Limited validity of Mayo endoscopic subscore in ulcerative colitis with concomitant primary sclerosing cholangitis

BACKGROUND Ulcerative colitis(UC)with concomitant primary sclerosing cholangitis(PSC)represents a distinct disease entity(PSC-UC).Mayo endoscopic subscore(MES)is a standard tool for assessing disease activity in UC but its relevance in PSC-UC remains unclear.AIM To assess the accuracy of MES in UC and PSC-UC patients,we performed histological scoring using Nancy histological index(NHI).METHODS MES was assessed in 30 PSC-UC and 29 UC adult patients during endoscopy.NHI and inflammation were evaluated in biopsies from the cecum,rectum,and terminal ileum.In addition,perinuclear anti-neutrophil cytoplasmic antibodies,fecal calprotectin,body mass index,and other relevant clinical characteristics were collected.RESULTS The median MES and NHI were similar for UC patients(MES grade 2 and NHI grade 2 in the rectum)but were different for PSC-UC patients(MES grade 0 and NHI grade 2 in the cecum).There was a correlation between MES and NHI for UC patients(Spearman's r=0.40,P=0.029)but not for PSC-UC patients.Histopathological examination revealed persistent microscopic inflammation in 88%of PSC-UC patients with MES grade 0(46%of all PSC-UC patients).Moreover,MES overestimated the severity of active inflammation in an additional 11%of PSCUC patients.CONCLUSION MES insufficiently identifies microscopic inflammation in PSC-UC.This indicates that histological evaluation should become a routine procedure of the diagnostic and grading system in both PSC-UC and PSC.

Beta thalassemia syndromes:New insights

Beta thalassemia(β-thalassemia)syndromes are a heterogeneous group of inherited hemoglobinopathies caused by molecular defects in the beta-globin gene that lead to the impaired synthesis of beta-globin chains of the hemoglobin.The hallmarks of the disease include ineffective erythropoiesis,chronic hemolytic anemia,and iron overload.Clinical presentation ranges from asymptomatic carriers to severe anemia requiring lifelong blood transfusions with subsequent devastating complications.The management of patients with severeβ-thalassemia represents a global health problem,particularly in low-income countries.Until recently,management strategies were limited to regular transfusions and iron chelation therapy,with allogeneic hematopoietic stem cell transplantation available only for a subset of patients.Better understanding of the underlying pathophysiological mechanisms ofβ-thalassemia syndromes and associated clinical phenotypes has paved the way for novel therapeutic options,including pharmacologic enhancers of effective erythropoiesis and gene therapy.

Role of microRNAs in translation regulation and cancer

MicroRNAs(miRNAs) are pervasively expressed and regulate most biological functions. They function by modulating transcriptional and translational programs and therefore they orchestrate both physiological and pathological processes, such as development, cell differentiation, proliferation, apoptosis and tumor growth. miRNAs work as small guide molecules in RNA silencing, by negatively regulating the expression of several genes both at mRNA and protein level, by degrading their mRNA target and/or by silencing translation. One of the most recent advances in the field is the comprehension of their role in oncogenesis. The number of miRNA genes is increasing and an alteration in the level of miRNAs is involved in the initiation, progression and metastases formation of several tumors. Some tumor types show a distinct miRNA signature that distinguishes them from normal tissues and from other cancer types. Genetic and biochemical evidence supports the essential role of miRNAs in tumor development. Although the abnormal expression of miRNAs in cancer cells is a widely accepted phenomenon, the cause of this dysregulation is still unknown. Here, we discuss the biogenesis of miRNAs, focusing on the mechanisms by which they regulate protein synthesis. In addition we debate on their role in cancer, highlighting their potential to become therapeutic targets.

Interplay of SOX transcription factors and microRNAs in the brain under physiological and pathological conditions

Precise tuning of gene expression,accomplished by regulato ry networks of transcription factors,epigenetic modifiers,and microRNAs,is crucial for the proper neural development and function of the brain cells.The SOX transcription factors are involved in regulating diverse cellular processes during embryonic and adult neurogenesis,such as maintaining the cell stemness,cell prolife ration,cell fate decisions,and terminal diffe rentiation into neurons and glial cells.MicroRNAs represent a class of small non-coding RNAs that play important roles in the regulation of gene expression.Together with other gene regulatory factors,microRNAs regulate different processes during neurogenesis and orchestrate the spatial and temporal expression important for neurodevelopment.The emerging data point to a complex regulatory network between SOX transcription factors and microRNAs that govern distinct cellular activities in the developing and adult brain.Deregulated SOX/mic roRNA interplay in signaling pathways that influence the homeostasis and plasticity in the brain has been revealed in various brain pathologies,including neurodegenerative disorders,traumatic brain injury,and cancer.Therapeutic strategies that target SOX/microRNA interplay have emerged in recent years as a promising tool to target neural tissue regeneration and enhance neuro restoration.N umerous studies have confirmed complex intera ctions between microRNAs and SOX-specific mRNAs regulating key features of glioblastoma.Keeping in mind the crucial roles of SOX genes and microRNAs in neural development,we focus this review on SOX/microRNAs interplay in the brain during development and adulthood in physiological and pathological conditions.Special focus was made on their interplay in brain pathologies to summarize current knowledge and highlight potential future development of molecular therapies.

Novel mutation in the ligand-binding domain of the androgen receptor gene （1790p） associated with complete androgen insensitivity syndrome

Mutations in the X-linked androgen receptor （AR） gene cause androgen insensitivity syndrome （AIS）, resulting in an impaired embryonic sex differentiation in 46,XY genetic men. Complete androgen insensitivity （CAIS） produces a female external phenotype, whereas cases with partial androgen insensitivity （PALS） have various ambiguities of the genitalia. Mild androgen insensitivity （MAIS） is characterized by undermasculinization and gynecomastia. Here we describe a 2-month-old 46,XY female patient, with all of the characteristics of CAIS. Defects in testosterone （T） and dihydrotestosterone （DHT） synthesis were excluded. Sequencing of the AR gene showed the presence in exon 6 of a T to C transition in the second base of codon 790, nucleotide position 2369, causing a novel missense Leu790Pro mutation in the ligand-binding domain of the AR protein. The identification of a novel AR mutation in a girl with CAIS provides significant information due to the importance of missense mutations in the ligand-binding domain of the AR, which are able to induce functional abnormalities in the androgen binding capability, stabilization of active conformation, or interaction with coactivators.

Identification of SARS-CoV-2 by gold nanoparticles

The SARS-CoV-2 outbreaks highlighted the need for effective,reliable,fast,easy-to-do and cheap diagnostics procedures.We pragmatically experienced that an early positive-case detection,inevitably coupled with a mass vaccination campaign,is a milestone to control the COVID-19 pandemic.Gold nanoparticles(AuNPs)can indeed play a crucial role in this context,as their physicochemical,optics and electronics properties are being extensively used in photothermal therapy(PTT),radiation therapy(RT),drug delivery and diagnostic.AuNPs can be synthesized by several approaches to obtain different sizes and shapes that can be easily functionalized with many kinds of molecules such as antibodies,proteins,probes,and lipids.In addition,AuNPs showed high biocompatibility making them useful tool in medicine field.We thus reviewed here the most relevant evidence on AuNPs as effective way to detect the presence of SARS-CoV-2 antigens.We trust future diagnostic efforts must take this‘old-fashioned’nanotechnology tool into consideration for the development and commercialization of reliable and feasible detection kits.

A New Generation of Drugs: Synthetic Peptides Based on Natural Regulatory Peptides

Natural regulatory peptides are biologically active compounds that are produced by various cells and provide a link among the main regulatory systems of the body. The field of research into the biologic activity of endogenous regulatory peptides is extremely vast. These peptides affect the cardiovascular, immune, reproductive, endocrine, digestive, and other systems, alter energy metabolism, and are especially effective in the regulation of the central nervous system. Despite of the wide range of preventive and therapeutic effects of natural regulatory peptides and proteins, their application in clinical practice is difficult. This is primarily because of their extreme instability, as they are rapidly degraded by proteases of the gastrointestinal tract, blood, cerebrospinal fluid, and other biologic media. Compounds with higher stability (i.e., a considerably longer half-life compared with that of natural molecules) and the ability to provide a directional effect on the various body systems were obtained from modifications of endogenous regulatory peptides. Synthetic analogs of regulatory peptides, as a rule, contain only natural amino acids in their composition, and their biodegradation does not lead to the formation of toxic products;thus, they have fewer side effects. This review focuses on the consideration of two synthetic regulatory peptides, Semax and Selank, which were the bases for the creation of new drugs that are used effectively in the treatment of various diseases of the nervous system. The synthetic analog of an adrenocorticotropic hormone 4-10 fragment (ACTH4-10) Semax is a powerful neuroprotective agent that is particularly effective as a therapy for stroke. Selank was synthesized on the basis of the natural immunomodulator tuftsin. Selank is a powerful anxiolytic that is used as a therapy for generalized anxiety disorder and neurasthenia without sedative and muscle-relaxant effects. This review presents the results of research aimed at studying the influence of these peptides on the transcriptome of brain cells. The problems of drugs developed based on the clinical activities of Semax and Selank are discussed separately.

Analysis of known point mutations and SNPs in genes responsible for monogenic Parkinson’s disease in Russian patients

Background: Parkinson’s disease (PD) is caused by complex interactions between genetic and environmental factors. Mendelian forms of PD rarely occur in practice, but respective genes may play some role in pathogenesis of a common sporadic form of the disease. Methods: We analyzed most frequent known point mutations (PMs) and single-nucleotide polymorphisms (SNPs) in genes responsible for monogenic PD in 408 Russian patients, using arrayed primer extension (APEX), real-time PCR, and restriction fragment length polymorphism analysis. Results: We detected only three heterozygous PMs in the PARK2 gene in three non-related patients with early-onset sporadic PD. No association between PD and the studied SNPs was identified. Conclusion: The examined PMs and SNPs in genes responsible for monogenic PD do not contribute significantly to the development of sporadic PD in Russia.

Polymorphisms in the SNCA Gene: Association with the Risk of Development of the Sporadic Form of Parkinson’s Disease and the Level of SNCA Gene Expression in Peripheral Blood of Patients from Russia

Parkinson’s disease (PD) is one of the most common human neurodegenerative disorders caused by the loss of dopaminergic neurons in the brain. The α-synuclein (SNCA) gene is one of the most studied genes involved in the pathogenesis of PD. In our study, we conducted a genetic analysis of promoter and intron single-nucleotide polymorphisms (SNPs) in the SNCA gene. We also analyzed the association of genotypes of these SNPs with expression levels of SNCA mRNA. One of four SNPs in the SNCA gene, and the rs2736990 polymorphism, associates with the risk of the sporadic form of PD in Russian population. The risk of PD was increased almost twofold in carriers of allele C (odds ratios = 1.9, 95% confidence interval: 1.2-2.91, p = 0.003). However, no association was found between any of the genotypes of SNPs tested (rs2583988, rs2619363, rs2619364 and rs2736990) and alterations in SNCA levels. Our findings support the hypothesis that the rs2736990 polymorphism is associated with PD. SNPs rs2583988, rs2619363 and rs2619364 in the promoter region of the SNCA gene themselves do not significantly influence the expression of SNCA. Most likely, SNCA gene expression is a very complex process that is affected by different genetic and epigenetic factors.

Transcriptome profiling of 6-OHDA model of Parkinson’s disease

Analysis of monogenic forms and candidate genes of Parkinson’s disease (PD) does not allow to describe completely the contribution of genetic factors to the etiopathogenesis of the disorder. An approach associated with an analysis of changes in a transcriptome pattern during the development of the disease in model objects can be used to identify new candidate genes that are involved in the pathogenesis of PD. In this work, we performed a transcriptome analysis of a PD model, created via stereotaxic unilateral introduction of the 6-hydroxidopamine (6-OHDA) into the substantia nigra pars compacta (SNpc) of a rat brain, to identify new candidate genes for PD. We studied transcriptome alterations in the substantia nigra of the rat brains 2 weeks after toxin administration, when the rats developed the Parkinson-like phenotype, and 4 weeks after toxin administration, when maximal changes in the behavior of animals were observed. The transcriptome analysis of the substantia nigra of the rat brains at the first time point (2 weeks) revealed changes in expression of genes that were clustered with high significance (p < 0.01, modified Fisher extract p value) into three metabolic pathways according to protein participation: modification of the extracellular matrix, signal transduction (including genes encoding signal peptides), and inflammation processes. This likely indicates that, during this time nonspecific effects associated with the response to surgery took place in the substantia nigra of the rats. Concomitantly, the situation changed dramatically and a response associated with damage to the nervous tissue was observed 4 weeks after neurotoxin administration. As a result, we identified five metabolic pathways containing predominantly genes, that encode protein products that are involved in the processes of neuron projection, normal functioning of the soma and dendrites of neurons, synaptic transmission, and transmission of nerve impulses (p < 0.01, modified Fisher extract p value).

Similar effects of mouse and human <i>pub</i>gene on proliferation and embryoid bodies formation in mouse embryonic stem cells <i>in vitro</i>

Previously we have demonstrated that pub gene modulates expression of PU.1 transcription factor and plays an important role in differentiation of embryonic stem cells not only at early stages (during formation of embryoid bodies), but also during differentiation into ectodermal, mesodermal and endodermal derivatives in vitro. We have compared the influence of elevated expression of two homological genes mpub and hpub of mouse and human respectively on early stages of differentiation of murine embryonic stem cells. Overexpression of both genes caused an increase in the number of formed embryoid bodies but did not alter the proliferative activity of transfected embryonic stem cells. It was also observed that expression of mpub and hpub led to decreased expression of pu.1 mRNA.

Complete Nucleotide Sequence of the Mitochondrial DNA of <i>Halyomorpha halys</i>(Stal) (Hemiptera: Pentatomidae) Specimens Collected Across Georgia

The brown marmorated stink bug, Halyomorpha halys (Stal) (Hemiptera: Pentatomidae) is an invasive species native to East Asia that has spread across Asia, Europe, and North America. H. halys causes damages to various grains, fruits, and vegetables, which is exemplified by the significant damage to the hazelnut harvest in Georgia (during 2016). This report describes the first attempted genetic study of the spread of H. halys in Georgia. The first main goal of this research was to identify the haplotype of an invasive population in Georgia. For this purpose, the mitochondrial cytochrome c oxidase I subunit (COI) gene fragment from 65 samples of H. halys collected from different regions across Georgia was sequenced on an Applied Biosystems 3100 or 3700 genetic analyzer. In all cases, only the H1 haplotype, which is native to China, was identified. The second goal of this research was to determine the complete mitochondrial DNA sequence of H. halys (Stal) specimens collected across Georgia. The complete mitochondrial DNA of H1 haplotype sequenced on an Illumina MiSeq platform. The mitochondrial DNA of the Georgian H1 haplotype has a length of 15,478 base pairs. Using the sequence of the H22 haplotype of H. halys (native to Korea) as a reference, 62 single nucleotide polymorphisms (SNPs), three inversions, and four single T insertions were identified. Furthermore, 60 SNPs and four insertions in two tRNA and one rRNA genes were identified among 18 mitochondrial genes from the Georgian H1 haplotype. Nine of these SNPs resulted in amino acid substitutions. Furthermore, the detection of SNPs revealed many other polymorphic sites beyond the COI gene, which can be used to detect new haplotypes.

Synthetic Peptides Affect the Expression of Gdnf and Gdnf Receptors in Rats with 6-OHDA-Induced PD-Like Parkinsonism

Parkinson’s disease (PD) is the second most common severe neurodegenerative disorder. It is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta. Unfortunately, PD remains incurable. Therapy based on regulatory peptides, particularly neuroprotective peptides, which can sustain or activate neuron plasticity to enable their survival and function in difficult environments and after violated homeostasis, is a promising approach to cure PD. Some studies show that the synthetic analogs of natural peptides may be used as an etiological or at least a complementary therapy in PD. Therefore, in the present pilot study, we investigated the effects of the synthetic peptides Semax and dopamine neuron stimulating peptide (DNSP-5), and a new synthetic Semax-DNSP-5 hybrid peptide (SD) on the functioning of brain neurons. An analysis of the levels of dopamine (DA), noradrenaline (NA), 5-hydroxytriptamine (5-HT), an expression analysis of Gdnf and Gdnf receptor genes Gfra1, Gfra2, Gfra3, Gfra4, and Gfral in various regions of the brain of rats with 6-OHDA-induced PD-like parkinsonism, and a study of the motor activity of the rats in an “open field” test showed that DNSP-5 and SD elevated the level of DA in the nonlesioned striatum. DNSP-5 also increased the expression of Gfra1 and Gfra2 in the nonlesioned striatum and lesioned substantia nigra (SN) which suggested that DNSP-5 had compensatory and neuroprotective properties. SD demonstrated similar, albeit less pronounced effects to DNSP-5 on DA metabolism and gene expression. Of the peptides studied, only SD tended to increase the horizontal and vertical activity of rats. In conclusion, these findings suggest that DNSP-5 and SD have potential neuroprotective properties and may stimulate the surviving DA neurons.

Insights into platinum-induced peripheral neuropathy–current perspective

Cancer is a global health problem that is often successfully addressed by therapy, with cancer survivors increasing in numbers and living longer world around. Although new cancer treatment options are continuously explored, platinum based chemotherapy agents remain in use due to their efficiency and availability. Unfortunately, all cancer therapies affect normal tissues as well as cancer, and more than 40 specific side effects of platinum based drugs documented so far decrease the quality of life of cancer survivors. Chemotherapy-induced peripheral neuropathy is a frequent side effects of platinum-based chemotherapy agents. This cluster of complications is often so debilitating that patients occasionally have to discontinue the therapy. Sensory neurons of dorsal root ganglia are at the core of chemotherapy-induced peripheral neuropathy symptoms. In these postmitotic cells, DNA damage caused by platinum chemotherapy interferes with normal functioning. Accumulation of DNA-platinum adducts correlates with neurotoxic severity and development of sensation of pain. While biochemistry of DNA-platinum adducts is the same in all cell types, molecular mechanisms affected by DNA-platinum adducts are different in cancer cells and non-dividing cells. This review aims to raise awareness about platinum associated chemotherapy-induced peripheral neuropathy as a medical problem that has remained unexplained for decades. We emphasize the complexity of this condition both from clinical and mechanistical point of view and focus on recent findings about chemotherapy-induced peripheral neuropathy in in vitro and in vivo model systems. Finally, we summarize current perspectives about clinical approaches for chemotherapy-induced peripheral neuropathy treatment.

Antibodies Against Annexin V and Prothrombin,Their Correlation with Other Anti-phospholipid Antibodies in Recurrent Pregnancy Loss

Objective To study the findings of serum antibodies against annexin V, prothrombin, ph-inositol, ph-acid, ph-ethanolamine, ph-serine, ph-glycerol, cardiolipin, and beta2-glycoprotein I and analyze the trophoblast annexin V receptors Methods Sera from 156patients aged 26-41 years with recurrent pregnancy loss （3-7 times） were investigated. Eighty-four fertile healthy women aged 24-38 years were included in a control group. ELISA methods were used for detecting a panel of sera anti-phospholipid antibodies. Immunolocalization of annexin V receptors in 143 trophoblast specimens of 156 patients was investigated by the immunofluorescence technique using Annexin V-FITC, Apoptosis and Annexin V-CY3 commercial kits. Results Positivity for anti-phospholipid antibodies mainly against ph-serine, ph- ethanolamine, and ph-inositol was found together in 80. 8%（126 out of 156 patients）, anti-prothrombin antibodies in 12% （18）, and anti-annexin V antibodies in 13. 5% （21） women. No significant levels of anti-phospholipid antibodies were found in 6 controls. Placenta immunohistopathology also exhibited some changes manifested by the presence of apoptotic and necrotic cells in trophoblast, and very few microthrombotization in some intervillous spaces. Conclusion Our detailed study demonstrated the prevalence of majority of antiphospholipid antibodies as a high risk factor for repeated reproductive failure. Very low microthrombosis in placentas could be explained by the changes of haemocoagulation properties out of uterus.

SOX transcription factors and glioma stem cells:Choosing between stemness and differentiation

Glioblastoma(GBM)is the most common,most aggressive and deadliest brain tumor.Recently,remarkable progress has been made towards understanding the cellular and molecular biology of gliomas.GBM tumor initiation,progression and relapse as well as resistance to treatments are associated with glioma stem cells(GSCs).GSCs exhibit a high proliferation rate and self-renewal capacity and the ability to differentiate into diverse cell types,generating a range of distinct cell types within the tumor,leading to cellular heterogeneity.GBM tumors may contain different subsets of GSCs,and some of them may adopt a quiescent state that protects them against chemotherapy and radiotherapy.GSCs enriched in recurrent gliomas acquire more aggressive and therapy-resistant properties,making them more malignant,able to rapidly spread.The impact of SOX transcription factors(TFs)on brain tumors has been extensively studied in the last decade.Almost all SOX genes are expressed in GBM,and their expression levels are associated with patient prognosis and survival.Numerous SOX TFs are involved in the maintenance of the stemness of GSCs or play a role in the initiation of GSC differentiation.The fine-tuning of SOX gene expression levels controls the balance between cell stemness and differentiation.Therefore,innovative therapies targeting SOX TFs are emerging as promising tools for combatting GBM.Combatting GBM has been a demanding and challenging goal for decades.The current therapeutic strategies have not yet provided a cure for GBM and have only resulted in a slight improvement in patient survival.Novel approaches will require the fine adjustment of multimodal therapeutic strategies that simultaneously target numerous hallmarks of cancer cells to win the battle against GBM.

Parasitic Plants <i>Striga</i>and <i>Phelipanche</i>Dependent upon Exogenous Strigolactones for Germination Have Retained Genes for Strigolactone Biosynthesis

Strigolactones are plant hormones with multiple functions, including regulating various aspects of plant architecture such as shoot branching, facilitating the colonization of plant roots by arbuscular mycorrhizal fungi, and acting as seed germination stimulants for certain parasitic plants of the family Orobanchaceae. The obligate parasitic species Phelipanche aegyptiaca and Striga hermonthica require strigolactones for germination, while the facultative parasite Triphysaria versicolor does not. It has been hypothesized that P. aegyptiaca and S. hermonthica would have undergone evolutionary loss of strigolactone biosynthesis as a part of their mechanism to enable specific detection of exogenous strigolactones. We analyzed the transcriptomes of P. aegyptiaca, S. hermonthica and T. versicolor and identified genes known to act in strigolactone synthesis (D27, CCD7, CCD8, and MAX1), perception (MAX2 and D14) and transport (PDR12). These genes were then analyzed to assess likelihood of function. Transcripts of all strigolactone-related genes were found in P. aegyptiaca and S. hermonthica, and evidence points to their encoding functional proteins. Gene open reading frames were consistent with homologs from Arabidopsis and other strigolactone-producing plants, and all genes were expressed in parasite tissues. In general, the genes related to strigolactone synthesis and perception appeared to be evolving under codon-based selective constraints in strigolactone-dependent species. Bioassays of S. hermonthica root extracts indicated the presence of strigolactone class stimulants on germination of P. aegyptiaca seeds. Taken together, these results indicate that Phelipanche aegyptiaca and S. hermonthica have retained functional genes involved in strigolactone biosynthesis, suggesting that the parasites use both endogenous and exogenous strigolactones and have mechanisms to differentiate the two.

Retinoic acid affects basic cellular processes and SOX2 and SOX18 expression in breast carcinoma cells

Genetic and molecular heterogeneity,together with intrinsic and acquired resistance to therapy,represent the major obstacles to the successful treatment of different types of breast carcinoma.Increasing evidence demonstrates that SOX transcription factors in breast carcinomas could act both as oncogenes and tumor suppressors and have been associated with tumor stage and grade,poor prognosis,and therapy resistance.Both SOX2 and SOX18 overexpression has been correlated with poor prognosis in breast carcinomas,and these genes are recognized as potential antitumor targets.Our aim was to evaluate the effect of retinoic acid(RA),a well-known cyto-differentiating agent,on breast carcinoma cells in vitro and to investigate the potential of RA treatment to modify the expression of SOX2 and SOX18 genes.By applying various experimental approaches,we evaluated the effect of RA on basic cellular processes in SK-BR-3 and MCF7 breast carcinoma cell lines.We have shown that RA inhibits cell growth,reduces the number of Ki-67 positive cells,and causes cell-cycle arrest.RA effect was more prominent in SK-BR-3 cell line that lacks SOX2 expression,including a higher decrease in cell viability,reduction in colony formation,and significant remodeling of cellular structure.We have shown that RA treatment led to the downregulation of SOX2 expression in MCF7 cells and to the reduction of SOX18 expression in both cell lines.By functional analysis,we showed that the anti-proliferative effect of RA in both cell lines was not based on the activity of stemness marker SOX2,pointing to a SOX2-independent mechanism of action.The ability of RA to reduce SOX2/SOX18 expression raises the possibility that these genes can be used as biomarkers to distinguish RA-responders from non-responders.Together,our study shows that the response of breast carcinoma cell lines to RA treatment may vary,highlighting that the development of RA-based therapy should consider differences in breast carcinoma subtypes.

About the Conflicts between the Unitary Quantum Theory and the Special and General Relativity Theories

The authors discuss contradictions between the principal branches of the modern physical picture of the universe. Space and time have been shown in the Unitary Quantum Theory (UQT) not to be connected one with the other, unlike in the Special Theory of Relativity. In UQT, time becomes Newtonian again, and the growth of the particle’s mass with growing speed proceeds from other considerations of physics. Unlike the quantum theory, the modern gravitation theory (the general theory of relativity) is not confirmed by experiments and needs to be considerably revised.

The Glycosylphosphatidylinositol Anchor Regulates T Cell Antigen Receptor Induced IL-2 Production

Differential contributions of the glycosylphosphatidylinositol (GPI)-anchor and GPI-anchored proteins (GPI-AP) to signalling remain poorly understood. Here we show that GPI-AP deficient murine clones produce on average 18 and 181-fold more IL-2 mRNA and protein, respectively, upon T cell receptor (TCR) stimulation, in a cell-intrinsic fashion. This phenotype is formally attributed to a mutation within the transferase complex that predicates the initial step in GPI-anchor biosynthesis. Conditional disruption of the transferase complex enabled the generation of primary GPI-AP deficient CD4+ T cells, which produce on average 10- and 23-fold more IL-2 mRNA and protein, respectively, upon TCR stimulation. Conditional disruption of the transamidase complex yields GPI-sufficient, GPI-AP deficient primary CD4+ T cells. TCR stimulation of these cells yields levels of IL-2 mRNA and protein ranging from 1 - 3 and 3-fold, respectively, of controls. These results provide the first evidence of a profound impact of GPI in the regulation of TCR signalling.