Sequential Progression Research Articles

Molecular understanding of hierarchy and lineage of mesenchymal stem cells in vivo

Mesenchymal stem cell (MSC) is a type of tissue stem cell. In clinical studies, cultured MSCs have shown important therapeutic effects on diseases via the reduction of neurological defects and regulation of immune responses. However, in vivo MSC localization, function, and properties are poorly understood; therefore, the molecular understanding of MSCs hierarchy is less advanced compared to hematopoietic stem cell hierarchy. To address these issues, we developed a method that enables us to visualize MSCs, manipulate their function, and analyze their molecular biology in vivo. Paired-related homeobox 1 (Prrx1)-positive cells are transiently observed during limb skeletal development in mice. Prrx1-positive cells form heterogeneous populations comprising multiple mesenchymal progenitors with different lineages that are developing into osteoblasts, chondrocytes, adipocytes, fibroblasts, and tendon and ligament cells. Our results suggest that osteoblast differentiation in the calvaria begins at the Prrx1+Sca1+ MSC stage with sequential progression to Prrx1+Sca1- cells, then Osterix+Prrx1-Sca1- osteoblast precursors, which eventually form mature α1(I)-collagen+ osteoblasts. Using Runt-related transcription factor 2 (Runx2) conditional knockout mice, furthermore, we found that the essential period of Runx2 function in intramembranous ossification likely begins at the Prrx1+Sca1+ MSC stage and ends at the Osterix+Prrx1-Sca1- osteoblast precursor stage (before mature the α1(I)-collagen+ osteoblasts appear). This approach will enable us to understand the in vivo molecular biology features of MSCs, leading to their therapeutic applications for tissue repair and regeneration. This development can also contribute to the field of pluripotent stem cell by enabling the transplantation of lineage-restricted mesenchymal progenitors.

Nimbolide, a neem limonoid inhibits cytoprotective autophagy to activate apoptosis via modulation of the PI3K/Akt/GSK-3\u03b2 signalling pathway in oral cancer

Of late, nimbolide, a limonoid from the neem tree (Azadirachta indica) has gained increasing research attention owing to its potent antiproliferative and apoptosis-inducing effects. The present study was designed to investigate the effect of nimbolide on autophagy and the time point at which the phosphorylation status of GSK-3β and PI3K dictate the choice between autophagy and apoptosis in SCC131 and SCC4 oral cancer cells. Additionally, we analysed changes in the expression of proteins involved in autophagy and apoptosis after therapeutic intervention with nimbolide in a hamster model of oral oncogenesis. Furthermore, we also demonstrate changes in the expression of key genes involved in apoptosis and autophagy during the stepwise evolution of hamster and human OSCCs. Nimbolide-induced stereotypical changes in oral cancer cells characteristic of both apoptosis and autophagy. Time-course experiments revealed that nimbolide induces autophagy as an early event and then switches over to apoptosis. Nimbolide negatively regulates PI3K/Akt signalling with consequent increase in p-GSK-3βTyr216, the active form of GSK-3β that inhibits autophagy. Downregulation of HOTAIR, a competing endogenous RNA that sponges miR-126 may be a major contributor to the inactivation of PI3K/Akt/GSK3 signalling by nimbolide. Analysis of key markers of apoptosis and autophagy as well as p-AktSer473 during sequential progression of hamster and human OSCC revealed a gradual evolution to a pro-autophagic and antiapoptotic phenotype that could confer a survival advantage to tumors. In summary, the results of the present study provide insights into the molecular mechanisms by which nimbolide augments apoptosis by overcoming the shielding effects of cytoprotective autophagy through modulation of the phosphorylation status of Akt and GSK-3β as well as the ncRNAs miR-126 and HOTAIR. Development of phytochemicals such as nimbolide that target the complex interaction between proteins and ncRNAs that regulate the autophagy/apoptosis flux is of paramount importance in cancer prevention and therapeutics.

Immune environment in serrated lesions of the colon: intraepithelial lymphocyte density, PD-1, and PD-L1 expression correlate with serrated neoplasia pathway progression

The serrated neoplasia pathway accounts for approximately 20% of colorectal carcinomas (CRCs). Sessile serrated adenomas (SSAs), the main precursor lesion of the serrated pathway, are molecularly driven by MLH1 promoter methylation and microsatellite instability (MSI) in their progression to CRC. MSI-high (MSI-H) lesions are highly immunogenic and associated with a high density of tumor-infiltrating lymphocytes. Our study's aim was to determine how the kinetics of this immune environment relates to SSAs in their progression through low-grade (SSA-LD) to high-grade dysplasia (SSA-HD) and CRC. We analyzed 74 cases (16 CRCs, 14 SSAs-HD, and 44 SSAs-LD). Cases of hyperplastic polyp and SSA without dysplasia were analyzed for comparison. MSI status, intraepithelial lymphocyte (IEL) density, and immune checkpoint expression were assessed by immunohistochemistry for mismatch repair proteins, CD3, and PD-1/PD-L1, respectively. Average IEL density was 12, 18.6, 21.6, and 31 for SSA, SSA-LD, SSA-HD, and CRC, respectively, as opposed to 8.1 in normal colon (P < .0001). Average PD-1/PD-L1 lymphocytic expression was 1.1/1.0, 1.2/2.9, 4.8/6.9, and 12.4/15.2 in SSA, SSA-LD, SSA-HD, and CRC, respectively, compared with 0.5/0 in normal crypts (P < .0001). IEL and PD-1/PD-L1 lymphocytic expression values of MSI-H lesions were 22.6, 27.7, and 36.8, and 3/6.5, 6.2/10.6, and 18.3/17.6 in MSI-H SSA-LD, SSA-HD, and CRCs, respectively (P ranged from .0478 to .3529). PD-L1 epithelial expression was positive in 40% of SSAs, 59.1% of SSAs-LD, 100% of SSAs-HD, and 60% of CRCs (P < .0001). Increased IELs and PD-1/PD-L1 expression correlate with sequential progression of SSAs, through development of cytologic dysplasia, to CRC and MSI-H status.

Deconstructing progression of amyotrophic lateral sclerosis in stages: a Markov modeling approach

Objectives: Propose an empirical amyotrophic lateral sclerosis (ALS) staging approach called Fine’til 9 (FT9) based on how many of the patient’s ALS functional rating scale (ALSFRS-R) subscores are 9 or less (of normal 12). Gain insights into progression of ALS by applying Markov models to ALS stages by multiple systems (King’s, Milan–Torino system (MITOS) and FT9).Methods: Patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) dataset were staged using ALSFRS-R responses. Risks of progression through stages and death were estimated, as were effects of prognostic variables on these risks.Results: A total of 29,947 time points in 3199 patients from the PRO-ACT dataset were assigned stages. Although the three systems were moderately correlated, MITOS stages were heavily skewed toward advanced disease, whereas King’s and FT9 stages were more balanced. Non-sequential progression was observed with King’s system. Markov models adequately described transitions from stage to stage in the first year of observation, but underestimated risks beyond that point. Regardless of staging method, initial rate of ALSFRS-R decline had a powerful effect on rate of progression through sequential stages, whereas age predominantly influenced stage-specific mortality.Conclusion: King’s and FT9 are more sensitive to observed progression of disease in clinical trials than MITOS. FT9 can partition the course similar to King’s, and may have advantages of sequential progression and easy applicability to retrospective data. Markov transition intensity estimates may be of value for counseling, health economic studies, and research design. In particular, this framework permits estimation of multidimensional effects of variables (including treatment) on outcome.

Molecular progression to cervical precancer, epigenetic switch or sequential model?

The evolution of precancerous cervical lesions is poorly understood. A widely held model of cervical intraepithelial neoplasia grade 3 (CIN3) development is sequential progression from normal through CIN1 and CIN2 to CIN3. Another hypothesis, the “molecular switch” model, postulates that CIN3 can evolve directly from human papillomavirus (HPV)‐infected normal epithelium without progressing through CIN1 and CIN2. To shed light on this process, we compared DNA methylation of selected human biomarkers and HPV types in two groups of CIN1: CIN1 that were near or adjacent to CIN3 (adjacent‐CIN1) and CIN1 that were the principal lesions with no CIN3 detected (principal‐CIN1). 354 CIN (CIN1 and CIN3) and normal tissue areas were dissected and typed for HPV from 127 women who underwent loop electrosurgical excision procedures (LEEP). Methylation of genes EPB41L3 and the viral regions of HPV16‐L1/L2, HPV18‐L2, HPV31‐L1, and HPV33‐L2 were determined by a highly accurate quantitative pyrosequencing of bisulfite converted DNA. There was a significant trend of increased methylation with disease grade comparing normal to CIN1 and CIN3 (p < 0.0001). Adjacent‐CIN1 predominantly shared the same HPV types as the CIN3, however, methylation differed substantially between adjacent‐CIN1 and CIN3 (p = 0.008). In contrast diagnostically principal‐CIN1 had an indistinguishable methylation distribution compared to adjacent‐CIN1 (EPB41L3: p = 0.49; HPVme‐All: p = 0.11). Our results suggest that progression from normal epithelium to CIN1 or CIN3 is usually promoted by the same HPV type but occurs via distinct DNA epigenotypes, thus favoring the “molecular switch” model.

Modeling Persistent Trends in Distributions

ABSTRACTWe present a nonparametric framework to model a short sequence of probability distributions that vary both due to underlying effects of sequential progression and confounding noise. To distinguish between these two types of variation and estimate the sequential-progression effects, our approach leverages an assumption that these effects follow a persistent trend. This work is motivated by the recent rise of single-cell RNA-sequencing experiments over a brief time course, which aim to identify genes relevant to the progression of a particular biological process across diverse cell populations. While classical statistical tools focus on scalar-response regression or order-agnostic differences between distributions, it is desirable in this setting to consider both the full distributions as well as the structure imposed by their ordering. We introduce a new regression model for ordinal covariates where responses are univariate distributions and the underlying relationship reflects consistent changes in the distributions over increasing levels of the covariate. This concept is formalized as a trend in distributions, which we define as an evolution that is linear under the Wasserstein metric. Implemented via a fast alternating projections algorithm, our method exhibits numerous strengths in simulations and analyses of single-cell gene expression data. Supplementary materials for this article are available online.

MIND model for triple-negative breast cancer in syngeneic mice for quick and sequential progression analysis of lung metastasis.

Mouse models of breast cancer with specific molecular subtypes (e.g., ER or HER2 positive) in an immunocompetent or an immunocompromised environment significantly contribute to our understanding of cancer biology, despite some limitations, and they give insight into targeted therapies. However, an ideal triple-negative breast cancer (TNBC) mouse model is lacking. What has been missing in the TNBC mouse model is a sequential progression of the disease in an essential native microenvironment. This notion inspired us to develop a TNBC-model in syngeneic mice using a mammary intraductal (MIND) method. To achieve this goal, Mvt-1and 4T1 TNBC mouse cell lines were injected into the mammary ducts via nipples of FVB/N mice and BALB/c wild-type immunocompetent mice, respectively. We established that the TNBC-MIND model in syngeneic mice could epitomize all breast cancer progression stages and metastasis into the lungs via lymphatic or hematogenous dissemination within four weeks. Collectively, the syngeneic mouse-TNBC-MIND model may serve as a unique platform for further investigation of the underlying mechanisms of TNBC growth and therapies.

The Impact of Institutional Pressures of Climate Change Concerns on Corporate Environmental Reporting Practices: A Descriptive Study of Malaysia’s Environmentally Sensitive Public Listed Companies

Malaysian companies have dramatically increased their corporate environmental reporting (CER) practices in response to institutional pressures related to concerns about climate change. Based on a content analysis of annual reports, sustainability reports, and websites of 209 Malaysian environmentally sensitive public listed companies (ESPLCs), we describe CER practices with respect to various environmental strategies implemented by companies over a 5-year period. The results show that environmental strategies include pursuing sequential progression from noncompliance to compliance, and beyond in response to external factors such as institutional pressures and climate change concerns. This progression is manifested by the extent and quality of CER practices as pursued by Malaysian ESPLCs.

Investigation of fluidized bed agglomerate growth process using simulations and SEM-EDX characterization of laboratory-generated agglomerates

This study elucidates the sequential progression of agglomerate growth in fluidized beds through an investigation of physics and chemistry of particle-particle interaction. In fluidized bed gasification and combustion systems, agglomeration occurs by sticking of ash particles that are wetted by slag-liquid. Penn State has developed an agglomeration modeling methodology that considers non-uniform temperature, gaseous atmosphere and heterogeneity in ash chemical composition to predict slag-liquid formation and agglomerate growth rate. Simulations performed on three high rank coals with a consideration of these heterogeneous conditions, along with a microscopic (SEM) particle-level analysis of agglomerates facilitated an understanding of steps involved in their formation.The results of this study indicated that agglomerate growth in fluidized bed systems is initiated at the particle-level by low-melting components rich in iron- and calcium-based minerals. Agglomeration can begin at lower temperatures than the fluidized bed operating temperatures of 850 °C and the severity of agglomerate growth issues can be identified based on the slag-liquid level in the system. Understanding the stages involved in the process of agglomerate growth discussed in this paper can help develop early detection methods and mitigation strategies.

Order effects in the translation process

AbstractThis study investigates how the order in which various translation memory match-types occur in a target language version of a text may influence translator behavior and cognition. Empirical research designs often attempt to mitigate for possible confounds from order effects, yet explicit recognition of the time-series nature of data collection can yield a better understanding of the influence that translation technologies have on the translation task. Data are drawn from a previous study that investigated technical, temporal, and cognitive effort in a translation memory environment, and here we analyze the time-series data for potential order effects. Findings show that order effects are present in some instances during the sequential progression through the target text, particularly with respect to technical and cognitive effort. Results are also suggestive of a potential first impression effect.

Control on frontal thrust progression by the mechanically weak Gondwana horizon in the Darjeeling-Sikkim Himalaya

This study integrates field evidence with laboratory experiments to show the mechanical effects of a lithologically contrasting stratigraphic sequence on the development of frontal thrusts: Main Boundary Thrust (MBT) and Daling Thrust (DT) in the Darjeeling-Sikkim Himalaya (DSH). We carried out field investigations mainly along two river sections in the DSH: Tista-Kalijhora and Mahanadi, covering an orogen-parallel stretch of ~20 km. Our field observations suggest that the coal-shale dominated Gondwana sequence (sandwiched between the Daling Group in the north and Siwaliks in the south) has acted as a mechanically weak horizon to localize the MBT and DT. We simulated a similar mechanical setting in scaled model experiments to validate our field interpretation. In experiments, such a weak horizon at a shallow depth perturbs the sequential thrust progression, and causes a thrust to localize in the vicinity of the weak zone, splaying from the basal detachment. We correlate this weak-zone-controlled thrust with the DT, which accommodates a large shortening prior to activation of the weak zone as a new detachment with ongoing horizontal shortening. The entire shortening in the model is then transferred to this shallow detachment to produce a new sequence of thrust splays. Extrapolating this model result to the natural prototype, we show that the mechanically weak Gondwana Sequence has caused localization of the DT and MBT in the mountain front of DSH.

Polyploidy and Mitotic Cell Death Are Two Distinct HIV-1 Vpr-Driven Outcomes in Renal Tubule Epithelial Cells.

Prior studies have found that HIV, through the Vpr protein, promotes genome reduplication (polyploidy) in infection-surviving epithelial cells within renal tissue. However, the temporal progression and molecular regulation through which Vpr promotes polyploidy have remained unclear. Here we define a sequential progression to Vpr-mediated polyploidy in human renal tubule epithelial cells (RTECs). We found that as in many cell types, Vpr first initiates G2 cell cycle arrest in RTECs. We then identified a previously unreported cascade of Vpr-dependent events that lead to renal cell survival and polyploidy. Specifically, we found that a fraction of G2-arrested RTECs reenter the cell cycle. Following this cell cycle reentry, two distinct outcomes occur. Cells that enter complete mitosis undergo mitotic cell death due to extra centrosomes and aberrant division. Conversely, cells that abort mitosis undergo endoreplication to become polyploid. We further show that multiple small-molecule inhibitors of the phosphatidylinositol 3-kinase-related kinase (PIKK) family, including those that target ATR, ATM, and mTOR, indirectly prevent Vpr-mediated polyploidy by preventing G2 arrest. In contrast, an inhibitor that targets DNA-dependent protein kinase (DNA-PK) specifically blocks the Vpr-mediated transition from G2 arrest to polyploidy. These findings outline a temporal, molecularly regulated path to polyploidy in HIV-positive renal cells.IMPORTANCE Current cure-focused efforts in HIV research aim to elucidate the mechanisms of long-term persistence of HIV in compartments. The kidney is recognized as one such compartment, since viral DNA and mRNA persist in the renal tissues of HIV-positive patients. Further, renal disease is a long-term comorbidity in the setting of HIV. Thus, understanding the regulation and impact of HIV infection on renal cell biology will provide important insights into this unique HIV compartment. Our work identifies mechanisms that distinguish between HIV-positive cell survival and death in a known HIV compartment, as well as pharmacological agents that alter these outcomes.

Network Features and Dynamical Landscape of Naive and Primed Pluripotency

Although the broad and unique differentiation potential of pluripotent stem cells relies on a complex transcriptional network centered around Oct4, Sox2, and Nanog, two well-distinct pluripotent states, called “naive” and “primed”, have been described in vitro and markedly differ in their developmental potential, their expression profiles, their signaling requirements, and their reciprocal conversion. Aiming to determine the key features that segregate and coordinate these two states, data-driven optimization of network models is performed to identify relevant parameter regimes and reduce network complexity to its core structure. Decision dynamics of optimized networks is characterized by signal-dependent multistability and strongly asymmetric transitions among naive, primed, and nonpluripotent states. Further model perturbation and reduction approaches reveal that such a dynamical landscape of pluripotency involves a functional partitioning of the regulatory network. Specifically, two overlapping positive feedback modules, Klf4/Esrrb/Nanog and Oct4/Nanog, stabilize the naive or the primed state, respectively. In turn, their incoherent feedforward and negative feedback coupling mediated by the Erk/Gsk3 module is critical for robust segregation and sequential progression between naive and primed states before irreversible exit from pluripotency.

A Study on the Transmission Process of Eotjungmori Passage in Pansori

A Study on the Transmission Process of Eotjungmori Passage in Pansori

Investigation into metastatic processes and the therapeutic effects of gemcitabine on human pancreatic cancer using an orthotopic SUIT-2 pancreatic cancer mouse model.

Prognosis of pancreatic cancer is poor, thus the development of novel therapeutic drugs is necessary. During preclinical studies, appropriate models are essential for evaluating drug efficacy. The present study sought to determine the ideal pancreatic cancer mouse model for reliable preclinical testing. Such a model could accurately reflect human pancreatic cancer phenotypes and predict future clinical trial results. Systemic pathology analysis was performed in an orthotopic transplantation model to prepare model mice for use in preclinical studies, mimicking the progress of human pancreatic cancer. The location and the timing of inoculated cancer cell metastases, pathogenesis and cause of fatality were analyzed. Furthermore, the efficacy of gemcitabine, a key pancreatic cancer drug, was evaluated in this model where liver metastasis and peritoneal dissemination occur. Results indicated that the SUIT-2 orthotopic pancreatic cancer model was similar to the phenotypic sequential progression of human pancreatic cancer, with extra-pancreatic invasion, intra-peritoneal dissemination and other hematogenous organ metastases. Notably, survival was prolonged by administering gemcitabine to mice with metastasized pancreatic cancer. Furthermore, the detailed effects of gemcitabine on the primary tumor and metastatic tumor lesions were pathologically evaluated in mice. The present study indicated the model accurately depicted pancreatic cancer development and metastasis. Furthermore, the detailed effects of pancreatic cancer drugs on the primary tumor and on metastatic tumor lesions. We present this model as a potential new standard for new drug development in pancreatic cancer.

Cdk7 Is Required for Activity-Dependent Neuronal Gene Expression, Long-Lasting Synaptic Plasticity and Long-Term Memory.

In the brain, de novo gene expression driven by learning-associated neuronal activities is critical for the formation of long-term memories. However, the signaling machinery mediating neuronal activity-induced gene expression, especially the rapid transcription of immediate-early genes (IEGs) remains unclear. Cyclin-dependent kinases (Cdks) are a family of serine/threonine kinases that have been firmly established as key regulators of transcription processes underling coordinated cell cycle entry and sequential progression in nearly all types of proliferative cells. Cdk7 is a subunit of transcriptional initiation factor II-H (TFIIH) and the only known Cdk-activating kinase (CAK) in metazoans. Recent studies using a novel Cdk7 specific covalent inhibitor, THZ1, revealed important roles of Cdk7 in transcription regulation in cancer cells. However, whether Cdk7 plays a role in the regulation of transcription in neurons remains unknown. In this study, we present evidence demonstrating that, in post-mitotic neurons, Cdk7 activity is positively correlated with neuronal activities in cultured primary neurons, acute hippocampal slices and in the brain. Cdk7 inhibition by THZ1 significantly suppressed mRNA levels of IEGs, selectively impaired long-lasting synaptic plasticity induced by 4 trains of high frequency stimulation (HFS) and prevented the formation of long-term memories.

Problematic khat use as a possible risk factor for harmful use of other psychoactive substances: a mixed method study in Ethiopia

BackgroundSubstance use disorders along with neuropsychiatric disorders contributed about 14% of the global burden of disease. Harmful alcohol use, is a known contributor for many harms (accidents, suicide, violence, and complication of other psychiatric and medical disorders). In the Western countries, alcohol and nicotine are gateway drugs to cannabis use, and cannabis use is a risk factor for other illicit drugs such as cocaine and heroin. Khat use is another psychoactive substance which is common in East African and Arabian Peninsula. But there is a knowledge gap regarding the position of khat use or problematic khat use in sequential progression of different psychoactive substances. Therefore, we aimed to understand and investigate the relationship of problematic khat use and other psychoactive substances in Ethiopia.MethodsExploratory mixed methods study was employed. Quantitative cross sectional survey was done among 102 khat users, and 4 focus group discussions and 11 in-depth interviews were conducted to understand the pathways between khat use and other psychoactive substances use in 2014. Non random sampling (purposive and snowballing) was employed for both quantitative and qualitative studies. Khat users from khat cafeterias, shops, and from other open markets of khat in Addis Ababa were invited to participate.ResultCurrently significant majorities of khat users (86.3%) used at least one other psychoactive substance after they started khat use. The prevalence of harmful drinking was 53.9% among khat users. Problematic khat use was a significant predictor of harmful drinking (p < 0.05). About one from ten respondents engaged to risky sexual behavior pushed by the effect of khat after chewing.ConclusionThe proportion of psychoactive substances use especially harmful drinking among khat users was observed higher compared to other cross sectional surveys conducted among general population. In Ethiopia, intervention and policy on harmful alcohol use could consider problematic khat use as one possible risky factor. A rigorous methodology which could test gateway hypothesis of problematic psychoactive substances use could be warranted.

Tractional Abnormalities of the Central Foveal Bouquet in Epiretinal Membranes: Clinical Spectrum and Pathophysiological Perspectives

To investigate the tractional alterations of the central bouquet (CB) in idiopathic epiretinal membranes (ERMs). Retrospective, consecutive, observational case series. ERMs were classified according to a 4-stage grading system. The CB was defined as a circular area of approximately 100μm composed of densely packed cones (and Müller cells) in the central fovea. Tractional abnormalities of the CB were identified with spectral-domain optical coherence tomography. Exvivo histopathologic analysis was performed. In this study 263 eyes with ERMs were included. Mean follow-up was 21.2 ± 16.7months. At baseline, tractional abnormalities of the CB were diagnosed in 58 out of 263 eyes (22%) and divided into 3 categories: cotton ball sign (defined as a fuzzy hyperreflective area between the ellipsoid zone and the interdigitation zone in the central fovea), foveolar detachment, and acquired vitelliform lesion. The presence of ectopic inner foveal layers was negatively correlated with the presence of CB tractional abnormalities (P= .002). Visual acuity was highest in association with the cotton ball sign and lowest in the acquired vitelliform lesion group. Sequential morphologic progression was identified in 7 eyes. Exvivo histopathologic analysis illustrated characteristic staining patterns supporting a potential mechanism of traction by Müller cells in the CB. The cotton ball sign, foveolar detachment, and acquired vitelliform lesion may comprise a continuum in the same clinical spectrum and may represent subsequent stages of CB abnormalities. Foveal Müller cells may play an integral role in the transmission of mechanical forces to the central foveal cones.

Unraveling the origin of twin related domains and grain boundary evolution during grain boundary engineering

Grain boundary engineering of Fe-based austenitic stainless steels and other materials has been successful in producing a large increase in twin and twin related grain boundaries from a wide range of thermomechanical treatments. However, the exact mechanisms and effective grain boundary network descriptors to create the heavily twinned microstructures are yet to be fully understood. In this study, we provide insight into the grain boundary engineering process by examining sequential progression of the same spatial location of a twin related microstructure through thermomechanical processing. The results show that clusters of twin related grain boundaries called twin related domains form during primary recrystallization. The size of the twin related domains increases as the level of strain falls toward the critical strain for recrystallization. Growth of twin related domains during recrystallization results in the formation of twin boundaries behind the migrating grain boundary front. Formation of higher order twin boundaries occurs when two separate grain boundary fronts of the same twin related domain impinge upon each other. We also present relevant microstructural descriptors with emphasis on twin related domain statistics to recrystallization phenomena in grain boundary engineering materials.

“Chess for overall development” software in the frame of Reflection and Activity

The paper discusses “Chess for overall development” project, which is based on Reflection and Activity Approach in helping overcome learning diÿculties. The project has been running for over 12 years now, putting theory of the approach into practice in several cities throughout the Russian Federation. One of the key elements in this project is developing the ability to think in mind using chess problems and sequential progress through material where solving of problems becoming more idea-based and less action-based using the notion of the stage-by-stage formation of mental actions. Unlike other methods teachers use to teach chess, the Chess for Overall Development project views chess primarily as a psychological instrument for helping develop the ability to think in mind. The basis for the ideas of the project is L. S. Vygotsky’s cultural-historical psychology. Vygotsky’s notions on the development of the human psyche are implemented and partially expanded as part of the project. In recent years the software “Chess for overall development” was made designed with full compatibility with the principles of the reflection and activity approach and implementing the notion of the ability to think in mind development and sequential transition from material to ideal plane of mental actions. We present detailed description of the software features as well as its approbation results collected in schools, universities and hospitals.