Induced reprogramming of adult murine cardiomyocytes to pluripotency in vivo

Partial cell reprogramming has been demonstrated in certain mouse tissues by in situ overexpression of Oct3/4, Klf4, Sox2 and cMyc (OKSM) transcription factors, and can trigger rejuvenation and/or augment regeneration of aged or injured tissues. In vivo reprogramming of adult mouse cardiomyocytes has been elusive, but success could overcome the lack of endogenous cardiomyocyte turnover that contributes to the poor resolution of heart disease. Here, we exploited cell type-specific Cre recombination and conditional, doxycycline-inducible, control of gene expression to generate cardiomyocyte-specific, inducible, reprogrammable mice. Eighteen days of doxycycline-induced OKSM expression in this model established a gene expression program characteristic of the pluripotent state and triggered the generation of teratomas of confirmed cardiomyocyte origin. These findings confirm that OKSM reprograms adult mouse cardiomyocytes to pluripotency and will enable studies of the contribution of reprogrammed cardiomyocytes to cardiac regeneration.

CD4+ T cell help creates memory CD8+ T cells with innate and help-independent recall capacities

CD4+ T cell help is required for the generation of CD8+ cytotoxic T lymphocyte (CTL) memory. Here, we use genome-wide analyses to show how CD4+ T cell help delivered during priming promotes memory differentiation of CTLs. Help signals enhance IL-15-dependent maintenance of central memory T (TCM) cells. More importantly, help signals regulate the size and function of the effector memory T (TEM) cell pool. Helped TEM cells produce Granzyme B and IFNγ upon antigen-independent, innate-like recall by IL-12 and IL-18. In addition, helped memory CTLs express the effector program characteristic of helped primary CTLs upon recall with MHC class I-restricted antigens, likely due to epigenetic imprinting and sustained mRNA expression of effector genes. Our data thus indicate that during priming, CD4+ T cell help optimizes CTL memory by creating TEM cells with innate and help-independent antigen-specific recall capacities.

Wooden architecture of sieve farmsteads in Biłgoraj on the example of the farmstead at Nadstawna 32 St.

At the turn of the 17th and 19th centuries, the sieving industry developed in the Biłgoraj region, which became the dominant branch of crafts and trade. In a special way it contributed to the development of the city - its construction, tradition, culture, and in present times to the identity of its current inhabitants. It was due to this industry that the local population of that time travelled to the city and recruited Biłgoraj sieve makers [1]. Unfortunately, as a result of wars, unstable situation in the country, declining profitability of sieves, as well as economic changes, this line of industry collapsed, leaving a small but valuable mark. The last preserved sieve house along with farm buildings is a "sieve farmstead” built in 1810 at Nadstawna 32 St. (formerly called Krasickiego 50 St.) [2] left in its original position, i.e. in situ. The object stood out against the background of wooden buildings due to its rich functional program, characteristic and representative form of the building together with regional architectural details.

An inhibitor of HIV-1 protease modulates constitutive eIF2α dephosphorylation to trigger a specific integrated stress response

Inhibitors of the HIV aspartyl protease [HIV protease inhibitors (HIV-PIs)] are the cornerstone of treatment for HIV. Beyond their well-defined antiretroviral activity, these drugs have additional effects that modulate cell viability and homeostasis. However, little is known about the virus-independent pathways engaged by these molecules. Here we show that the HIV-PI Nelfinavir decreases translation rates and promotes a transcriptional program characteristic of the integrated stress response (ISR). Mice treated with Nelfinavir display hallmarks of this stress response in the liver, including α subunit of translation initiation factor 2 (eIF2α) phosphorylation, activating transcription factor-4 (ATF4) induction, and increased expression of known downstream targets. Mechanistically, Nelfinavir-mediated ISR bypassed direct activation of the eIF2α stress kinases and instead relied on the inhibition of the constitutive eIF2α dephosphorylation and down-regulation of the phophatase cofactor CReP (Constitutive Repressor of eIF2α Phosphorylation; also known as PPP1R15B). These findings demonstrate that the modulation of eIF2α-specific phosphatase cofactor activity can be a rheostat of cellular homeostasis that initiates a functional ISR and suggest that the HIV-PIs could be repositioned as therapeutics in human diseases to modulate translation rates and stress responses.

MODELLING THE SOFTWARE TESTING PROCESS

An approach to formal modelling the program testing process is proposed in the paper. Considerations are based on some program reliability-growth model that is constructed for assumed scheme of the program testing process. In this model the program under the testing is characterized by means of so-called characteristic matrix and the program testing process is determined by means of so-called testing strategy. The formula for determining the mean value of the predicted number of errors encountered during the program testing is obtained. This formula can be used if the characteristic matrix and the testing strategy are known. Formulae for evaluating this value when the program characteristic matrix is not known are also proposed in the paper.

Genome-scale expression and transcription factor binding profiles reveal therapeutic targets in transgenic ERG myeloid leukemia

Key Points ERG overexpression in transgenic mice induces a transcriptional leukemia stem cell program characteristic of human AML. PIM1 and RAS are relevant ERG therapeutic targets.

A developmental science commentary on Charney's “Behavior genetics and postgenomics”

Charney's target article convincingly demonstrates the need for the discipline of quantitative human behavior genetics to discard its false assumptions and to employ the techniques, assumptions, and research program characteristic of modern developmental psychobiology.

Recruiting International Students to Your Campus

The purpose of this paper was to determine what institutional, program, and recruitment characteristics influenced international students to attend institutions in the United States. Two hundred sixteen international students at a Southern public research university responded to the survey (53% response rate) from 56 countries representing 8 regions. An empirical analysis using t-tests and analysis of variance was conducted to determine what characteristics international students found to be most important when selecting an institution. Regardless of degree level, all students ranked faculty/student ratio as an important program characteristic. Second, students ranked both the admission process and time to degree as important characteristics. Third, doctoral, master’s, and bachelor’s students respectively ranked funding as an important characteristic in their decision making process. There are three basic implications for recruitment officers. First, as size matters, international students need to feel connected to faculty and staff.