorter DFS (p = 0.018) and OS (p = 0.031). If elevated ALP levels decreased after clinical treatment, the incidence of lung metastasis rate decreased (p = 0.028); DFS and OS were both prolonged (p < 0.001). Pre-ALP was also positively correlated with MMP-9 expression (p = 0.015) in tumor tissue. Conclusions Pre-ALP was an independent prognostic factor for the survival of osteosarcoma patients in south China, and correlated with MMP-9 expression and lung metastasis. ALP can also serve as a prognostic marker for treatment, and merit large-scale validation studies.

Abstract Background Our goals are to develop a computational histopathology pipeline for characterizing tumor types that are being generated by The Cancer Genome Atlas (TCGA) for genomic association. TCGA is a national collaborative program where different tumor types are being collected, and each tumor is being characterized using a variety of genome-wide platforms. Here, we have developed a tumor-centric analytical pipeline to process tissue sections stained with hematoxylin and eosin (H&E) for visualization and cell-by-cell quantitative analysis. Thus far, analysis is limited to Glioblastoma Multiforme (GBM) and kidney renal clear cell carcinoma tissue sections. The final results are being distributed for subtyping and linking the histology sections to the genomic data. Results A computational pipeline has been designed to continuously update a local image database, with limited clinical information, from an NIH repository. Each image is partitioned into blocks, where each cell in the block is characterized through a multidimensional representation (e.g., nuclear size, cellularity). A subset of morphometric indices, representing potential underlying biological processes, can then be selected for subtyping and genomic association. Simultaneously, these subtypes can also be predictive of the outcome as a result of clinical treatments. Using the cellularity index and nuclear size, the computational pipeline has revealed five subtypes, and one subtype, corresponding to the extreme high cellularity, has shown to be a predictor of survival as a result of a more aggressive therapeutic regime. Further association of this subtype with the corresponding gene expression data has identified enrichment of (i) the immune response and AP-1 signaling pathways, and (ii) IFNG, TGFB1, PKC, Cytokine, and MAPK14 hubs. Conclusion While subtyping is often performed with genome-wide molecular data, we have shown that it can also be applied to categorizing histology sections. Accordingly, we have identified a subtype that is a predictor of the outcome as a result of a therapeutic regime. Computed representation has become publicly available through our Web site.

Following the recent emphasis on supervisory interactions in abusive supervision, this study explains why and how supervisors' job insecurity and authoritarianism are related to abusive supervision and how subordinates' characteristics, agreeableness and negotiating resistance interact with the effects of supervisors' characteristics. We conducted a field study with 261 supervisor and subordinate dyads in South Korea, and the study findings confirmed that supervisors' authoritarianism is positively related to abusive supervision and that the effect is enhanced when subordinates are highly agreeable and display resistant behaviors. The study contributes to the leadership literature, particularly on abusive supervision and personality. Moreover, our findings have practical implications for employees to manage their work relationships with their supervisors or subordinates. [ABSTRACT FROM AUTHOR]

Background: In this study, we explored the potential of predicting dysglycemia in patients who need to continuously manage blood glucose levels using a non-invasive method via electrocardiography (ECG). Methods: The data were collected from patients with diabetes, and heart rate variability (HRV) features were extracted via ECG processing. A residual block-based one-dimensional convolution neural network model was used to predict dysglycemia. Results: The dysglycemia prediction results at each time point, including at the time of blood glucose measurement, 15 min prior to measurement, and 30 min prior to measurement, exhibited no significant differences compared with the blood glucose measurement values. This result confirmed that the proposed artificial intelligence model for dysglycemia prediction performed well at each time point. Additionally, to determine the optimal number of features required for predicting dysglycemia, 77 HRV features were individually eliminated in the order of decreasing importance with respect to the prediction accuracy; the optimal number of features for the model to predict dysglycemia was determined to be 12. The dysglycemia prediction results obtained 30 min prior to measurement, which exhibited the highest prediction range in this study, were as follows: accuracy = 90.5, sensitivity = 87.52, specificity = 92.74, and precision = 89.86. Conclusions: Furthermore, we determined that no significant differences exist in the blood glucose prediction results reported in previous studies, wherein various vital signs and blood glucose values were used as model inputs, and the results obtained in this study, wherein only ECG data were used to predict dysglycemia. [ABSTRACT FROM AUTHOR]

Geometries and electronic properties associated with relative stabilities and energy gaps of porous (InP)12n (n = 1–12) nanoclusters (NCs) (nanowires and nanosheets) are systemically studied by density functional method. The relative stabilities of (InP)12n NCs through the calculated fragmentation energies and cluster‐binding energies are determined and discussed. Interestingly, the calculated energy gaps of (InP)12n nanowires and nanosheets are localized at regions of visible light energy ranges. (InP)12n are relatively wide‐band semiconductor solar energy nanomaterial. The calculated density of states reveals large‐sized porous (InP)12n nanosheets and nanowires with narrow pore size distribution and slight thickness and a large surface area manifest ultrahigh specific capacitance of trapping solar light energies and high light‐to‐electricity conversion efficiencies in solar energy absorption or conversion or photovoltaicsm. Particularly, (InP)12n NCs maintain their elemental properties of individual (InP)12 clusters in the energy gaps of (InP)12n (n > 4). NCs are almost independent of variable sizes. Specifically, the size‐dependent charge transfers of In atoms in (InP)12n NCs exhibit that ionic and covalent bonding exist in (InP)12n NCs and can stabilize (InP)12n NCs. Comparison with experiment results available is made. [ABSTRACT FROM AUTHOR]