Time evolution operators of a strongly ionizing medium are calculated by a time-dependent unitary transformation (TDUT) method. The TDUT method has been employed in quantum mechanical system composed of discrete states. This method is especially helpful for solving molecular rotational dynamics in quasi-adiabatic regimes because the strict unitary nature of the propagation operator allows us to set the temporal step size large; a tight limitation on the temporal step size ($\delta t <<1$) can be circumvented by the strict unitary nature. On the other hand, in a strongly ionizing system where the Hamiltonian is not Hermitian, the same approach cannot be directly applied because it is demanding to define a set of field-dressed eigenstates. In this study, the TDUT method was applied to the ionizing regime using the Kramers-Henneberger frame, in which the strong-field-dressed discrete eigenstates are given by the field-free discrete eigenstates in a moving frame. Although the present work verifies the method for a one-dimensional atom as a prototype, the method can be applied to three-dimensional atoms, and molecules exposed to strong laser fields.

This paper presents sufficient conditions for almost global stability of nonlinear switched systems consisting of both stable and unstable subsystems. Techniques from the stability analysis of switched systems have been combined with the multiple Lyapunov density approach - recently proposed by the authors for the almost global stability of nonlinear switched systems composed of stable subsystems. By using slow switching for stable subsystems and fast switching for unstable subsystems lower and upper bounds for mode-dependent average dwell times are obtained. In addition to that, by allowing each subsystem to perform slow switching and using some restrictions on total operation time of unstable subsystems and stable subsystems, we have obtained a lower bound for an average dwell time.

In recent years, the photophysical properties of crystalline metal-organic frameworks (MOFs) have become increasingly relevant for their potential application in light-emitting devices, photovoltaics, nonlinear optics and sensing. The availability of high-quality experimental data for such systems makes them ideally suited for a validation of quantum mechanical simulations, aiming at an in-depth atomistic understanding of photophysical phenomena. Here we present a computational DFT study of the absorption and emission characteristics of a Zn-based surface-anchored metal-organic framework (Zn-SURMOF-2) containing anthracenedibenzoic acid (ADB) as linker. Combining band-structure and cluster-based simulations on ADB chromophores in various conformations and aggregation states, we are able to provide a detailed explanation of the experimentally observed photophysical properties of Zn-ADB SURMOF-2: The unexpected (weak) red-shift of the absorption maxima upon incorporating ADB chromophores into SURMOF-2 can be explained by a combination of excitonic coupling effects with conformational changes of the chromophores already in their ground state. As far as the unusually large red-shift of the emission of Zn-ADB SURMOF-2 is concerned, based on our simulations, we attribute it to a modification of the exciton coupling compared to conventional H-aggregates, which results from a relative slip of the centers of neighboring chromophores upon incorporation in Zn-ADB SURMOF-2.

FeIFeI Fe2(S2C3H6)(CO)6(µ-CO) (1a-CO) and its FeIFeII cationic species (2a+-CO) are the simplest model of the CO-inhibited [FeFe] hydrogenase active site, which is known to undergo CO photolysis within a temperature- dependent process whose products and mechanism are still a matter of debate. Using Density Functional Theory (DFT) and Time-Dependent Density Functional Theory (TDDFT) computations, the ground state and low-lying excited state potential energy surfaces (PESs) of 1a-CO and 2a+-CO have been explored aimed at elucidating the dynamics of the CO photolysis yielding Fe2(S2C3H6)(CO)6 (1a) and Fe2(S2C3H6)(CO)6+ (2a+), two simple models of the catalytic site of the enzyme. Two main results came out from these investigations. First, a-CO and 2a+-CO are both bound with respect to any CO dissociation with lowest free energy barriers around 10 kcal mol-1, suggesting that at least 2a+-CO might be synthetized. Second, focusing on the cationic form, we found at least two clear excited state channels along the PESs of 2a+-CO that are unbound with respect to equatorial CO dissociation.

Real-time evolution of the electron densities under excitations in La₂CuO₄ was calculated by the time-dependent density functional theory (TDDFT). The author found, for the first time, under excitations, the electron cloud of Cu²⁺ changes obviously and the characteristic frequencies are 83 meV and 36 meV, respectively, for two different modes. The results are unexpected and close to that of lattice vibrations. The results show that the electron cloud of Cu²⁺ (just like the lattice) can be the electron-pairing medium in high temperature copper oxide superconductors.

The open communication is an exigent need for future power system where the time delay is unavoidable. In order to secure the stability of the grid, the frequency must remain within its limited range which is achieved through the load frequency control. The load frequency control signals are transmitted through communication networks which induces time delay that could destabilize the power systems. So, in order to guarantee the stability the delay margin should be computed. In this paper, we present a new method for calculating the delay margin in load frequency control systems. The transcendental time delay characteristics equation is transformed to frequency dependant equation. The spectral radius is used to find the frequencies at which the roots crosses the imaginary axis. The crossing frequencies are determined through the sweeping test and the binary iteration algorithm. A one-area load frequency control system is chosen as case study. The effectiveness of the proposed method has been proved through comparing with the most recent published methods. The method shows its merit with less conservativeness and less computations. The PI controller gains are preferable to be chosen large to reduce the damping, however, the delay margin decreases with increasing the PI controller gains.

Many systems in nature and laboratories are far from equilibrium and exhibit significant fluc- tuations, invalidating the key assumptions of small fluctuations and short memory time in or near equilibrium. A full knowledge of Probability Distribution Functions (PDFs), especially time- dependent PDFs, becomes essential in understanding far-from-equilibrium processes. We consider a stochastic logistic model with multiplicative noise, which has gamma distributions as stationary PDFs. We numerically solve the transient relaxation problem, and show that as the strength of the stochastic noise increases the time-dependent PDFs increasingly deviate from gamma distributions. For sufficiently strong noise a transition occurs whereby the PDF never reaches a stationary state, but instead forms a peak that becomes ever more narrowly concentrated at the origin. The addition of an arbitrarily small amount of additive noise regularizes these solutions, and re-establishes the existence of stationary solutions. In addition to diagnostic quantities such as mean value, standard deviation, skewness and kurtosis, the transitions between different solutions are analyzed in terms of entropy and information length, the total number of statistically distinguishable states that a system passes through in time.

Since its initial development in the 1970’s by Phil Burke and his collaborators, the R-matrix theory and associated computer codes have become the de facto approach for the calculation of accurate data for general electron-atom/ion/molecule collision and photoionization processes. The use of a non-orthonormal set of orbitals based on B-splines, now called the B-spline R-matrix (BSR) approach, was pioneered by Zatsarinny. It has considerably extended the flexibility of the approach and improved particularly the treatment of complex many-electron atomic and ionic targets, for which accurate data are needed in many modelling applications for processes involving low-temperature plasmas. Both the original R-matrix approach and the BSR method have been extended to the interaction of short, intense electromagnetic (EM) radiation with atoms and molecules. Here we provide an overview of the theoretical tools that were required to facilitate the extension of the theory to the time domain. As an example of a practical application, we show results for two-photon ionization of argon by intense short-pulse extreme ultraviolet radiation

Breast Cancer (BC) is the second most common type of cancer worldwide and displays the highest cancer-related mortality among women worldwide. Targeted therapies have revolutionized the way BC has been treated in the last decades improving life expectancies of millions of women. Among the different molecular pathways that have been of interest for the development of targeted therapies are the Cyclin-Dependent Kinases (CDK). CDK inhibitors are a class of molecules that already exist in nature and those belonging to the INK4 protein family specifically inhibit the CDK4/6 proteins. CDK4/6 inhibitors specifically block the transition from the G1 to the S phase of the cell cycle by dephosphorylation of the retinoblastoma tumor suppressor protein. In the past four years CDK4/6 inhibitors palbociclib, ribociclib, and abemaciclib received their first FDA approval for the treatment of Hormone Receptor (HR)-positive and Human Epidermal growth factor Receptor 2 (HER2)-negative breast cancer after showing significant improvements in progression-free survival in the PALOMA-1, MONALEESA-2 and the MONARCH-2 randomized clinical trials, respectively. After the encouraging results from these clinical trials, CDK4/6 inhibitors have also been investigated in the other BC subtypes. In HER2-positive BC, combination of CDK4/6 inhibitors with HER2-targeted therapies showed promise in preclinical studies and their clinical evaluation is ongoing. Moreover, in triple-negative BC, CDK4/6 inhibitors efficacy has been investigated in combination with other targeted therapies or immunotherapies. This review summarizes the molecular background and clinical efficacy of CDK4/6 inhibitors as single agents or in combination with other targeted therapies for the treatment of BC. Future directions of ongoing clinical trials and predictive biomarkers will be further debated.

A new type of ordinary differential equation is introduced and discussed, namely, the time-dependent order ordinary differential equations. These equations can be solved via fractional calculus and are mapped into Volterra integral equations of second kind with singular integrable kernel. The solutions of the time-dependent order differential equations smoothly deforms solutions of the classical integer order ordinary differential equations into one-another, and can generate or remove singularities. An interesting symmetry of the solution in relation to the Riemann zeta function and Harmonic numbers was also proved.

With reference to our recently proposed Planck Scale White Hole Cosmology (PS-WHC) or Flat Space Cosmology (PS-FSC), we make an attempt to quantify galactic dark matter and flat rotation speeds in terms of galactic visible matter and cosmic mass. Considering recently observed dwarf galaxies having very little dark matter and assuming a time dependent reference mass unit of $M_X\cong \left(\mbox{3.0 to 4.0}\right)\times 10^{38}$ kg, we suggest an empirical relation for galactic dark matter $M_d$ via galactic visible mass $M_v$ as,$M_d \cong \frac{M_v^{3/2}}{M_X^{1/2}}$. This relation helps in fitting flat rotation speeds starting from 8 km/sec (for Segue 2) to 500 km/sec (for UGC12591). Modifying MOND's galactic flat rotation speed relation with Hubble mass $M_0\cong \left(\frac{c^3}{2GH_0}\right)$ of the universe, ratio of galactic flat rotation speed $V_G$ to speed of light $c$ can be shown to be approximately $\frac{V_G}{c} \cong 0.5 \left(\frac{M_v}{M_0}\right)^{1/4}$. Considering the sum of galactic dark matter and visible matter, ratio of galactic flat rotation speed to speed of light can be shown to be approximately $\frac{V_G}{c}\cong 0.25 \left(\frac{M_v+M_d}{M_0}\right)^{1/4}$. With further study, dark matter's nature, effect and distribution can be understood in terms of visible matter's extended gravity and extended theories of gravity can be understood with 'distance cosmic mass' rather than the empirical 'minimum acceleration'.

Magneto-electrochemistry (MEC) is a unique paradigm in science, where electrochemical experiments are carried out as a function of an applied magnetic field, creating a new horizon of potential scientific and technological applications. Over the time, detailed understanding of this research domain was developed to identify and rationalize the possible effects exerted by a magnetic field on the various microscopic processes occurring in an electrochemical system, such as: electrolyte properties governed by charge-transfer process (electric conductivity, viscosity, and diffusivity), mass transfer, electrochemical kinetics and on the structure/quality of products formed either at the working electrode or in the electrochemical cell. Particularly, magnetic field controlled chiral architecture obtained from deposited metal, alloys and catalyst and their excellent enantio-recognition in experimental frame is highly appealing. Interestingly, Hall effect was also demonstrated in electrolytic medium via an impressive experimental technique which is being employed for further theoretical understanding in the field of magneto-electrochemical science. Later, a highly reproducible local temperature variation was observed in electrochemical electrolytes exposed to perpendicular magnetic and electric fields. However, until recent studies, none of the above mentioned reports considered the possibility of a spin-dependent related charge-transfer process. Recent experimental and theoretical studies reveal that electron’s transmission through chiral molecules is spin-selective and this effect has been referred to as chiral-induced spin-selectivity (CISS) effect. The CISS effect pave the way for the building up of a system characterized by a net magnetic moment exploiting the spin-filtering ability of chiral molecules. This interplay between chirality and magnetism may shed light on fundamental scientific aspects underlying the enantio-recognition and highly efficient electron-transfer that occurs in biological process.

This paper focuses on the so-called proportional intensity-based software reliability models (PI-SRMs), which are extensions of the common non homogeneous Poisson process (NHPP)-based SRMs, and describe the probabilistic behavior of software fault-detection process by incorporating the time-dependent software metrics data observed in the development process. Especially we generalize the seminal PI-SRM in Rinsaka, Shibata and Dohi (2006) by introducing eleven well-known fault-detection time distributions, and investigate their goodness-of-fit and predictive performances. In numerical illustrations with four data sets collected in real software development projects, we utilize the maximum likelihood estimation to estimate model parameters with three time-dependent covariates; test execution time, failure identification work and computer time-failure identification, and examine the performances of our PI SRMs in comparison with the existing NHPP-based SRMs without covariates. It is shown that our PI-STMs could give better goodness-of-fit and predictive performances in many cases.

A theoretical nonlocal thermoelastic model for studying the effects of the thermal conductivity variability on a rotating nanobeam has been described in the present article. The theory of thermal stress is employed using the Euler–Bernoulli beam model and generalized heat conduction with phase lags. It is believed that the thermal conductivity of the current model varies linearly according to temperature. Due to variable harmonic heat, the considered nanobeam excited and was subjected to a time-varying exponential decay load. Using the Laplace transform process, the analytical solutions for displacement, deflection, thermodynamic temperature and bending moment of rotating nanobeams are provided in final forms and a numerical example has been taken to address the problem. A comparison of the stated results was displayed and additionally, the influences of non-local parameters and varying load were analyzed and examined. We also investigate how the linear changes in the temperature of physical properties can influence both the static and dynamic responses to the rotating nanobeam.

Results are presented concerning the influence on the water splitting process of enantiopure tartaric acid present in bulk solution. Stainless steel and electrodeposited nickel are used as working electrode (WE) surface. The latter is obtained by electrodeposition on the two poles of a magnet. The influence and role played by the chiral compound in solution has been assessed by comparing the current values, in cyclic voltammetry (CV) experiments, recorded in the potential range at which oxygen evolution reaction (OER) occurs. In the case of tartaric acid and nickel WE a spin polarization of about 4 % is found. The use of the chiral environment (bulk solution) and ferromagnetic chiral Ni electrode allows for observing the OER at a more favourable potential: about 50 mV (i.e. a cathodic, less positive, shift of the potential at which the oxygen evolution is observed).

The epithelial cell adhesion molecule (EpCAM) is a stem cell and carcinoma antigen, which mediates cellular adhesion and proliferative signaling by the proteolytic cleavage. In contrast to low expression in normal epithelium, EpCAM is frequently overexpressed in various carcinomas, which correlates with poor prognosis. Therefore, EpCAM has been considered as a promising target for tumor diagnosis and therapy. Using the Cell-Based Immunization and Screening (CBIS) method, we previously established an anti‐EpCAM monoclonal antibody (EpMab-37; mouse IgG1, kappa). In this study, we investigated the antibody‐dependent cellular cytotoxicity (ADCC), complement‐dependent cytotoxicity (CDC), and an antitumor activity by a defucosylated mouse IgG2a-type of EpMab-37 (EpMab-37-mG2a-f) against an EpCAM‐expressing breast cancer cell line (BT-474). EpMab-37-mG2a-f recognized BT-474 cells with a moderate binding-affinity [a dissociation constant (KD): 2.9x10-8 M] by flow cytometry. EpMab-37-mG2a-f exhibited ADCC and CDC for BT-474 cells by murine splenocytes and complements, respectively. Furthermore, administration of EpMab-37-mG2a-f significantly suppressed the BT-474 xenograft tumor development compared with the control mouse IgG. These results indicated that EpMab-37-mG2a-f exerts antitumor activities against the BT-474 xenograft, and could provide valuable therapeutic regimen for the breast cancers.

Background: Dengue is the most common arthropod-borne sickness worldwide, impacting at least 50 million people each year. The dengue virus has four primary serotypes. Infection with one serotype confers homotypic immunity but not heterologous immunity, and secondary infections may be more severe. Although blood transfusions and organ donations have also been observed, the Aedes aegypti mosquito is the primary vector for the transmission of dengue. Infection causes a continuum of clinical illness, from asymptomatic infection to dengue fever, DHF, and dengue shock syndrome (DSS).Aim: To assess the presence of anti DENV IgG and anti DENV IgM antibodies specific to the four dengue serotypes in blood donor service donors and the importance of pre-donation screening in routine blood collection procedures.Method: 3 mL of peripheral venous blood from 507 blood donors was collected in tubes with BD vacutainer gel tube for serum separation after epidemiological records were reviewed. After that, serum was separated and tests were performed by SD Bioline Dengue Duo. Participants in the study completed a social and epidemiological questionnaire that contained information such as age, gender, and dengue diagnosis.Result: Out of the 507 blood samples that were taken, 473 (93.3%) came from male blood donors, while the remaining 34 (6.7%) belonged to female blood donors. The ratio of males to females is 13.91 to 1. The age range is 18–60 years, and the mean and standard deviation are both 27.7 and 6.5. 183 of the 507 samples produced anti DENV IgG positivity, while 324 did not. The ratio of positive to negative was 1.25:2.Conclusion: According to the findings of this study, quantitative methods for determining the presence of anti-dengue antibodies or detecting the dengue virus in blood donors in endemic areas should be devised in order to ensure the quality of blood transfusions.

The recent advances in Human-Computer Interaction and Artificial Intelligence have significantly increased the importance of identifying human emotions from different sensory cues. Hence, understanding the underlying relationships between emotions and sensory cues have become a subject of study in many fields including Acoustics, Psychology, Psychiatry, Neuroscience and Biochemistry. This work is a preliminary step towards investigating cues for human emotion on a fundamental level by aiming to establish relationships between tonal frequencies of sound and emotions. For that, an online perception test is conducted, in which participants are asked to rate the perceived emotions corresponding to each tone. The results show that a crossover point for four primary emotions lies in the frequency range of 417–440 Hz, thus consolidating the hypothesis that the frequency range of 432–440 Hz is neutral from human emotion perspective. It is also observed that the frequency dependant relationships between emotion pairs Happy—Sad, and Anger—Calm are approximately mirrored symmetric in nature.

ccJE+Advax is an inactivated cell culture Japanese encephalitis (JE) vaccine formulated with Advax™, a novel polysaccharide adjuvant based on delta inulin. This vaccine has previously shown promise in murine and equine studies and the current study sought to better understand its mechanism of action and assess the feasibility of single dose vaccine protection. Mice immunised with ccJE-Advax had higher serum neutralisation titres than those immunised with ccJE alone or with alum adjuvant. ccJE+Advax induced extraordinarily broad cross-neutralising antibodies against multiple flaviviruses including West Nile virus (WNV), Murray Valley Encephalitis Virus (MVEV), St Louis Encephalitis virus (SLE) and Dengue-1 and -2 viruses. Notably, the DENV-2 cross-neutralising antibodies from ccJE+Advax immunised mice uniquely had no DENV-2 antibody dependent enhancement (ADE) activity, by contrast to high ADE activity seen with DENV-1 cross-reactive antibodies induced by mbJE or ccJE alone or with alum adjuvant. JEV-stimulated splenocytes from ccJE+Advax immunised mice showed increased IL-17 and IFN-γ production, consistent with a mixed Th1 and Th17 response, whereas ccJE-alum was associated with production of mainly Th2 cytokines. There is an ongoing lack of human vaccines against particular flaviviruses, including WNV, SLE and MVEV. Given its ability to provide single-dose JEV protection as well as to induce broadly neutralising antibodies free of ADE activity, ccJE+Advax vaccine could be highly useful in all situations where rapid protection is desirable but ADE needs to be avoided, e.g. during a local outbreak or for use in travellers or the military requiring rapid travel to JEV endemic regions.

Understanding the detailed timing of crop phenology and their variability enhances grain yield and quality by providing precise scheduling of irrigation, fertilization, and crop protection mechanisms. Advances in information and communication technology (ICT) provide a unique opportunity to develop agriculture-related tools that enhance wall-to-wall upscaling of data outputs from point-location data to wide-area spatial scales. Because of the heterogeneity of the worldwide agro-ecological zones where crops are cultivated, it is unproductive to perform plant phenology research without providing means to upscale results to landscape-level while safeguarding field-scale relevance. This paper presents an advanced, reproducible, and open-source software for plant phenology prediction and mapping (PPMaP) that inputs data obtained from multi-location field experiments to derive models for any crop variety. This information can then be applied consecutively at a localized grid within a spatial framework to produce plant phenology predictions at the landscape level. This software supports the development of process-oriented and temperature-driven plant phenology models by intuitively and interactively leading the user through a step-by-step progression to the production of spatial maps for any region of interest. Maize (Zea mays L.) was used to demonstrate the robustness, versatility, and high computing efficiency of the resulting modeling outputs of the PPMaP. The framework is implemented in R, providing a flexible and easy‐to‐use GUI interface. Since this allows appropriate scaling to the larger spatial domain, the software can effectively be used to determine the spatially explicit length of growing period (LGP) of any variety.

Measurements of copper and zinc in transfusion-dependent thalassemia (TDT) show contradictory results.Aim of the study: To examine serum levels of these minerals in TDT in relation to iron overload indices and erythron variables. Methods: This study recruited 60 children with TDT and 30 healthy children aged 3-12 years old.Results: Zinc was significantly higher in TDT children than in control children, whilst copper and the copper to zinc ratio were significantly lowered in TDT. Serum zinc was significantly associated with the number of blood transfusions and iron overload variables (including serum iron and TS%) and negatively with erythron variables (including hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin). Serum copper was significantly and negatively associated with the same iron overload and erythron variables. The copper to zinc ratio was significantly correlated with iron, TS%, ferritin, hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin. Albumin levels were significantly higher in TDT children than in control children. Conclusion: Our results suggest that the increase in zinc in children with TDT may be explained by iron loading anemia and hemolysis and the consequent shedding of high amounts of intracellular zinc into the plasma. Increased albumin levels and treatment with Desferral may further contribute towards higher zinc levels in TDT. We suggest that the elevations in zinc in TDT are a compensatory mechanism protecting against infection, inflammation, and oxidative stress. Previous proposals for prophylactic use of zinc supplements in TDT may not be warranted.

Background and Research Highlights: Despite all the concerns and initiatives, natural resources like forests, as well as biodiversity are decreasing at an alarming rate worldwide. Conservation is considered as one of the major tools to prevent such loss and rapid degradation. Evidence around the world shows the adverse effects of conservation laws and policies on indigenous peoples and other local communities. Objectives: This study was conducted in one of the forest-dependent communities situated in Sundarban (world’s largest mangrove forest) to understand the impact of conservation laws and policies on their livelihood. Materials and Methods: A qualitative methodology was designed to collect data, using focus group discussions and case study with community people, and individual interviews with the personnel from NGOs and relevant government departments. Findings: Strict conservation policies and restrictions in accessing forest resources made lives and livelihoods of the local community insecure and unstable, thus putting the community in a vulnerable situation. The had to leave their traditional mode of income and look for alternative livelihood options. Almost no evidence was found in relation to upkeeping their rights in conservation activities. Prohibited movement, provision of punishment for entering into the forest without proper permission and struggles in everyday life were some of the highlighted issues. They had no participation in conservation activities, management of alternative livelihood options, and even they were not sensitized before putting restrictions. Although they had a history of emotional and physical attachment with the forest, existing activities did not consider these issues. In addition, corruption and abuse of power by law enforcement agencies towards the local community intensified the sufferings. Conclusion: This study argues that the realization of human rights in conservation activities and the sensitization of the implementing stakeholders are prerequisites for ensuring the sustainability of both biodiversity and the affected people.

The discovery of microRNAs (miRNAs) has fundamentally transformed our understanding of gene regulation. The competing endogenous RNA (ceRNA) hypothesis postulates that not only messenger RNAs but also other RNA transcripts, such as long non-coding RNAs and pseudogenes, can act as natural miRNA sponges. These RNAs influence each other’s expression levels by competing for the same pool of miRNAs through miRNA response elements on their target transcripts, thereby modulating gene expression and protein activity. In recent years, these ceRNA regulatory networks have gained considerable attention in cancer research. Several studies have identified cancer-specific ceRNA networks. Nevertheless, prior bioinformatic analyses have focused on long non-coding RNAs-associated ceRNA networks. Here, we identify an extended-ceRNA network (including both long non-coding RNAs and pseudogenes) shared across a group of four hormone-dependent (HD) cancers, i.e., prostate, breast, colorectal, and endometrial cancers, using data from The Cancer Genome Atlas (TCGA). We performed a functional enrichment analysis for differentially expressed genes in the shared ceRNA network of HD cancers, followed by a survival analysis to determine their prognostic ability. We identified two long non-coding RNAs, nine genes, and seventy-four miRNAs in the shared ceRNA network across four HD cancers. Among them, two genes and forty-one miRNAs were associated with at least one HD cancer survival. This study is the first to investigate pseudogene associated ceRNAs across a group of related cancers and highlights the value of this approach to understanding shared molecular pathogenesis in a group of related diseases.

River valley bottoms have hydrological, geomorphological, and ecological importance and are buffers for protecting the river from upland nutrient loading coming from agriculture and other sources. They are relatively flat, low-lying areas of the terrain that are adjacent to the river and bound by increasing slopes at the transition to the uplands. These areas have under natural conditions, a groundwater table close to the soil surface. The objective of this paper is to present a stepwise GIS approach for the delineation of river valley bottom within drainage basins and use it to perform a national delineation. We developed a tool that applies a concept called cost distance accumulation with spatial data inputs consisting a river network and slope derived from a digital elevation model. We then used wetlands adjacent to rivers as a guide finding the river valley bottom boundary from the cost distance accumulation. We present results from our tool for the whole country of Denmark carrying out a validation within three selected areas. The results reveal that the tool visually performs well and delineates both confined and unconfined river valleys within the same drainage basin. We use the most common forms of wetlands (meadow and marsh) in Denmark's river valleys known as Groundwater Dependent Ecosystems (GDE) to validate our river valley bottom delineated areas. Our delineation picks about half to two-thirds of these GDE. However, we expected this since farmers have reclaimed Denmark's low-lying areas during the last 200 years before the first map of GDE was created. Our tool can be used as a management tool, since it can delineate an area that has been the focus of management actions to protect waterways from upland nutrient pollution.

Transfusion dependent thalassemia (TDT) patients are treated with continued blood transfusions and show a higher prevalence of depression. TDT with consequent iron overload and inflammation is associated with increased severity of depressive symptoms in TDT children.Aim of the study: To construct a pathway-phenotype which combines iron overload and neuro-immune biomarkers with depressive symptom subdomains in TDT children.Methods: We measured iron status parameters (iron, ferritin, transferrin saturation percentage) and inflammatory (interleukin-1β and tumour necrosis factor-α) biomarkers in TDT (n=111) and healthy (n=53) children and analyzed the results using machine learning.Results: Cluster analysis separated TDT children with depression from those without depression and revealed two depressive subgroups one with low self-esteem and another with increased social-irritability scores. Exploratory factor analysis validated four depressive symptom dimensions as reliable constructs, namely key depressive, physiosomatic, lowered self-esteem and social-irritability dimensions. Partial Least Squares showed that 73.0% of the variance in a latent vector extracted from those four clinical subdomains, immune-inflammatory and iron overload biomarkers was explained by exposure variables including the number of blood transfusions and hospitalizations and use of deferoxamine. The exposure data, iron and immune biomarkers, and symptom subdomains are reflective manifestations of a single latent trait, which shows internal consistency reliability and predictive relevance.Conclusions: The nomological network combining exposure, pathways and behavioral phenome manifestations provides an index of overall severity and disease risk and, therefore, constitutes a new drug target, indicating that iron overload and immune activation should be targeted to treat depression due to TDT.

The transfer of protein-encoding genetic information from DNA to RNA to protein, a process formalized as the “Central Dogma of Molecular Biology”, has undergone a significant evolution since its inception. It was amended to account for the information flow from RNA to DNA, the reverse transcription, and for the information transfer from RNA to RNA, the RNA-dependent RNA synthesis. These processes, both potentially leading to protein production, were initially described only in viral systems, and although RNA-dependent RNA polymerase activity was shown to be present, and RNA-dependent RNA synthesisfound to occur, in mammalian cells, its function was presumed to be restricted to regulatory. However, recent results, obtained with multiple mRNA species in several mammalian systems, strongly indicate the occurrence of protein-encoding RNA to RNA information transfer in mammalian cells. It can result in the rapid production of the extraordinary quantities of specific proteins as was seen in cases of terminal cellular differentiation and during cellular deposition of extracellular matrix molecules. A malfunction of this process may be involved in pathologies associated either with the deficiency of a protein normally produced by this mechanism or with the abnormal abundanceof a protein or of its C-terminal fragment. It seems to be responsible for some types of familial thalassemia and may underlie the overproduction of beta amyloid in sporadic Alzheimer’s disease. The aim of the present article is to systematize the current knowledge and understanding of this pathway. The outlined framework introduces unexpected features of the mRNA amplification such as its ability to generate polypeptides non-contiguously encoded in the genome, its second Tier, a physiologically occurring intracellular polymerase chain reaction, iPCR, a Two-Tier Paradox and RNA Dark Matter. RNA-dependent mRNA amplification represents a new mode of genomic protein-encoding information transfer in mammalian cells. Its potential physiological impact is substantial, it appears relevant to multiple pathologies and its understanding opens new venues of therapeutic interference, it suggests powerful novel bioengineering approaches and its further rigorous investigations are highly warranted.

SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. Like other members of this family, the virus possesses a positive-sense single-stranded RNA genome. The genome encodes for the nsp12 protein, which houses the RNA-dependent-RNA polymerase (RdRP) activity responsible for the replication of the viral genome. A homology model of nsp12 was prepared using the structure of the SARS nsp12 (6NUR) as a model. The model was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp12. This exercise showed that vitamin B12 (methylcobalamin) may bind to the active site of the nsp12 protein. A model of the nsp12 in complex with substrate RNA and incoming NTP showed that Vitamin B12 binding site overlaps with that of the incoming nucleotide. A comparison of the calculated energies of binding for RNA plus NTP and methylcobalamin suggested that the vitamin may bind to the active site of nsp12 with significant affinity. It is, therefore, possible that methylcobalamin binding may prevent association with RNA and NTP and thus inhibit the RdRP activity of nsp12. Overall, our computational studies suggest that methylcobalamin form of vitamin B12 may serve as an effective inhibitor of the nsp12 protein.

In this paper, we examine the mathematical and physical consistencies of the three primary couple stress theories: original Mindlin-Tiersten-Koiter couple stress theory (MTK-CST), modified couple stress theory (M-CST) and consistent couple stress theory (C-CST). As has been known for many years, MTK-CST suffers from some fundamental inconsistencies, such as the indeterminacy of the couple-stress tensor. Therefore, despite the fact that MTK-CST has a fundamental position in the evolution of size-dependent continuum mechanics, it is not a reliable theory within continuum mechanics, for example, in developing new size-dependent multi-physics formulations. We also observe that M-CST not only inherits all inconsistences from the original MTK-CST, but also suffers from new additional inconsistencies, such as the introduction of a new non-physical governing equation. These inconsistencies refute the claim of those who state that the couple-stress tensor may be chosen symmetric. Therefore, the apparent success of MTK-CST and M-CST in describing a size-effect for some problems, such as two-dimensional plate and beam bending, is not enough to justify these theories as suitable for general cases. In fact, the symmetric couple-stresses in M-CST create torsional or anticlastic deformation, not bending. On the other hand, C-CST, with a skew-symmetric couple-stress tensor, is the consistent continuum mechanics suitable for solving different size-dependent solid, fluid and multi-physics problems.

Arthropod-borne flaviviruses represent human pathogens of global medical importance, against which no effective small molecule-based antiviral therapy is currently available. Arbidol (umifenovir) is a broad spectrum antiviral compound approved in Russia and China for prophylaxis and treatment of influenza. This compound showed activity against numerous DNA and RNA viruses. Its mode of action is based predominantly on the impairment of critical steps of virus-cell interaction. Here we demonstrate that arbidol possesses a micromolar inhibition activity (EC50 values ranging from 10.57 ± 0.74 to 19.16 ± 0.29 µM) in Vero cells infected with Zika virus, West Nile virus, and tick-borne encephalitis virus, three medically important representatives of arthropod-borne flaviviruses. Interestingly, no antiviral effect of arbidol is observed in porcine stable kidney cells (PS), human neuroblastoma cells (UKF-NB-6), human hepatoma cells (Huh-7 cells) indicating that the antiviral effect of arbidol is strongly cell-type dependent. Arbidol presents a significant increasing in cytotoxicity profiles when tested in various cell lines in the order: Huh-7 < HBCA < PS < UKF-NB-6 < Vero with CC50 values ranging from 18.69 ± 0.1 to 89.72 ± 0.19 µM. Antiviral activity and acceptable cytotoxicity profiles suggest that arbidol could be a promising candidate for further investigation as a potential therapeutic agent in treating flaviviral infections.

We consider the problem of scheduling $n$ jobs with identical processing times and given release as well as delivery times on $m$ uniform machines. The goal is to minimize the makespan, i.e., the maximum full completion time of any job. This problem is well-known to have an open complexity status even if the number of jobs is fixed. We present a polynomial-time algorithm for the problem which is based on the earlier introduced algorithmic framework blesscmore (``branch less and cut more''). We extend the analysis of the so-called behavior alternatives developed earlier for the version of the problem with identical parallel machines and show how the earlier used technique for identical machines can be extended to the uniform machine environment if a special condition on the job parameters is imposed. The time complexity of the proposed algorithm is $O(\gamma m^2 n\log n)$, where $\gamma$ can be either $n$ or the maximum job delivery time $q_{\max}$. This complexity can even be reduced further by using a smaller number $\kappa<n$ in the estimation describing the number of jobs of particular types. However, this number $\kappa$ becomes only known when the algorithm has terminated.

Glioblastoma multiforme (GBM) is one of the deadliest cancers. Temozolomide (TMZ) is the most common chemotherapy used for GBM patients. Recently, combination chemotherapy strategies have more effective antitumor effects and focus on slowing down the development of chemotherapy resistance. A combination of TMZ and cholesterol lowering medications (statins) is currently under investigation in in vivo and clinical trials. In our current investigation, we have used a triple combination therapy of TMZ, Simvastatin (Simva), and Acetylshikonin (ASH) and investigated its apoptotic mechanism in GBM cell lines (U87 and U251). We used viability, apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), caspase-3/-7, acridine orange (AO) and immunoblotting autophagy assays. Our results showed that TMZ/Simva/ASH combination therapy significantly induced more apoptosis compared to TMZ, Simva, ASH, and TMZ/Simva treatments in GBM cells. Apoptosis via TMZ/Simva/ASH treatment induced mitochondrial damage (increase of ROS, decrease of MMP) and induced caspase-3/7 activation in both GBM cell lines. Compared to all single treatments and the TMZ/Simva treatment, TMZ/Simva/ASH significantly increased positive acidic vacuole organelles. We further confirmed that the increase of AVOs during the TMZ/Simva/ASH treatment was due to partial inhibition of autophagy flux (accumulation of LC3β-II and decrease in p62 degradation) in GBM cells. Our investigation also showed that TMZ/Simva/ASH-induced cell death was depended on autophagy flux as further inhibition of autophagy flux increased TMZ/Simva/ASH-induced cell death in GBM cells. Finally, our results showed that TMZ/Simva/ASH treatment potentially depends on an increase of Bax expression in GBM cells. Our current investigation might open new avenues for more effective treatment of GBM but further investigations are required for better identification of the mechanisms.

Human metapneumovirus is one of major causes of common cold among children, especially infants. Its key enzyme is RNA-dependent RNA-polymerase, which performs both replication and transcription, including capping and cap methylation. The goal of the work is to find possible inhibitors of RNA-dependent RNA-polymerase across the active compounds of Rosaceae plants. The candidates were selected by molecular docking to cap-transferring domain of RNA-polymerase (PDB ID: 4UCZ) in Autodock VINA. Among all the substances tested by docking, ellagic acid derivatives showed the most promising results (affinity values below -10 kcal/mol). Hence, they could be treated as possible candidate drugs against metapneumoviral infection after experimental examination. The main advantage of using these substances should be their low toxicity, which is quite uncommon for selective RNA polymerase inhibitors used in clinical practice. Occurrence of ellagic acid derivatives among the plants from Rosaceae family like raspberry could explain their effect during common cold.

The lateral pressure generated by liquefied soil on pile is a critical parameter in the analysis of soil-pile interaction in liquefaction-susceptible sites. Previous studies have shown that liquefied sand behaves like a non-Newton fluid, and its effect on piles has rate-dependent properties. In this study, a simplified pseudo-static method for liquefiable soil-pile interaction analysis is proposed by treating the liquefied soil as a thixotropic fluid, which considers the rate-dependent behavior. The viscous shear force generated by the relative movement between the viscous fluid (whose viscosity coefficient varies with excess pore pressure and shear strain rate) and the pile was assumed to be the lateral load on the pile. The results from the simplified analysis show that the distribution of bending moment is in good agreement with experiments data. Besides, the effects of various parameters, including relative density, thickness ratio of non-liquefiable layer to liquefiable layer, and frequency of input ground motion, on the pile-soil rate-dependent interaction were discussed in detail.

In this paper, we address the energy eigenvalues of two-dimensional Dirac oscillator perturbed by dynamical noncommutative space. We derived the relativistic Hamiltonian of Dirac oscillator in dynamical noncommutative space ($\tau$-space), in which the space-space Heisenberg–like commutation relations and noncommutative parameter are position-dependent. Then used this Hamiltonian to calculate the first-order correction to the eigenvalues and eigenvectors, based on the second quantization and using the perturbation theory. It is shown that the energy shift depends on the dynamical noncommutative parameter $\tau$. Knowing that with a set of two-dimensional Bopp-shift transformation, we mapped the noncommutative problem to the standard commutative one.

Objective: To investigate the protein expression levels of cyclin‑dependent kinase subunit 2 (CKS2) and cluster of differentiation (CD) 47 in gastric cancer (GC) and their clinical significances. Methods: A total of 126 GC patients who underwent radical resection were selected as study subjects. Additionally, 32 patients with benign gastric tumor, 42 patients with low-grade intraepithelial neoplasia (LGIEN), and 49 patients with high-grade intraepithelial neoplasia (HGIEN) who underwent surgery were selected as the control groups. Immunohistochemistry was used to detect the expression of CKS2 and CD47 in surgical specimens. We statistically analyzed the clinical significance of the expression of the two factors. Results: (1) The positivity rates for CKS2 in benign gastric tumor tissue, LGIEN tissue, HGIEN tissue, and GC tissue gradually increased, i.e., 6.3% (2/32), 30.9% (13/42), 38.8% (19/49), and 60.3% (76/126), respectively, and the positivity rates for CD47 were 18.8% (6/32), 38.1% (16/42), 46.9% (23/49), and 65.9% (83/126), respectively. (2) High expression of CKS2 and CD47 were associated with tumor diameter, Lauren classification, number of lymph node metastases, and TNM stage. In addition, the immunohistochemical scores for CKS2 and CD47 were positively correlated (r=0.625, P=0.000). (3) The median follow-up time of 126 patients was 46.5 months, and the overall survival rate was 40.5% (51/126). Survival analysis showed that compared with that in the CKS2 (-) group, the overall survival rate for patients in the CKS2 (+) group was significantly worse (25.0% vs 64.0%, 2=15.67, P=0.000) and that compared with the CD47 (-) group, the CD47 (+) group had significantly worse overall survival (30.1% vs 60.5%, 2=15.67, P=0.000). (4) The overall survival rates of CKS2(+)CD47(+) group, CKS2(+)CD47(-) group, CKS2(-)CD47(+) group, and CKS2 (-)CD47 (-) group were 20.0%(13/65), 58.3%(7/12), 57.1%(8/14), 65.7% (23/35), respectively, the prognosis of patients in CKS2(+)CD47(+) group was significantly poor. Conclusion: High expression levels of CKS2 and CD47 were closely related to the occurrence of GC and can be used as independent risk factors to assess the prognosis of patients.

Potential dependent special relativity and Gauss's law for the electric field have been used for gravity by assuming vacuum energy to be generated when the energy is a minimum useful expression for vacuum energy has been found. This expression shows that elementary particles are generated by gravity vacuum filling their hollow balls; using Schrödinger equation for spherically symmetric particles vacuum energy is quantized. Treating mass as vibrating spheres thus solving Schrödinger, coordinate harmonic oscillator energy relation has been found.

Regression models are mostly used in all fields of sciences for modelling the relationship between a dependent variable and independent variable(s). The least square method is often used to estimate the parameters in a linear model because it is the best linear unbiased estimator. These estimates can only be reliable if the assumption of normality is satisfied. In some cases the dependent variable might be bimodal and shows a non-linear relationship with the independent variable(s). In this case, a non-linear model should be used. In non-linear model, the standard errors are often obtained by linearizing the nonlinear function around the parameter, assuming central limit theorem. After the linearization, the least square parameter estimates are obtained. It should be noted that the error of the non-linear model is different from that of the transformed linear model. Thus, there is a need to transform back to the original non-linear model. In this note, a novel non-linear function was developed into a non-linear regression model, called Normal-Power model. The least square method was used to estimate the parameter of the transformed model. Its usefulness in regression model was demonstrated using real data of Nigeria Economy-Tourism model.

Dengue fever is a viral mosquito-borne infection, a major international public health concern. With 2.5 billion people at risk of acquiring the infection around the world, disease severity is influenced by the immunological status of the individual, seronegative or seropositive, prior to natural infection. Caused by four antigenically related but distinct serotypes, DENV-1 to DENV-4, infection by one serotype confers life-long immunity to that serotype and a period of temporary cross-immunity (TCI) to other serotypes. The clinical response on exposure to a second serotype is complex with the so-called Antibody-Dependent enhancement (ADE) process, a disease augmentation phenomenon when pre-existing antibodies to previous dengue infection do not neutralize but rather enhance the new infection, used to explain the etiology of severe disease. In this paper, we present a minimalistic mathematical model framework developed to describe qualitatively the dengue immunological response mediated by antibodies. Three models are analyzed and compared: i) primary dengue infection, ii) secondary dengue infection with the same (homologous) dengue virus and iii) secondary dengue infection with a different (heterologous) dengue virus. We explore the features of viral replication, antibody production, and infection clearance over time. The model is developed based on body cells and free virus interactions resulting in infected cells activating antibody production. Our mathematical results are qualitatively similar to the ones described in the empiric immunology literature, providing insights on the immunopathogenesis of severe disease. Results presented here are of use for future research directions to evaluate the impact of dengue vaccines.

Background: Clinical cases reports with snake accidents show that venom bite induces increased oxidative stress including several markers of lipid peroxidation and other oxidative stress marker in plasma. Methods: The main findings of this work were performed with BthTx-II on paw edema of animals treated with the toxin and biochemical measurement of COX-2, PGE2, MDA and the effects of peroxiredoxin inhibitors on edema and myotoxicity were also evaluated. Results: The results show that edema and myotoxocity induced by PLA2 (BthTx-II) induces a strong mobilization of arachidonic acid and an increase in cellular oxidative stress as measured by increased malondialdehydo (MDA) concentration and protein carbonylation. Thus, these findings establish the strong link between oxidative stress, arachidonic acid mobilization and that these events may explain the presence of oxidative stress markers in snake-bitten patients. Experiments performed with animals previously treated with commercially purchased inhibitors showed enzymes such as thioredoxin (TXN), thioredoxin reductase (TXNRD) and other glutathione (GSH)-related antioxidant defenses could play an essential role controlling and defining the end of edema on the late phase of PLA2 BthTx-II-induced process. Conclusion. This study showed that thioate-dependent antioxidant enzymes play an important role in resolving the edema induced by BthTx-II.

Prompt removal of misfolded membrane proteins and misassembled membrane protein complexes is essential for membrane homeostasis. However, the elimination of these toxic proteins from the hydrophobic membrane environment has high energetic barriers. Transmembrane FtsH is the only known ATP-dependent protease responsible for this task, unlike other well-studied soluble ATP-dependent proteases. The mechanisms by which FtsH recognizes, unfolds, translocates, and proteolyzes its substrates remain unclear. Here, we report the crystal structures of the Thermotoga maritima FtsH periplasmic domain (PD) in an associative trimeric state at a 1.5-1.95 Å resolution. We also describe the pH-dependent oligomerization states of the isolated PD using dynamic light scattering. These observations help us understand how FtsH recognizes membrane-anchored misfolded proteins.

As the natural resources are getting exhausted, the concept of sustainable development of region has received increasing attentions, especially for resource-dependent cities. In this paper an innovative method that emergy analysis and IPAT (Human Impact Population Affluence Technology) model were combined in order to analyze the quantitative relationship of economic growth and energy consumption and further to evaluate its overall sustainability level. Taiyuan, a traditional, resource-dependent city in China, is selected as the case study region. The main results show that total emergy of Taiyuan increased from 9.023× 1023 sej in 2007 to 9.116× 1023sej in 2014, with 38% reduction on non-renewable emergy and 125% growth on imported emergy. Regional emergy money ratio (RMB) was reduced by 48% from 5.31× 1013sej/$ in 2007 to 2.74× 1013sej/$ in 2014, indicating that the increasing speed of consuming resources and energy was faster than the increase of GDP, and that Taiyuan’s money purchasing power declined. The lower emergy sustainability index (ESI) indicates that Taiyuan was explored and produced large quantities of mineral resources, which puts more stress on the environment as a consequence, and that this is not sustainable in the long run. The IPAT analysis demonstrates that Taiyuan sticks to the efforts of energy conservation and environmental protection, in order to promote regional sustainable development, it is necessary to take an integrated effort. Policy insights suggest that resourceful regions should improve include energy and resource efficiency, optimizing energy and resourceful structure.

Physicists have employed various approaches to solve the “paradox” and offered a consistent conclusion that the traveller twin is younger than the homebody twin. However, some authors attribute the cause of differential aging to acceleration, while others believe that acceleration should not be regarded as the source of differential aging, but frame switch is. So far there is no agreement on this issue. Actually, acceleration and frame switch should not be regarded as the source of differential aging. The author will introduce a thought experiment in which two very long spacecraft are moving in opposite directions at a speed close to the speed of light to discuss the real cause of differential aging. The author found that the real cause of differential aging in the twin “paradox” is because of the asymmetry of destination choice. People always choose their destinations in the universe rather than in spacecraft. The destinations are always stationary relative to the homebody twin and moving relative to the traveller twin. Once we choose a destination in a reference frame, the distance is the proper length in this reference frame, but the distance will contract in another moving reference frame, thus the recording time will be shorter.

This addendum contains clarifications and a sharpening of some of the results on the VIT transform framework developed in [1]. The focus is on the right-coefficient and left- coefficient forms of the transform, the extraction of a first-order term from a left polynomial fraction, and the application to linear time-varying systems.

We have introduced a sign operator of energy, analogous to the operator helicity, but in the direction of what we call energy vector. However, this energy vector needs a time vector. To give physical senses to the components of such a time vector, we try to explain the time dilation in special relativity and try to relate the components of the time vector to the tunneling times when an electron crosses a potential barrier.

Climate change such as sea level rise, change in temperature, precipitation, and storminess are expected to impact significantly coastal lagoons. The nature and magnitude of these impacts are uncertain. The objective of the research is to determine the climate change impacts on mixing and circulation at Songkhla lagoon, Thailand. Songkhla lagoon is the largest lagoonal water resource in Thailand and Southeast Asia. The lagoon is a combined freshwater and estuarine complex of high productivity which represents an extraordinary combination of environmental resources believed to be unique in the region. This work is part of a Climate Change impact assessment framework. It is the validation phase (step 5) of the framework applying a case study. Delft 3D was used to simulate CC scenarios in the climate downscaling models, part of the previous framework steps. These results were compared to the current conditions to determine the main changes in mixing and circulation in the coastal lagoon. Three indicators were applied to quantify the impacts: flushing time, salinity intrusion and stratification. The results suggest an increase in water velocities at the inlet in future scenarios and a decrease of flushing time. Salinity and stratification showed more complex changes in futures scenarios.

A number of experimental tests of time orientability are described as well as clear experimental signatures from non time orientability (time reversal). Some tests are well known, while others are based on more recent theoretical work. Surprisingly, the results all suggest that time is not orientable at a microscopic level; even definitive tests are positive. At a microscopic level the direction of time can reverse and a consistent forward time direction cannot be defined. That is the conclusion supported by a range of well-known experiments. The conflict between quantum theory and local realism; electrodynamics with electric charges; and spin half transformation properties of fermions; can all be interpreted as evidence of time reversal. While particle-antiparticle annihilation provides a definitive test. It offers both a new view of space-time and an novel interpretation of quantum theory with the potential to unify classical and quantum theories.

Calcium/calmodulin (CaM)-dependent protein kinase kinase 2 (CaMKK2) regulates bone remodeling through its effects on osteoblasts and osteoclasts. However, its role in osteocytes, the most abundant bone cell type, and the master regulator of bone remodeling, remains unknown. Here we report that the conditional deletion of CaMKK2 from osteocytes using Dentine matrix protein 1 (Dmp1)-8kb-Cre mice led to enhanced bone mass only in female mice owing to a suppression of osteoclasts. Conditioned media isolated from female CaMKK2-deficient osteocytes inhibited osteoclast formation and function in in vitro assays, indicating a role for osteocyte-secreted factors. Proteomics analysis revealed significantly higher levels of extracellular calpastatin, a specific inhibitor of calcium-dependent cysteine proteases calpains, in female CaMKK2 null osteocyte conditioned media, compared to media from female control osteocytes. Further, exogenously added non-cell permeable recombinant calpastatin domain I elicited a marked, dose-dependent inhibition of female wild-type osteoclasts and depletion of calpastatin from female CaMKK2-deficient osteocyte conditioned media reversed the inhibition of matrix resorption by osteoclasts. Our findings reveal a novel role for extracellular calpastatin in regulating female osteoclast function and unravel a novel CaMKK2-mediated paracrine mechanism of osteoclast regulation by female osteocytes.

The resistance of cancer cell subpopulations, including cancer stem cell (CSC) populations, to apoptosis-inducing chemotherapeutic agents is a key barrier to improved outcomes for cancer patients. The cationic amphiphilic drug hexamethylene amiloride (HMA) has been previously demonstrated to efficiently kill bulk breast cancer cells independent of tumor subtype or species, but acts poorly toward non-transformed cells derived from multiple tissues. Here we demonstrate that HMA is similarly cytotoxic toward breast CSC-related subpopulations that are resistant to conventional chemotherapeutic agents, but poorly cytotoxic toward normal mammary stem cells. HMA inhibits the sphere-forming capacity of FACS-sorted human and mouse mammary CSC-related cells in vitro, specifically kills tumor but not normal mammary organoids ex vivo, and inhibits metastatic outgrowth in vivo, consistent with CSC suppression. Moreover, HMA inhibits viability and sphere formation by lung, colon, pancreatic, brain, liver, prostate and bladder tumor cell lines, suggesting that its effects may be applicable to multiple malignancies. Mechanistically, HMA elicits the permeabilization of the limiting lysosomal membrane, a hallmark feature of the lysosome-dependent cell death pathway. Our observations expose a key vulnerability intrinsic to cancer stem cells, and point to novel strategies for the exploitation of cationic amphiphilic drugs in cancer treatment.

Neurological complications of infection by the mosquito-borne Zika virus (ZIKV) include Guillain-Barré syndrome (GBS), an acute inflammatory demyelinating polyneuritis. GBS was first associated with recent ZIKV epidemics caused by the emergence of ZIKV Asian lineage in South Pacific. Here, we hypothesize that ZIKV-associated GBS relates to a molecular mimicry between viral envelope E (E) protein and neural proteins involved in GBS. Analysis of ZIKV epidemic strains showed that glycan loop (GL) region of the E protein includes an IVNDT motif which is conserved in voltage-dependent L-type calcium channel subunit alpha-1C (Cav1.2) and Heat Shock 70 kDa protein 12A (HSP70 12A). Both VSCC-alpha 1C and HSP70 12A belong to protein families which have been associated with neurological autoimmune diseases in central nervous system. The purpose of our in silico analysis is to point out that IVNDT motif of ZIKV E-GL region should be taken in consideration for the development of safe and effective anti-Zika vaccines by precluding the possibility of adverse neurologic events including autoimmune diseases such as GBS.

We propose an iterative scheme for feature-based positioning using a new weighted dissimilarity measure with the goal of reducing the impact of large errors among the measured or modeled features. The weights are computed from the location-dependent standard deviations of the features and stored as part of the reference fingerprint map (RFM). Spatial filtering and kernel smoothing of the kinematically collected raw data allow efficiently estimating the standard deviations during RFM generation. In the positioning stage, the weights control the contribution of each feature to the dissimilarity measure, which in turn quantifies the difference between the set of online measured features and the fingerprints stored in the RFM. Features with little variability contribute more to the estimated position than features with high variability. Iterations are necessary because the variability depends on the location, and the location is initially unknown when estimating the position. Using real WiFi signal strength data from extended test measurements with ground truth in an office building, we show that the standard deviations of these features vary considerably within the region of interest and are neither simple functions of the signal strength nor of the distances from the corresponding access points. This is the motivation to include the empirical standard deviations in the RFM. We then analyze the deviations of the estimated positions with and without the location-dependent weighting. In the present example the maximum radial positioning error from ground truth are reduced by 40% comparing to kNN without the weighted dissimilarity measure.

This work presents a novel approach to construct surrogate models of parametric Differential Algebraic Equations based on a tensor representation of the solutions. The procedure consists in building simultaneously, for every output of the reference model, an approximation given in tensor-train format. A parsimonious exploration of the parameter space coupled with a compact data representation allows to alleviate the curse of dimensionality. The approach is thus appropriate when many parameters with large domains of variation are involved. The numerical results obtained for a nonlinear elasto-viscoplastic constitutive law show that the constructed surrogate model is sufficiently accurate to enable parametric studies such as the calibration of material coefficients.

Initial attempts to develop monoclonal antibodies as therapeutics to resolve influenza infections focused mainly on searching for antibodies with the potential to neutralise the virus in vitro with classical haemagglutination inhibition and micro-neutralisation assays. This led to the identification of many antibodies that bind to the head domain of haemagglutinin (HA) which generally have potent neutralisation capabilities that block viral entry or viral membrane fusion. However, this class of antibodies has a narrow breadth of protection in that they are usually strain specific. This led to the emphasis on stalk targeting antibodies which are able to bind a broad range of viral targets that span across different influenza subtypes. Recently, a third class of antibodies targeting the vestigial esterase (VE) domain have been characterised. In this review, we describe the key features of neutralising VE targeting antibodies and compare them with head and stalk class antibodies.

In this paper, we study the problem of controllability of impulsive neutral evolution integrodifferential equations with state dependent delay in Banach spaces. The main results are completely new and are obtained by using Sadovskii's fixed point theorem, theory of resolvent operators, and an abstract phase space. An example is given to illustrate the theory.

Can physical objects be in time-symmetry? Physical objects can only exist in a medium that has physical attributes, which means this medium is a type of energy. Is time energy? This article will show that time is not energy and there is no possibility that physical objects could be in time-symmetry. Physical objects only can be in symmetry in the time-invariant space in which they exist. In this perspective time measured with clocks is the result of the observer’s measurement in the time-invariant space. The time-symmetry model is flawed.

Capacity Expansion Models (CEMs) are optimization models used for long-term energy planning on national to continental scale. They are typically computationally demanding, thus in need of simplification, where one such simplification is to reduce the temporal representation. This paper investigates how using representative periods to reduce the temporal representation in CEMs distorts results compared to a benchmark model of a full chronological year. The test model is a generic CEM applied to Europe, equipped with a novel formulation for storage in model versions with reduced temporal representation. We test the performance of reduced models at penetration levels of wind and solar of 90%. Three measures for accuracy are used: (i) system cost, (ii) total capacity mix and (iii) regional capacity. We find that: (i) the system cost is well represented (~5% deviation from benchmark) with as few as ten representative days, (ii) the capacity mix is in general fairly well (~20% deviation) represented with 50 or more representative days, and (iii) the regional capacity mix displays large deviations (>50%) from benchmark for as many as 250 representative days. We conclude that modelers should be aware of the error margins when presenting results on these three aspects.

Today, due to recent developments in technology, children devote plenty of time for screen viewing. However, its harmful effects are not yet clear. The purpose of present study was to examine the associations among screen viewing and sleep duration, and body mass index (BMI) in under-five years old children. This cross-sectional study was conducted with 322 under-five healthy children that were selected using multistage stratified cluster sampling method in 2017. The data that were gathered by time-use diary method were analyzed using Kolmogorov-Smirnov test, Spearman correlation tests, multiple linear regression analysis, one-way ANCOVA, two-way ANCOVA. There was a negative correlation between screen time and sleep duration (rs = -0.42, p = 0.00), positive correlation between screen time and BMI (rs = 0.38, p = 0.00) and sleep duration negatively correlated with BMI (rs = -0.22, p = 0.00). screen viewing was a predictive factor for both sleep duration (β = -0.26, p = 0.00) and BMI (β = -0.26, p = 0.00). screen viewing had a significant impact on sleep duration (4, 314) = 5.02, P = 0.001) and BMI (F (4, 314) = 1.16, P=0.298). Results of this study indicated that screen viewing is related to sleep duration and BMI in under-five children. furthermore, screen time has an impact on sleep duration and BMI scores of children. findings of our study suggest that sleep duration negatively is associated with BMI in under-five-year-old children.

Favipiravir is a broad-spectrum inhibitor of viral RNA-dependent RNA polymerase (RdRp) currently being used to manage COVID-19 in several countries. By acting as a substrate for RdRp, favipiravir gets incorporated into the nascent viral RNA and prevents strand extension. A high mutation rate of SARS-CoV-2 RdRp may facilitate antigenic drift as an answer to the host immune response, thereby generating resistance of virus to favipiravir. Therefore, it is extremely crucial to predict potential mutational sites in the RdRp and the emergence of structural modifications contributing to drug resistance. Here, we used high-throughput interface-based protein design to generate >100,000 designs and identify mutation hotspot residues in the favipiravir-binding site of RdRp. Several mutants had lower binding affinities to favipiravir, out of which hotspot residues with a high propensity to undergo positive selection were identified. The results showed that the designs retained an average of 97 to 98% sequence identity, suggesting that SARS-CoV-2 can develop favipiravir resistance with just a few mutations. Notably, we observed that out of 134 mutations predicted designs, 63 specific mutations were already present in the CoV-GLUE database, thus attaining ~47% correlation match with the clinical sequencing data. The findings improve our understanding of the potential signatures of adaptation in SARS-CoV-2 against favipiravir and management of COVID-19. Furthermore, they can help develop exhaustive strategies for robust antiviral design and discovery.

Exercise affects various organs. However, its effects on nutrient digestion and absorption in the intestinal tract are not well understood. A few studies have reported that exercise training in-creases the expression of carbohydrate digestion and absorption molecules. Exercise was also shown to increase the concentration of blood glucagon like peptide-2(GLP-2), which regulates carbohydrate digestion and absorption in small intestinal epithelium. Therefore, we investigated the effects of exercise on intestinal digestion and absorption molecules and the levels of GLP-2. 6-wk-old of male mice were divided into 2 groups; sedentary (SED) and low-intensity exercise (LEx). LEx mice were required to run on a treadmill (12.5 m/min, 60 min), whereas SED mice rested. All mice were euthanized 1 h after exercise or rest and plasma, jejunum, ileum, and colon were sampled. Samples were analyzed using EIA and immunoblotting. The levels of plasma GLP-2 and the expression of the GLP-2 receptor, sucrase-isomaltase (SI), and glucose transporter (GLUT2) in the jejunum were increased in LEx group. We showed that acute low-intensity exer-cise affects the intestinal carbohydrate digestion and absorption molecules via GLP-2. Our results suggest that exercise might provide new benefits to the small intestine for people with intestinal frailty.

COVID-19 has emerged as deadly pandemic worldwide with no vaccine or suitable antiviral drugs to prevent or cure the disease. Because of the time-consuming process to develop new vaccines or antiviral agents, there has been a growing interest in repurposing some existing drugs to combat SARS-CoV-2. Vitamin D is known to be protective against acute respiratory distress syndrome (ARDS), pneumonia and cytokine storm. Recently it has been used as a repurposed drug for the treatment of H5N1 virus-induced lung injury. Circumstantial evidences indicate that people with low level of vitamin D are more susceptible to SARS-CoV-2. Although, vitamin D was suggested to interfere with viral replication, its interaction with any SARS-CoV-2 protein is unexplored yet. Beside this, ivermectin, a well-known anti-parasitic agent, exhibits potent anti-viral activities in vitro against viruses such as HIV-1 and dengue. Very recently, ivermectin has been found to reduce viral load of SARS-CoV-2 in vitro. We have analyzed available structures of SARS-CoV-2 proteins to identify probable binding partner(s) of vitamin D and ivermectin through knowledge-based docking studies and figured out possible implication of their binding in SARS-CoV-2 infection. Our observations suggest that the non-structural protein nsp7 possesses a potential site to house 25-hydroxyvitamin D3 (VDY) or the active form of Vitamin D, calcitrol. Binding of vitamin D with nsp7 likely to hamper the formation of nsp7-nsp8 complex which is required to bind with RNA dependent RNA polymerase (RdRP), nsp12 for optimal function. On the other hand, potential binding site of ivermectin has been identified in the S2 subunit of trimeric spike(S) glycoprotein of SARS-CoV-2. We propose that deeply inserted mode of ivermectin binding at three inter-subunit junctions may restrict large scale conformational changes of S2 helices which is necessary for efficient fusion of viral and host membrane. Our study, therefore, opens up avenues for further investigations to consider vitamin D and ivermectin as potential drugs against SARS-CoV-2.

We are using the book “Towards Quantum Gravity with an article by Claus Kiefer as to a quantum gravity interpretation of the density matrix in the early universe. The density matrix we are using is a one loop approximation, with inflaton value and potential terms, like V(phi) using the Padmanabhan values one can expect if the scale factor is a ~ a(Initial) times t ^ gamma , from early times . In doing so, we isolate out presuming a very small initial time step candidates initial time values which are from a polynomial for time values due to the Kiefer Density value.

In this paper, we study the Parisian time of a reflected Brownian motion with drift on a finite collection of rays. We derive the Laplace transform of the Parisian time using a recursive method, and provide an exact simulation algorithm to sample from the distribution of the Parisian time. The paper is motivated by the settlement delay in the real-time gross settlement (RTGS) system. Both the central bank and the participating banks in the system are concerned about the liquidity risk, and are interested in the first time that the duration of settlement delay exceeds a predefined limit, we reduce this problem to the calculation of the Parisian time. The Parisian time is also crucial in the pricing of Parisian type options; to this end, we will compare our results with the existing literature.

Future cyber-physical systems may extend over broad geographical areas, like cities or regions, thus requiring the deployment of large real-time networks. A strategy to guarantee predictable communication over such networks is to synthesize an offline time-triggered communication schedule. However, this synthesis problem is computationally hard (NP-complete), and existing approaches do not scale satisfactorily to the required network sizes. This article presents a segmented offline synthesis method which substantially reduces this limitation, being able to generate time-triggered schedules for large hybrid (wired and wireless) networks. We also present a series of algorithms and optimizations that increase the performance and compactness of the obtained schedules while solving some of the problems inherent to segmented approaches. We evaluate our approach on a set of realistic large-size multi-hop networks, significantly larger than those considered in the existing literature. The results show that our segmentation reduces the synthesis time up to two orders of magnitude.

In Newtonian mechanics, time as well as space are perceived as absolute entities. In 2 Einstein’s special relativity, time is frame dependent. Time is also affected by gravitational field 3 and as the field varies in space, time also varies throughout space. In the present article, a 4 thermodynamic-based time is investigated. The entity is called "irreversibility", which is generated 5 when availability (also known as exergy) is destroyed. Since each thermodynamic system may 6 generate different amount of irreversibility, this quantity is system dependent. The time’s arrow is 7 automatically satisfied, since irreversibility generation always proceeds in one direction (toward 8 future). We have demonstrated that, like common time, irreversibility is frame dependent, and 9 affected by gravity in the similar manner as the common time. For this reason, we propose to 10 assign the entity irreversibility of the system as thermodynamic time. A possible application of the 11 thermodynamic time is an interpretation and managing of the aging of biological systems. The 12 metabolic efficiency is related to the irreversibility of the chemical processes and affect the aging of 13 the system. Our sensation of time-flow may be attributed to the flow of availability and destruction 14 of it through the living system. It is shown by other authors that entropy generation (equivalent to 15 irreversibility) is a parameter for the human life span. Since the thermodynamic time is based on a 16 concept of thermodynamics that is universal, further applications to other subjects, such as biological 17 clock, telomere, and cosmology are possible.

With the great development of intelligent transportation systems (ITS), travel time prediction has attracted the attentions of many researchers and a large number of prediction methods have been developed. However, as an unavoidable topic, the predictability of travel time series is the basic premise for travel time prediction has received less attention than the methodology. Based on the analysis of the complexity of travel time series, this paper defines travel time predictability to express the probability of correct travel time prediction and proposes an entropy-based method to measure the upper bound of travel time predictability. Multiscale entropy is employed to quantify the complexity of travel time series, and the relationships between entropy and the upper bound of travel time predictability are presented. Empirical studies are made with vehicle trajectory data in an express road section. The effectiveness of time scales, tolerance, and series length to entropy and travel time predictability are analysis, and some valuable suggestions about the accuracy of travel time predictability are discussed. Finally, the comparisons between travel time predictability and actual prediction results from two prediction models, ARIMA and BPNN, are conducted. Experimental results demonstrate the validity and reliability of the proposed travel time predictability.

We explore the field equations in a 4-d complex space-time, in the same way, that general relativity does for our usual 4-d real space-time, forming this way, a new "general relativity" in C⁴ space-time, free of sources. Afterwards, by embedding our usual 4-d real space-time in C⁴ space-time, we describe geometrically the energy-momentum tensor T_μν as the lost geometric information of this embedding. We further give possible explanation of dark eld and dark energy.

The COVID-19 pandemic affects all parameters, especially health care professionals, drugs and medical supplies. The KERRA is a mixed medicinal plant capsule that is used for the treatment of patients with high fever with food and drug administration approved by FDA Thailand. Recently, KERRA showed quicker recovery for COVID-19 patients. Therefore, it is possible that some ingredients in KERRA could inhibit SARS-CoV-2. In this study, two important replication-related enzymes in SARS-CoV-2, a main protease and an RNA-dependent RNA polymerase (RdRp), were used to study the effect of KERRA. The results showed that KERRA inhibited the SARS-CoV-2 main protease and SARS-CoV-2 RdRp with IC50 values of 49.91 ± 1.75 ng/mL and 36.23 ± 5.23 µg/mL, respectively. KERRA displayed no cytotoxic activity on macrophage cells at concentrations lower than 1 mg/mL and exhibited anti-inflammatory activity. Additionally, KERRA was against a feline coronavirus (feline infectious peritonitis [FIP]) infection with an EC50 value of 134.3 g/mL. This study supports the potential use of KERRA as a candidate drug for COVID-19.

Here, I introduce a concept called autonomous selection to refer to a source of selection that is part of the individuals upon which it acts. The concept is motivated by a set of phenomena with the following characteristics: Natural selection shaped a variant (e.g., gene, epigenetic mark, or combination thereof) to act in a manner that reduces the frequency of one or more heritable traits of the individual in which it is located if those traits are detrimental to individual or group fitness. Phenomena with these characteristics are peculiar to traditional evolutionary theory but have been identified rather frequently in recent decades. They are also relevant to adaptive evolution: By reducing the frequency of a trait detrimental to fitness, the variant accelerates the evolution of adaptations, which allows its holders to adapt better to constantly changing environments. The variant is shaped by (natural) selection, but also does (autonomous) selection. Several phenomena with these characteristics have been invoked by proponents of the extended evolutionary synthesis (EES). The concept of autonomous selection helps resolve some of the controversy surrounding the EES: EES proponents call attention to the incompleteness of contemporary theory, emphasizing individuals’ processes that influence which adaptations those individuals evolve. I argue for the special importance of individuals’ processes that do not just influence those individuals’ adaptations, but also accelerate the adaptive evolution of those individuals. All known phenomena that fit this description are examples of autonomous selection. Other phenomena raised by EES proponents do not meet this threshold.

Based on the Expected Utility Theory and Regret Theory, the Extended Regret Theory (ERT) is proposed in this paper to study the optimal pricing strategy of retailers in e-commerce environment. Taking the diversity of sales channels and the uncertainty of consumers in e-commerce environment into consideration, author of the paper designs an extended regret utility function which comprehensively considers both pessimistic and optimistic attitudes of decision makers in retailing industry to describe their regret-avoidance behavior. According to the sensitivity analysis, it is found that the optimal retail price decreases as the consumer price sensitivity coefficient increases, yet does not show variation with changes of the consumers pessimism degree. Moreover, the optimal retail price(s) obtained under EUT, ERT and combination of EUT and ERT represent the same.

Akt1 is a proto-oncogene that is over active in most cancers. Akt1 activation requires phosphorylation at Thr308; phosphorylation at Ser473 further enhances catalytic activity. Akt1 activity is also regulated via interactions between the kinase domain and the N-terminal auto-inhibitory pleckstrin homology (PH) domain. As it was previously difficult to produce Akt1 in site-specifically phosphorylated forms, the contribution of each activating phosphorylation site to auto-inhibition was unknown. Using a combination of genetic code expansion and in vivo enzymatic phosphorylation, we produced Akt1 variants containing programmed phosphorylation to probe the interplay between Akt1 phosphorylation status and the auto-inhibitory function of the PH domain. Deletion of the PH domain increased the enzyme activity for all three phosphorylated Akt1 variants. For the doubly phosphorylated enzyme, deletion of the PH domain relieved auto-inhibition by 295-fold. We next found that phosphorylation at Ser473 provided resistance to chemical inhibition by Akti-1/2 inhibitor VIII. The Akti-1/2 inhibitor was most effective against pAkt1T308 and showed 4-fold decreased potency with Akt1 variants phosphorylated at Ser473. The data highlight the need to design more potent Akt1 inhibitors that are effective against the doubly phosphorylated and most pathogenic form of Akt1.

A new method for short circuit fault location is proposed based on instantaneous signal measurement and its derivatives, and is based on the retardation phenomena. The difference between the times in which a signal is registered in two detectors is used to locate the fault. Although a description of faults in terms of a lumped circuit is useful for elucidating the methods for detecting the fault. This description will not suffice to describe the fault signal propagation hence a distributed models is needed which is given in terms of the telegraph equations. Those equations are used to derive a transmission line transfer function, and an exact analytical description of the short circuit signal propagating in the transmission line is obtained. The analytical solution was verified both by numerical simulations and experimentally.

How to build an optimal model where three terms “time, causality, and entropy” will be interrelated in a most correct way? This task has a semantic and physical aspect. We give in this article the solution that is based only on elementary perception. In physics, we experience time with our senses as the duration of material change running in space. This fact is the standpoint for our model where causality is only a principle, it is not a physical actuality and entropy runs only in space and not in time. Time is merely a duration of entropy increasing and is entering existence when measured by the observer.

Taking into account the growing interest in microalgae to be used as raw material for biodiesel production, this research is aimed at analyzing the rheological behaviour of microalgae suspensions (Chlorella sp) at different culture times under eight different conditions (temperature, salinity and CO₂, NO₃ and PO₄ levels) in order to estimate the energy demands of each step, with the purpose of optimizing a continuous feed tubular bioreactor construction. For each condition, it was calculated the biomass and oil yields, so as to correlate these results with rheological parameters. The suspension results indicated that the microalgae Chlorella sp is a non-Newtonian material with dilatant characteristics; the processing time hardly exerted an influence on the rheograms of the suspension of the microalgae Chlorella sp, except for the simultaneous conditions of low salinity and low CO₂ content; NO₃ and PO₄ contents and the amount of supplements influenced the rheological parameters of the suspension of the microalgae Chlorella sp, when in low concentration of CO₂ and low salinity levels.

The alteration of natural land cover to impervious surfaces during development increases stormwater runoff. Stormwater Control Measures (SCMs) are used to manage water quantity and enhance water quality by restoring the hydrologic cycle altered by development. Often, SCMs have an outflow pipe to handle overflows or to manage the release of water detained when infiltration is not possible. Traditionally, these are static controls (e.g. a small orifice is used to restrict the volume of outflow), however, these systems can be improved by instituting real-time controls (RTC). RTC improve the functionality of SCMs by dynamically controlling outflows to adjust to environmental conditions. A major impediment to the widespread implementation of RTC is the high cost of installation and operation. This study utilized machine learning methods to develop a forecasting approach for the implementation of low-cost RTC that were implemented on a programmable gate of the outlet structure of a multi-stage basin in southeastern Pennsylvania. The goals were to decrease the peak flow exiting the basin during rain events, increase the volume of water detained, decrease the number of overtopping events, maintain healthy vegetation in the basin, and protect the downstream vegetation from erosion. Multiple popular data science algorithms were evaluated including multiple linear regression and long short-term memory. These algorithms were used with a dataset, which consisted of four years of historical sensor data, collected in 5-minute intervals, to train models to predict water levels to optimize operations. The accuracy of 30 models with three different methods of handling missing values were compared. A long short-term memory model configured with a 30-minute lead time produced the best results. Having an approximate same lag time of 30 minutes for the contributing drainage area of the SCM provided a sufficient RTC functioning period to improve the performance of the outlet structure.

Time series data are significant and are derived from temporal data, which involve real numbers representing values collected regularly over time. Time series have a great impact on many types of data. However, time series have anomalies. We introduce hybrid algorithm named novel matrix profile (NMP) to solve the all-pairs similarity search problem for time series data. The proposed NMP inherits the features from two state-of-the art algorithms: similarity time-series automatic multivariate prediction (STAMP), and short text online microblogging protocol (STOMP). The proposed algorithm caches the output in an easy-to-access fashion for single- and multidimensional data. The proposed NMP algorithm can be used on large data sets and generates approximate solutions of high quality in a reasonable time. The proposed NMP can also handle several data mining tasks. It is implemented on a Python platform. To determine its effectiveness, it is compared with the state-of-the-art matrix profile algorithms i.e., STAMP and STOMP. The results confirm that the proposed NMP provides higher accuracy than the compared algorithms.

The futures market plays a significant role in hedging and speculating by investors. Although various models and instruments are developed for real-time trading, it is difficult to realize profit by processing and trading a vast amount of real-time data. This study proposes a real-time index futures trading strategy that uses the pattern of KOSPI 200 index futures time series data. We construct a pattern matching trading system (PMTS) based on a dynamic time warping algorithm that recognizes patterns of market data movement in the morning and determines the afternoon's clearing strategy. We adopt 13 and 27 representative patterns and conduct simulations with various ranges of parameters to find optimal ones. Our experimental results show that the PMTS provides stable and effective trading strategies with relatively low trading frequencies. Investor communities that have sustained financial markets are able to make more efficient investments by using the PMTS. In this sense, the system developed in this paper is a sustainable investment technique and helps financial markets achieve efficient sustainability.

Markov chain Monte Carlo sampling propagators, including numerical integrators for stochastic dynamics, are central to the calculation of thermodynamic quantities and determination of structure for molecular systems. Efficiency is paramount, and to a great extent, this is determined by the integrated autocorrelation time (IAcT). This quantity varies depending on the observable that is being estimated. It is suggested that it is the maximum of the IAcT over all observables that is the relevant metric. Reviewed here is a method for estimating this quantity. For reversible propagators (which are those that satisfy detailed balance), the maximum IAcT is determined by the spectral gap in the forward transfer operator, but for irreversible propagators, the maximum IAcT can be far less than or greater than what might be inferred from the spectral gap. This is consistent with recent theoretical results (not to mention past practical experience) suggesting that irreversible propagators generally perform better if not much better than reversible ones. Typical irreversible propagators involve a parameter controlling the mix of ballistic and diffusive movement. To gain insight into the effect of the damping parameter for Langevin dynamics, its optimal value is obtained here for a multidimensional quadratic potential energy function.

The exact solutions in the wave form are derived for the time fractional KdV and the time fractional Burgers' equations in conformable fractional derivative sense. The fractional variable change using the fundamental properties of the conformable derivative reduces both equations to some nonlinear ODEs. The predicted solution is assumed to be a finite series form of a function satisfying a particular first-order ODE whose solution contains an exponential function in the denominator. The solutions are represented in the explicit forms and illustrated by some choices of the parameters for various fractional orders of the equations.

The Sine-Gordon expansion method is implemented to construct exact solutions some conformable time fractional equations in Regularized Long Wave(RLW)-class. Compatible wave transform reduces the governing equation to classical ordinary differential equation. The homogeneous balance procedure gives the order of the predicted polynomial-type solution that is inspired from well-known Sine-Gordon equation. The substitution of this solution follows the previous step. Equating the coefficients of the powers of predicted solution leads a system of algebraic equations. The solution of resultant system for coefficients gives the necessary relations among the parameters and the coefficients to be able construct the solutions. Some solutions are simulated for some particular choices of parameters.

Background: Digital health significantly affects healthcare delivery. Moreover, empirical studies on the utilization of telehealth in Dubai are limited. Accordingly, this study examines the utilization of telehealth services in Dubai Health Authority (DHA) facilities and the factors associated with telehealth appointment completion and turnaround time. Methods: This cross-sectional study examines patients who used telehealth services in DHA from 2020 through 2021 using 241,822 records. A binary logistic regression model was constructed to investigate the association between appointment turnaround time as a dependent variable and patient and visit characteristics as independent variables. Results: Of the total scheduled telehealth visits, more than three-quarter (78.55%) were completed. Older patients, non-Emiratis, patients who had their visits in 2020, patients who had video visits, and those who sought family medicine as a specialty had a shorter turn-around time to receive their appointment. Conclusions: This study identifies several characteristics associated with the turn-around time. Moreover, technological improvements focusing on specialties that can readily be addressed through telehealth and further research in this domain will improve service provision and support building an evidence base.

The principal aim of a spectral observer is twofold: the reconstruction of a signal of time via state estimation and the decomposition of such a signal into the frequencies that make it up. A spectral observer can be catalogued as an online algorithm for time-frequency analysis because is a method that can compute on the fly the Fourier transform (FT) of a signal, without having the entire signal available from the start. In this regard, this paper presents a novel spectral observer with an adjustable constant gain for reconstructing a given signal by means of the recursive identification of the coefficients of a Fourier series. The reconstruction or estimation of a signal in the context of this work means to find the coefficients of a linear combination of sines a cosines that fits a signal such that it can be reproduced. The design procedure of the spectral observer is presented along with the following applications: (1) the reconstruction of a simple periodical signal, (2) the approximation of both a square and a triangular signal, (3) the edge detection in signals by using the Fourier coefficients, (4) the fitting of the historical Bitcoin market data from 2014-12-01 to 2018-01-08 and (5) the estimation of a input force acting upon a Duffing oscillator. To round out this paper, we present a detailed discussion about the results of the applications as well as a comparative analysis of the proposed spectral observer vis-à-vis the Short Time Fourier Transform (STFT), which is a well-known method for time-frequency analysis.

Thrombin (factor IIa) and factor Xa (FXa) are key enzymes at the junction of the intrinsic and extrinsic coagulation pathways and are the most attractive pharmacological targets for the development of novel anticoagulants. Twenty non-amidino N²-thiophencarbonyl- and N²-tosyl anthranilamides 1-20 and six amidino N²-thiophencarbonyl- and N²-tosylanthranilamides 21-26 were synthesized and evaluated prothrombin time (PT) and activated partial thromboplastin time (aPTT) using human plasma at concentration 30 μg/mL in vitro. From these results, compounds 5, 9, and 21-23 were selected to study the further antithrombotic activity. The anticoagulant properties of 5, 9, and 21-23 significantly exhibited a concentration-dependent prolongation of in vitro PT and aPTT, in vivo bleeding time, and ex vivo clotting time. These compounds concentration-dependently inhibited the activities of thrombin and FXa and inhibited the generation of thrombin and FXa in human endothelial cells. In addition, data showed that 5, 9, and 21-23 significantly inhibited thrombin catalyzed fibrin polymerization and mouse platelet aggregation and inhibited platelet aggregation induced U46619 in vitro and ex vivo. N-(3'-Amidinophenyl)-2-((thiophen-2''-yl)carbonyl amino)benzamide (21) was most active.

The exact solutions of some conformable time fractional PDEs are presented explicitly. The modified Kudryashov method is applied to construct the solutions to the conformable time fractional Regularized Long Wave-Burgers (RLW-Burgers, potential Korteweg-de Vries (KdV) and clannish random walker's parabolic (CRWP) equations. Initially, the predicted solution in the finite series of a rational form of an exponential function is substituted to the ODE generated from the conformable time fractional PDE by using wave transformation. The coefficients used in the finite series are determined by solving the algebraic system derived from the coefficients of the powers of the predicted solution.

Introduction: The purpose of this study was to determine the normative values of muscles’ contractile properties, lateral symmetry, and the impact of aging on muscle contractility in gymnastics. Materials and Methods: A survey of 81 athletes from different disciplines was undertaken: MAG (n = 26), WAG (n = 28), and RG (n = 27). The athletes’ average age was 15.41 ± 5.03 years. We try to establish the normative values for contraction time (muscle pairs) in gymnastics for Slovenian athletes for ten skeletal muscles. Results: Athletes’ age affects contractility in a negative way. Differences between the duration of contractility and age were found in all disciplines: m. BF (r = 0.48, p < 0.001), m. TB (r = 0.37, p < 0.013), m. ES (r = 0.17, p < 0.025), m. VL (r = 0.36, p < 0.00) and m. VM (r = 0.40, p < 0.000) at a statistical significance of p < 0.05. Conclusions: A comparison between the left and right sides shows little asymmetry in WAG and that the occurrence of injuries is in the middle range. In RG we see a bigger deviation, which could trigger the emergence of pain or injury in m. BF (13%) and m. GL (14.5%), but in MAG the deviation is greater in m. BB (12%), m. BF (11%) and m. GM (13%).

The anomaly detection task is very important in computer science. And there are a lot of anomaly detection methods. Different from some thresholding methods, some unsupervised methods could make us get more accurate and faster result, which is the object of the project. In this paper, I tried to use EWMA and some other methods in two datasets: Webank time consuming indicators dataset and AIOps Challenge dataset. The paper consists nine parts: background of the project, related work, description of algorithms, implementation details, experimental setup and data sets used, experimental results and discussion, future directions, reference and meeting notes.

There is a long standing ‘two times problem’ in that a satisfactory reconciliation between the time of physics and that of psychology has not been realized. A partial solution to the past/present/future phenomenon has been successfully given by the Hartle information gathering and processing system (IGUS) view. That model IGUS robot is enhanced here for the entire ‘two times problem’ to deal with not only the temporal experiences of the flow of time but also those of manifest time. A dualistic robot is proposed which has a veridical system of temporal experiences that are compatible with various spacetime cosmologies. It also has an illusory system of corresponding temporal experiences. This dualistic IGUS robot was made possible by discovering temporal experience within the brain that correspond to those of physics. The dualistic theory suggests that the veridical system, as a result of evolution, begets the illusory system to enhance behavioral adaptation. Thus, there is just one fundamental physical time which the brain does, indeed, possess and then enhances with illusory counterparts. Therefore, there should no longer be a need to reify illusory temporal experiences as modern spacetime cosmologies tend to do. Physical time already resides within human time.

Divergences have become a very useful tool for measuring similarity (or dissimilarity) between probability distributions. Depending on the field of application a more appropriate measure may be necessary. In this paper we introduce a family of divergences we call gamma-divergences. They are based on the convexity property of the functions that generate them. We demonstrate that these divergences verify all the usually required properties, and we extend them to weighted probability distribution. We investigate their properties in the context of kernel theory. Finally, we apply our findings to the analysis of simulated and real time series.

We propose a geographical time-space model extending time-space relief cartography introduced by Mathis and L’Hostis [,,,]. The novelty of the model resides in the use of cones to describe the terrestrial surface instead of graph faces, and in the use of curves instead of broken segments for edges. The approach lies a the intersection of two domains involving graphic representation: cartography, and three dimensional computer graphics. We implement the model on the Chinese space. The Chinese geographical time-space of the reference year 2006 is produced by the combination and the confrontation of the fast air transport system and of the 7.5 times slower road transport system. Slower, short range flights are represented as curved lines above the earth surface with longer length than the geodesic, in order to account for a slower speed. The very steep slope of cones expresses the relative difficulty of crossing terrestrial time-space, as well as the comparably extreme efficiency of long-range flights for moving between cities. Finally, the whole image proposes a coherent representation of the geographical time-space where fast city to city transport is combined with slow terrestrial systems that allow to reach any location.

In this paper, we present a relapse based demonstrating way to deal with investigate various arrangement MTC information. A commonplace use of this displaying approach incorporates three stages: first, define a model that approximates the connection between quality articulation and trial factors, with boundaries consolidated to address the exploration premium; second, utilize least-squares and assessing condition methods to gauge boundaries and their relating standard blunders; third, register test insights, P-qualities and NFD as proportions of factual criticalness. The benefits of this methodology are as per the following. To begin with, it tends to the exploration interest in a particular, precise way, and maximally uses all the information and other important data. Second, it represents both orderly and irregular varieties related with the information, and the consequences of such examination give not just quality explicit data applicable to the exploration objective, yet additionally its dependability, in this way helping agents to settle on better choices for subsequent investigations. Third, this methodology is truly adaptable, and can undoubtedly be stretched out to different sorts of MTC considers or other microarray explores by detailing various models dependent on the test plan of the investigations.

Nowadays, security is a top priority. In fact, biometrics uses cutting-edge technologies to identify terrorists and criminals. But the practice of distinguishing humans based on intrinsic physical or behavior traits goes back thousands of years. With the widespread use of computers in the late 20th century, new possibilities for digital biometrics emerged and new technologies were generously used. Among these, we remember high resolution security video cameras and drones. So, the aim of the present project is to study and explain the features of these technologies, especially the ones of the the Phantom 4 Pro+ aircraft and analyze its operating methods in order to identify human faces during live streaming of videos. For this purpose, it will be used Paul Viola and Michael Jones’ face detection algorithm, which includes Haar features and cascade classifiers to identify faces, eyes and ears of an individual.

The influence of the film thickness and the substrate’s refractive index on the surface mode at the superstrate is an important study step that may help clearing some of the misunderstandings surrounding their propagation mechanism. A single sub-wavelength slit perforating a thin metallic film is among the simplest nanostructure capable of launching Surface Plasmon Polaritons on its surrounding surface when excited by an incident field. Here, the impact of the substrate and the film thickness on surface waves is investigated. When the thickness of the film is comparable to its skin depth, SPP waves from the substrate penetrate the film and emerge from the superstrate, creating a superposition of two SPP waves, that leads to a beat interference envelope with well-defined loci which are the function of both the drive frequency and the dielectric constant of the substrate/superstrate. As the film thickness is reduced to the SPP’s penetration depth, surface waves from optically denser dielectric/metal interface would dominate, leading to volume plasmons that propagate inside the film at optical frequencies. Interference of periodic volume charge density with the incident field over the film creates charge bundles that are periodic in space and time.

Differences between the quantum mechanical and relativistic concepts of time are explained by applying the strong equivalence principle to the electron in an atomic clock. The resulting clock model calls for the microscopic equations of motion of the electron to be formulated in Minkowski space, and for the photon to be described relativistically as a four-dimensional localization of energy. The resulting Lagrangian formulation of quantum mechanics is completely analogous to the more familiar nonrelativistic Hamiltonian model based on the Schrödinger equation. It accounts for the 720 degree rotation of a wave function as the absorption of one 360 degree electromagnetic wave cycle and the emission of another, yielding two wave cycles to correspond with one clock cycle. Because the properties of energy are universal the equations are able to be extended to include galaxies in spite of vast differences in lifetime. They show that symmetry exists between the electromagnetic fields of atoms and the gravitational fields of galaxies due to the presence in both of radial and transverse fields. The description of galaxy structure is fundamentally distinct because it is based on the conjugate variables energy and time.

Efficient use of the operating room (OR) is crucial for any hospital. One of the major inefficiencies in the OR is surgical cases not starting or finishing on time as scheduled. When a case is delayed, it affects all subsequent cases in that OR. This study uses discrete choice analysis to determine the significant factors, including team familiarity, that influence OR case on-time start and finish. A case is considered on-time if the documented procedure start and finish times are no more than 10 minutes after the scheduled start and finish times. The analysis uses surgical case data from a large tertiary referral hospital and academic center in Greenville, South Carolina. The case data includes all surgical cases (15,091) performed during regular workdays in 2013. Two binary logit models are developed: one for case on-time start and one for case on-time finish. Results indicate that higher team familiarity between surgeon and anesthesiologist, surgeon and circulating nurse, surgeon and scrub nurse, and surgeon and CRNA improve the likelihood of an OR case on-time start and on-time finish. This finding indicates that the OR scheduling staff in the study hospital make a concerted effort to schedule the surgical teams with members who have worked well together in the past.

This paper proposes a novel three-phase voltage source inverter dead-time compensation strategy for accurate compensation in wide current regions of the inverter. In particular, an analysis of the output voltage distortion of the inverter, which appears as parasitic components of the switches, has been conducted for proper voltage compensation in the low current region, and an on-line compensation voltage controller has been proposed. Also, a new trapezoidal compensation voltage implementation method using the current phase is proposed to simplify realizing the trapezoidal shape of the three-phase compensation voltages. Finally, when the proposed dead-time compensation strategy is applied, the maximum phase voltage magnitude in the linear modulation voltage regions is defined to achieve smooth operation even at high modulation index. Simulations and experiments were conducted to verify the performance of the proposed dead-time compensation scheme.

Starting from December 2019, coronavirus disease 2019 (COVID-19) has emerged as a once-in-a-century pandemic with deadly consequences, which urgently calls for new treatments, cures and supporting apparatuses. Remdesivir was reported by World Health Organization (WHO) as the most promising drug currently available for the treatment of COVID-19. Here, we use molecular dynamics simulations and free energy perturbation methods to study the inhibition mechanism of remdesivir to its target SARS-CoV-2 virus RNA-dependent RNA polymerase (RdRp). In the absence of a crystal structure of the SARS-CoV-2 RdRp, we first construct the homology model of this polymerase based on a previously available structure of SARS-CoV NSP12 RdRp (with a sequence identify of 95.8%). We then build the putative binding mode by aligning the remdesivir + RdRp complex to the ATP bound poliovirus RdRp. The putative binding structure is further optimized with molecular dynamics simulations and demonstrated to be stable, indicating a reasonable binding mode for remdesivir. The relative binding free energy of remdesivir is calculated to be -8.28 ± 0.65 kcal/mol, much stronger than the natural substrate ATP (-4.14 ± 0.89 kcal/mol) which is needed for the polymerization. The ~800-fold improvement in the K_d from remdesivir over ATP indicates an effective replacement of APT in blocking of the RdRp binding pocket. Key residues D618, S549 and R555 are found to be the contributors to the binding affinity of remdesivir. These findings demonstrate that remdesivir can potentially act as a SARS-CoV-2 RNA-chain terminator, effectively stopping its RNA reproduction, with key residues also identified for future lead optimization and/or drug resistance studies.

The high level of dengue virus (DENV) seroprevalence in areas where Zika virus (ZIKV) is circulating and the cross-reactivity between these two viruses have raised concerns on the risk of increased ZIKV disease severity for patients with a history of previous DENV infection. To determine the role of DENV pre-immunity in ZIKV infection, we analysed the T and B cell responses against ZIKV in donors with or without previous DENV infection. Using PBMCs from donors living in an endemic area in Colombia, we have identified, by interferon (IFN)-γ enzyme-linked immunospot (ELISPOT) assay, most of the immunodominant ZIKV T-cell epitopes in the non-structural proteins NS1, NS3 and NS5. Analyses of the T and B-cell responses in the same donors revealed a stronger T-cell response against peptides conserved between DENV and ZIKV, with a higher level of ZIKV-neutralizing antibodies in DENV-immune donors, in comparison with DENV-naïve donors. Strikingly, the potential for antibody mediated enhancement of ZIKV infection was reduced in donors with sequential DENV and ZIKV infection in comparison with donors with DENV infection only. Altogether, these data suggest that individuals with DENV immunity present improved immune responses against ZIKV.

The absolute time and relative time are defined in terms of the 4-D Euclidean space. Our universe is the 3-D x₁x₂x₃ quantized photon space which follows the absolute time simultaneity when the universe moves along the absolute time axis of ct. The length expansion of Dx = gDx₀ is derived under the condition of the absolute time (ct) simultaneity. From the similarity between this length expansion of Dx = gDx₀ and the energy increasing of E = gE₀, it is assumed that the energy is proportional to the particle size of Dx. The extension of this assumption to the 4-D Euclidean space gives the new definition that the particle energy (E) is the 4-D volume. Then, the particle mass energy is defined as E= mc² = cDtDV = gE₀. The masses of the elementary particles are originated from the 4-D warped volume of the photon space because the particle is the warped photon space with the velocity of v < c. Therefore, the Higgs boson concept in the standard model (SM) is not needed in the present 3-D quantized space model (TQSM). The scalar boson with the spin of zero, photon with the spin of 1 and graviton with the spin of 2 are the two-boson states. Therefore, the observed Higgs boson is reinterpreted as the two-boson state of the scalar boson with the spin of zero. The cosmic muon observation and twin paradox are explained by using the absolute time and relative time. The relative time is the observed time in the twin paradox and cosmic muon observation. In the twin paradox, a person who travels the long distance is more aged than a person on the earth in terms of the relative time ages because of the space and time conversion effect (STCE effect) of the moving space distance (x). But twins are in the same ages in terms of the absolute time without STCE effect. The fast-moving cosmic muon has the expanded half-life from the time expansion of the relative time. Also, the quantum entanglement and Pauli exclusion principle are explained. The quantum base of the photon space line connects two entangled particles. Two particles and quantum base system is fluctuated along the absolute time axis by the time clicking when one particle is measured. Another particle is instantly selected by the time clicking. This is called as the quantum entanglement. The photons which are the flat photon space with the constant speed of c along the space axis and absolute time axis have the 4-D photon velocity of c_eff = 2^0.5 c. Total 10-D Euclidean space including three 3-D quantized spaces and one absolute time axis is required for the electric charges (EC), lepton charges (CC) and color charges (CC) of the elementary particles. The 3-D photon space is very stiff along the absolute time (ct) axis and very soft along the space axes. The Coulomb force through the photons (2EM waves) of the space fluctuations is much stronger than the Gravitational force through the gravitons (G waves) of the time fluctuations between two electrons.

While increasing empirical evidence suggests that global time series forecasting models can achieve better forecasting performance than local ones, there is a research void regarding when and why the global models fail to provide a good forecast. This paper uses anomaly detection algorithms and Explainable Artificial Intelligence (XAI) to answer when and why a forecast should not be trusted. To address this issue, a dashboard was built to inform the user regarding (i) the relevance of the features for that particular forecast, (ii) which training samples most likely influenced the forecast outcome, (iii) why the forecast is considered an outlier, and (iv) provide a range of counterfactual examples to understand value changes, in the feature vector or the predicted value, can lead to a different outcome. Moreover, a modular architecture and a methodology were developed to iteratively remove noisy data instances from the train set, to enhance the overall global time series forecasting model performance. Finally, to test the effectiveness of the proposed approach, it was validated on two publicly available real-world datasets.

We propose a novel tensor-based formalism for inferring causal structures from time series. An information theoretical analysis of transfer entropy (TE), shows that TE results from transmission of information over a set of communication channels. Tensors are the mathematical equivalents of these multi-channel causal channels. A multi-channel causal channel is a generalization of a discrete memoryless channel (DMC). We consider a DMC as a single-channel causal channel. Investigation of a system comprising three variables shows that in our formalism, bivariate analysis suffices to differentiate between direct and indirect relations. For this to be true, we have to combine the output of multi-channel causal channels with the output of single-channel causal channels. We can understand this result when we consider the role of noise. Subsequent transmission of information over noisy channels can never result in less noisy transmission overall. This implies that a Data Processing Inequality (DPI) exists for transfer entropy.

RNA silencing serves key roles in a multitude of cellular processes, including development, stress responses, metabolism, and maintenance of genome integrity. Dicer, Argonaute (AGO), double-stranded RNA binding (DRB), RNA-dependent RNA polymerase (RDR) and DNA-dependent RNA polymerases known as Pol IV and Pol V form core components to trigger RNA silencing. Common bean (Phaseolus vulgaris) is an important staple crop worldwide. In this study, we aimed to unravel the components of the RNA-guided silencing pathway in this non-model plant taking advantage of the availability of two genome assemblies of Andean and Meso-American origin. We identified six PvDCLs, thirteen PvAGOs, 10 PvDRB, 5 PvRDR, in both genotypes, suggesting no recent gene amplification or deletion after the gene pool separation. In addition, we identified one PvNRPD1 and one PvNRPE1 encoding the largest subunits of Pol IV and Pol V, respectively. These genes were categorized into subgroups based on phylogenetic analyses. Comprehensive analyses of gene structure, genomic localization and similarity among these genes were performed. Their expression patterns were investigated by means of expression models in different organs using online data and quantitative RT-PCR after pathogen infection. Several of the candidate genes were up-regulated after infection with the fungus Colletotrichum lindemuthianum.

External quantum efficiency of industrial-grade green InGaN light-emitting diodes (LEDs) has been measured in a wide range of operating currents at various temperatures from 13 K to 300 K. Unlike blue LEDs, the efficiency as a function of current is found to have a multi-peak character, which could not be fitted by a simple ABC-model. This observation correlated with splitting of LED emission spectra into two peaks at certain currents. The characterization data are interpreted in terms of non-uniformity of the LED active region, which is tentatively attributed to extended defects like V-pits. We suggest a new approach to evaluation of temperature-dependent light extraction and internal quantum efficiencies taking into account the active region non-uniformity. As a result, the temperature dependence of light extraction and internal quantum efficiencies have been evaluated in the temperature range mentioned above and compared with those of blue LEDs.