Gene signatures to therapeutics:Assessing the potential of ivermectin against t(4;14)multiple myeloma

BACKGROUND Multiple myeloma(MM)is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow.The translocation,(t)(4;14),results in high-risk MM with limited treatment alternatives.Thus,there is an urgent need for identification and validation of potential treatments for this MM subtype.Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets.AIM To elucidate the molecular basis and search for potential effective drugs of t(4;14)MM subtype by employing a comprehensive approach.METHODS The transcriptional signature of t(4;14)MM was sourced from the Gene Expression Omnibus.Two datasets,GSE16558 and GSE116294,which included 17 and 15 t(4;14)MM bone marrow samples,and five and four normal bone marrow samples,respectively.After the differentially expressed genes were identified,the Cytohubba tool was used to screen for hub genes.Then,the hub genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis.Using the STRING database and Cytoscape,protein–protein interaction networks and core targets were identified.Potential small-molecule drugs were identified and validated using the Connectivity Map database and molecular docking analysis,respectively.RESULTS In this study,a total of 258 differentially expressed genes with enriched functions in cancer pathways,namely cytokine receptor interactions,nuclear factor(NF)-κB signaling pathway,lipid metabolism,atherosclerosis,and Hippo signaling pathway,were identified.Ten hub genes(cd45,vcam1,ccl3,cd56,app,cd48,btk,ccr2,cybb,and cxcl12)were identified.Nine drugs,including ivermectin,deforolimus,and isoliquiritigenin,were predicted by the Connectivity Map database to have potential therapeutic effects on t(4;14)MM.In molecular docking,ivermectin showed strong binding affinity to all 10 identified targets,especially cd45 and cybb.Ivermectin inhibited t(4;14)MM cell growth via the NF-κB pathway and induced MM cell apoptosis in vitro.Furthermore,ivermectin increased reactive oxygen species accumulation and altered the mitochondrial membrane potential in t(4;14)MM cells.CONCLUSION Collectively,the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14)MM diagnosis and treatment,with ivermectin emerging as a potential therapeutic alternative.

Proof of Riemann Conjecture Based on Contradiction between Xi-Function and Its Product Expression

Riemann proved three results: analytically continue ζ(s) over the whole complex plane s =σ + it with a pole s =1;(Theorem A) functional equation ξ(t) = G(s0)ζ (s0), s0 =1/2 + it and (Theorem B) product expression ξ1(t) by all roots of ξ(t). He stated Riemann conjecture (RC): All roots of ξ (t) are real. We find a mistake of Riemann: he used the same notation ξ(t) in two theorems. Theorem B must contain complex roots;it conflicts with RC. Thus theorem B can only be used by contradiction. Our research can be completed on s0 =1/2 + it. Using all real roots rk and (true) complex roots zj = tj + iaj of ξ (z), define product expressions w(t), w(0) =ξ(0) and Q(t) > 0, Q(0) =1 respectively, so ξ1(t) = w(t)Q(t). Define infinite point-set L(ω) = {t : t ≥10 and |ζ(s0)| =ω} for small ω > 0. If ξ(t) has complex roots, then ω =ωQ(t) on L(ω). Finally in a large interval of the first module |z1|>>1, we can find many points t ∈ L(ω) to make Q(t) . This contraction proves RC. In addition, Riemann hypothesis (RH) ζ for also holds, but it cannot be proved by ζ.

Expression pattern and function analyses of the MADS thranscription factor genes in wheat(Triticum aestivum L.) under phosphorusstarvation condition

supported by the National Natural Science Foundation of China （31201674 and 31371618）;the National Transgenic Major Program, China （2011ZX08008）

Reconfiguration of face expressions based on the discrete capture data of radial basis function interpolation

Compactly supported radial basis function can enable the coefficient matrix of solving weigh linear system to have a sparse banded structure, thereby reducing the complexity of the algorithm. Firstly, based on the compactly supported radial basis function, the paper makes the complex quadratic function （Multiquadric, MQ for short） to be transformed and proposes a class of compactly supported MQ function. Secondly, the paper describes a method that interpolates discrete motion capture data to solve the motion vectors of the interpolation points and they are used in facial expression reconstruction. Finally, according to this characteris- tic of the uneven distribution of the face markers, the markers are numbered and grouped in accordance with the density level, and then be interpolated in line with each group. The approach not only ensures the accuracy of the deformation of face local area and smoothness, but also reduces the time complexity of computing.

THE IMPROVEMENT OF THE GENERAL EXPRESSION FOR THE STRESS FUNCTION φ OF THE TWO-DIMENSIONAL PROBLEM

In this paper, it is pointed that the general expression for the stress function of the plane problem in polar coordinates is incomplete. The problems of the curved bar with an arbitrary distributive load at the boundries can't he solved by this stress function. For this reason, we suggest two new stress functions and put them into the general expression. Then, the problems of the curved bar applied with an arbitrary distributive load at r=a,b boundaries can be solved. This is a new stress function including geometric boundary constants.

Expression and functional identification of the hypothetical adhesin P32 from Mycoplasma genitalium

Mycoplasma genitalium is the main causative agent for non-gonococcal and non-chlamydial urethritis. P32 is the putative surface-exposed membrane protein of M. genitalium and it has substaintial identity in amino acid sequence with adhesin protein P30 from M. pnewnoniae. Since M. pneumoniae mutants lacking P30 protein is defective in cytadherence, P32 protein has been proposed to be an essential adhesin implicated in the adherence of M. genitalium to host cells. The prokaryotic expression vector pET-30 ( + )/p32 was constructed in the present study, and the recombinant protein was expressed in E. coli and purified under denaturing condition. As demonstrated by the immunoblotting analysis, the recombinant protein could react with rabbit antisera against M. genitalium, and adherence inhibition assays were petformed with antisera against this recombinant protein. It was demonstrated that P32 protein apperared to be an adhesion protein of M. genitalium, thus providing the experimental basis for better understanding of the pathogenesis of M. genitalium infection and for the development of the related vaccines against the infection.

Numerical Treatments and Applications of the 3D Transient Green Function

How to evaluate time-domain Green function and its gradients efficiently is the key problem to analyze ship hydrodynamics in time domain. Based on the Bessel function, an Ordinary Differential Equation （ODE） was derived for time-domain Green function and its gradients in this paper. A new efficient calculation method based on solving ODE is proposed. It has been demonstrated by the numerical calculation that this method can improve the precision of the time-domain Green function. Numeiical research indicates that it is efficient to solve the hydrodynamic problems.

Genome-wide identification,phylogeny and expression analysis of the SBP-box gene family in maize(Zea mays)

The SQUAMOSA promoter binding protein （SBP）-box genes encode a kind of plant-specific transcription factors （TFs） and play important roles in the regulation of plant development. In this study, a genome-wide characterization of this family was conducted in maize （Zea mays）. Thirty-one SBP-box genes were identified to be distributed in nine chromosomes and 16 of them were complementary to the mature ZmmiR156 sequences. All the Z. mays SBP （ZmSBP） genes were classified into two clusters with eight subgroups according to the phylogenetic analysis of proteins, which were consistent with the pattern of exon-intron structures. The phylogenetic tree of the ZmSBP, Oryza sativa SBP-like （OsSPL） and Arabidopsis thaliana SBP-like （AtSPL） genes were constructed and all the SBP-box genes were divided into eight groups, which was the same as the classification of ZmSBP genes. The comparision of the expression profiles of all SBP-box genes in these three species indicated that most orthologous genes had similar expression patterns. The results from this study provided a basic understanding of the ZmSBP genes and might facilitate future researches for elucidating the SBP-box genes function in maize.

Transcriptome-based identification and expression analysis of the glutathione S-transferase(GST)family in tree peony reveals a likely role in anthocyanin transport

For red-flowered cultivars of tree peony(Paeonia suffruticosa),anthocyanin content is a critical factor determining the different petal pigmentations.Glutathione S-transferases(GSTs)are ubiquitous and multifunctional conjugating proteins that may be responsible for the transport of anthocyanin pigments from the cytoplasm to vacuole.The underlying function of the GST family in tree peony,however,remains unclear.In this study,we systematically isolated and identified a total of 54 putative full-length Ps GST genes through a combination of bioinformatics approaches from transcriptome databases.Intraspecific phylogenetic analyses revealed extensive differentiation in their coding sequences and divided them into 10 of the 14 known classes of plant GSTs.The phylogenetic relationships,evolutionary characteristics,protein domain,and motif organization were clearly conserved among the different phylogenetic subclasses.The results of the RNA-seq and quantitative real-time polymerase chain reaction experiments exhibited extensive variation in gene expression profiles among different developmental stages and varieties.Furthermore,the phylogenetic relationships,expression profiles,protein interactions,weighted gene co-expression network analysis,and correlation analysis results suggested that PsGSTF3(Unigene 0064200)is a candidate participant in anthocyanin transport and the promotion of pigment accumulation,exhibiting a strong positive correlation with anthocyanin content among different tissues(r=0.908**)and an increasing rate of anthocyanin content during the flower developmental process(r=0.961*).These results furthered our understanding of the transport and accumulation functions of the GST family as well as the enhancement of tree peony breeding through molecular biology techniques.

Characteristic Functional Structure of Infinitesimal Symmetry Transformations for Nonholonomic System

It was proved that velocity-dependent infinitesima l symmetry transformations of nonholonomic systems have a characteristic functio nal structure, which could be formulated by means of an auxiliary symmetry tra nsformation function and is manifestly dependent upon constants of motion of th e system. An example was given to illustrate the applicability of the results.

Building up a general selection strategy and catalytic performance prediction expressions of heteronuclear double-atom catalysts for N_(2)reduction

The severe environmental problems and the demand for energy urgently require electrocatalysis to replace Haber-Bosch for the nitrogen reduction reaction(NRR).The descriptors and important properties of single-atom and homonuclear double-atom catalysts have been preliminarily explored,but the relationship between the inherent properties and catalytic activity of heteronuclear double-atom catalysts with better performance remains unclear.Therefore,it is very significant to explore the prediction expressions of catalytic activity of heteronuclear double-atom catalysts based on their inherent properties and find the rule for selecting catalytic centers.Herein,by summarizing the free energy for the key steps of NRR on 55 catalysts calculated through the first-principle,the expressions of predicting the free energy and the corresponding descriptors are deduced by the machine learning,and the strategy for selecting the appropriate catalytic center is proposed.The selection strategy for the central atom of heteronuclear double-atom catalysts is that the atomic number of central B atom should be between group VB and VIIIB,and the electron difference between central A atom and B atom should be large enough,and the selectivity of NRR or hydrogen evolution reaction(HER)could be calculated through the prediction formula.Moreover,five catalysts are screened to have low limiting potential and excellent selectivity,and are further analyzed by electron transfer.This work explores the relationship between the inherent properties of heteronuclear double-atom catalysts and the catalytic activity,and puts forward the rules for selecting the heteronuclear double-atom catalytic center,which has guiding significance for the experiment.

Renin and angiotensinogen expression and functions in growth and apoptosis of human glioblastoma

The expression and function in growth and apoptosis of the renin-angiotensin system(RAS)was evaluated inhuman glioblastoma.Renin and angiotensinogen(AGT)mRNAs and proteins were found by in situ hybridisationand immunohistochemistry in glioblastoma cells.Angiotensinogen was present in glioblastoma cystic fluids.Thus,human glioblastoma cells produce renin and AGT and secrete AGT.Human glioblastoma and glioblastoma cellsexpressed renin,AGT,renin receptor,AT(2)and/or AT(1)mRNAs and proteins determined by RT-PCR and/

Molecular characterization, expression and function analysis of eukaryotic translation initiation factor(eIF1A) in Mangifera indica

Eukaryotic translation initiation factor 1A(eIF1A)functions as an important regulatory factor of protein synthesis and plays a crucial role in responses to abiotic stresses in plants.However,little is known about the eIF1A gene involved in fruit development and stress response of mango.In this study,the MieIF1A-b gene was isolated from Mangifera indica,and contains a 435-bp open reading frame,which encodes a putative protein of 144 amino acids(GenBank accession number:KP676599).The predicted MieIF1A-b protein had a molecular weight of 16.39 kDa with a pI of 4.6.Sequence homology analysis showed that MieIF1A-b shared high homology with Elaeis guineensis,Manihot esculenta,and Populus trichocarpa,with 96 and 95%identity,respectively.Quantitative reverse transcriptative PCR(qRT-PCR)analyses indicated that MieIF1A-b was expressed in all tested tissues,and had the highest expression level in fruit 80 d after flowering.The expression of MieIF1A-b was obviously regulated by NaCl and H2O2 treatments in leaves.Functional analysis indicated that the overexpression of MieIF1A-b in transgenic Arabidopsis thaliana enhanced the growth,phenotype and salinity tolerance compared with wild-type(WT)plants.The results indicated that MieIF1A-b may be correlated with the control of fruit development and salt adaptation,and it was a candidate gene for abiotic stress in mango.

IMPROVEMENT OF THE ALGORITHM PRINCIPLES FOR MINIMIZATION OF MULTI-OUTPUT FUNCTIONS

In this paper,the application of extraction principle for logic function minimiza-tion to multi-output case is studied.A defect in original algorithm in dealing with multi-outputextrema is made up,and on this base,three kinds of less-than terms in different conditions aredefined.In addition,three kinds of generalized definition of less-than terms are given,so as to findout more efficiently the covers with minimal number of terms and irredundant function outputs.This work makes the multi-output extraction principle closer to perfection.An algorithm basedon the work is presented.

Expression and Regulation of Plant Amino Acid Transporters and Their Application in Crop Genetic Improvement

Amino acid transporters( AATs) play an important role in transport process of various amino acids,which are indispensable in plant growth and development,while many putative AATs have been identified and the complete genomic sequences of the important plants have already been completed by splicing and assembling. There is still little knowledge about the expression,regulation and various biological functions of AATs in plants,including the major food crops. This study mainly reviewed the expression,regulation and various biological functions of AATs in plants,and the application of AATs in crop genetic improvement was also prospected. Thus,this review will provide important information for genetic improvement of staple food crops in plants.

The Advertisement Translation Based on the Prototype Theory

Based on the Prototype Theory,the prototypical feature of advertisement is found to be the combination of three language functions:the informative function,the expressive function,and the vocative function.The advertisement translation means the adjustment of the informative function and the expressive function according to the differences between languages or cultures in order to maximize the vocative function.The faithful translation is the closest to the prototype of the source text but not necessarily the best translation.

Different levels of facial expression recognition in patients with firstepisode schizophrenia:A functional MRI study

Background The impairment of facial expression recognition has become a biomarker for early identification of first-episode schizophrenia, and this kind of research is increasing.Aims To explore the differences in brain area activation using different degrees of disgusted facial expression recognition in antipsychotic-na?ve patients with firstepisode schizophrenia and healthy controls.Methods In this study, facial expression recognition tests were performed on 30 first-episode, antipsychoticna?ve patients with schizophrenia(treatment group) and 30 healthy subjects(control group) with matched age, educational attainment and gender. Functional MRI was used for comparing the differences of the brain areas of activation between the two groups.Results The average response time difference between the patient group and the control group in the ‘high degree of disgust' facial expression recognition task was statistically significant(1.359(0.408)/2.193(0.625), F=26.65, p<0.001), and the correct recognition rate of the treatment group was lower than that of the control group(41.05(22.25)/59.84(13.91, F=19.81, p<0.001). Compared with the control group, the left thalamus, right lingual gyrus and right middle temporal gyrus were negatively activated in the patients with first-episode schizophrenia in the ‘high degree of disgust' emotion recognition, and there was a significant activation in the left and right middle temporal gyrus and the right caudate nucleus. However, there was no significant activation difference in the ‘low degree of disgust' recognition.Conclusions In patients with first-episode schizophrenia, the areas of facial recognition impairment are significantly different in different degrees of disgust facial expression recognition.

Effect of a Natural Inulin-Containing Product, “Kikuimo Extract” on Intestinal Microbes and Gene Expression in the Liver and Adipose Tissue of Menopausal Monkeys

Inulin is a soluble and indigestible fiber derived from natural plants such as Jerusalem artichoke (Helianthus tuberosus), “Kikuimo”. In the current study, a nutrigenomics approach was utilized to evaluate the in vivo function of “Kikuimo Extract” (KE) in ovariectomized cynomolgus macaque, a post-menopausal non-human primate model. KE was administered orally before feeding, for 3 months for the following examinations: 1) the effect of KE on intestinal microbes was examined by quantitative analyses of the intestinal bacteria using real-time PCR with DNA extracted from monkey feces;2) the effect of KE on gene expression was investigated by real-time RT-PCR using RNA extracted from both the liver and adipose tissue of the monkeys. KE administration modulated menopause-mediated altered microbes to increase Lactobacilli, Veillonella, and Bacteroides in all monkeys. KE administration regulated the altered expression of functional genes, SCAP, LDLR, and LXRA (lipid metabolism);GLUT-4 (glucose transport);CYP1A1 and CYP1A2 (drug metabolism);and CYP-17-2 and CYP-19-2 (E2 synthesis) in the menopausal monkeys. In menopausal monkeys, KE showed potent prebiotic effect on beneficial microflora and regulating effect on altered expression of functional genes associated with metabolism and E2 production. Thus, KE appears to be a practical functional food that alleviates the altered conditions of intestinal microbes and gene expression in the liver and adipose tissue in a menopausal state.

Functional near-infrared spectroscopy can detect low-frequency hemodynamic oscillations in the prefrontal cortex during steady-state visual evoked potentialinducing periodic facial expression stimuli presentation

Brain oscillations are vital to cognitive functions,while disrupted oscillatory activity is linked to various brain disorders.Although high-frequency neural oscillations(>1 Hz)have been extensively studied in cognition,the neural mechanisms underlying low-frequency hemodynamic oscillations(LFHO)<1 Hz have not yet been fully explored.One way to examine oscillatory neural dynamics is to use a facial expression(FE)paradigm to induce steady-state visual evoked potentials(SSVEPs),which has been used in electroencephalography studies of high-frequency brain oscillation activity.In this study,LFHO during SSVEP-inducing periodic flickering stimuli presentation were inspected using functional near-infrared spectroscopy(fNIRS),in which hemodynamic responses in the prefrontal cortex were recorded while participants were passively viewing dynamic FEs flickering at 0.2 Hz.The fast Fourier analysis results demonstrated that the power exhibited monochronic peaks at 0.2 Hz across all channels,indicating that the periodic events successfully elicited LFHO in the prefrontal cortex.More importantly,measurement of LFHO can effectively distinguish the brain activation difference between different cognitive conditions,with happy FE presentation showing greater LFHO power than neutral FE presentation.These results demonstrate that stimuli flashing at a given frequency can induce LFHO in the prefrontal cortex,which provides new insights into the cognitive mechanisms involved in slow oscillation.

The Pragmatics of Space Expressions in Spoken Jordanian Arabic

This study aims at studying space expressions in Spoken Jordanian Arabic （SJA）. Moreover, it aims at discussingthe pragmatics of space expressions in SJA. The researchers use two methods to collect colloquial spaceexpressions. Firstly, the researchers use eight specific images for a little girl who is asked to determine her position.Secondly, space expressions are extracted through unstructured interviews and general observations. It has beenfound that using space expressions is vital for speakers. Moreover, some space expressions do not carry a pragmaticfunction. Some of space expressions may express different pragmatic functions, such as hospitality, threat, andencouragement. Some of the colloquial space expressions are culture-specific; they would not be clear apart fromtheir culture, since they might not be found in another dialect or language.