Controlling the Bureaucracy of the Antipoverty Program

Rapid progress made in various areas of regenerative medicine in recent years occurred both at the cellular level, with the Nobel prize-winning discovery of reprogramming (generation of induced pluripotent stem (iPS) cells) and also at the biomaterial level. The use of four transcription factors, Oct3/4, Sox2, c-Myc, and Klf4 (called commonly "Yamanaka factors") for the conversion of differentiated cells, back to the pluripotent/embryonic stage, has opened virtually endless and ethically acceptable source of stem cells for medical use. Various types of stem cells are becoming increasingly popular as starting components for the development of replacement tissues, or artificial organs. Interestingly, many of the transcription factors, key to the maintenance of stemness phenotype in various cells, are also overexpressed in cancer (stem) cells, and some of them may find the use as prognostic factors. In this review, we describe various methods of iPS creation, followed by overview of factors known to interfere with the efficiency of reprogramming. Next, we discuss similarities between cancer stem cells and various stem cell types. Final paragraphs are dedicated to interaction of biomaterials with tissues, various adverse reactions generated as a result of such interactions, and measures available, that allow for mitigation of such negative effects

Knockdown of ZNF268, which Is Transcriptionally Downregulated by GATA-1, Promotes Proliferation of K562 Cells

The human ZNF268 gene encodes a typical KRAB-C2H2 zinc finger protein that may participate in hematopoiesis and leukemogenesis. A recent microarray study revealed that ZNF268 expression continuously decreases during erythropoiesis. However, the molecular mechanisms underlying regulation of ZNF268 during hematopoiesis are not well understood. Here we found that GATA-1, a master regulator of erythropoiesis, repressed the promoter activity and transcription of ZNF268. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays showed that GATA-1 directly bound to a GATA binding site in the ZNF268 promoter in vitro and in vivo. Knockdown of ZNF268 in K562 erythroleukemia cells with specific siRNA accelerated cellular proliferation, suppressed apoptosis, and reduced expression of erythroid-specific developmental markers. It also promoted growth of subcutaneous K562-derived tumors in nude mice. These results suggest that ZNF268 is a crucial downstream target and effector of GATA-1. They also suggest the downregulation of ZNF268 by GATA-1 is important in promoting the growth and suppressing the differentiation of K562 erythroleukemia cells

Altered translation of GATA1 in Diamond-Blackfan anemia

Ribosomal protein haploinsufficiency occurs in diverse human diseases including Diamond-Blackfan anemia (DBA)[superscript 1, 2], congenital asplenia[superscript 3] and T cell leukemia[superscript 4]. Yet, how mutations in genes encoding ubiquitously expressed proteins such as these result in cell-type– and tissue-specific defects remains unknown[superscript 5]. Here, we identify mutations in GATA1, encoding the critical hematopoietic transcription factor GATA-binding protein-1, that reduce levels of full-length GATA1 protein and cause DBA in rare instances. We show that ribosomal protein haploinsufficiency, the more common cause of DBA, can lead to decreased GATA1 mRNA translation, possibly resulting from a higher threshold for initiation of translation of this mRNA in comparison with other mRNAs. In primary hematopoietic cells from patients with mutations in RPS19, encoding ribosomal protein S19, the amplitude of a transcriptional signature of GATA1 target genes was globally and specifically reduced, indicating that the activity, but not the mRNA level, of GATA1 is decreased in patients with DBA associated with mutations affecting ribosomal proteins. Moreover, the defective hematopoiesis observed in patients with DBA associated with ribosomal protein haploinsufficiency could be partially overcome by increasing GATA1 protein levels. Our results provide a paradigm by which selective defects in translation due to mutations affecting ubiquitous ribosomal proteins can result in human disease.National Institutes of Health (U.S.) (Grant P01 HL32262)National Institutes of Health (U.S.) (Grant U54 HG003067-09

Podwyższenie kapitału zakładowego bez zmiany umowy spółki — problem prawa pierwszeństwa

Share capital increase under present provisionsof articles of association — pre-emptive right problemThe article relates to the increase of share capital in limited liability company spółka z ograniczoną odpowiedzialnością without altering the articles of association. Particularly, the article encompasses the subject whether it is admissible to restrict the pre-emptive right of current share­holders to subscribe shares in increased capital in the procedure of “simplified increase of capital,” arguments against such admissibility raised both in legal literature and judical opinions and arguments in favor of such admissibility. The thesis presented in the article is that the restriction of exclusion of pre-emptive right of current shareholders is de lege lata admissible in the procedure of “simplified increase of share capital.”Share capital increase under present provisionsof articles of association — pre-emptive right problemThe article relates to the increase of share capital in limited liability company spółka z ograniczoną odpowiedzialnością without altering the articles of association. Particularly, the article encompasses the subject whether it is admissible to restrict the pre-emptive right of current share­holders to subscribe shares in increased capital in the procedure of “simplified increase of capital,” arguments against such admissibility raised both in legal literature and judical opinions and arguments in favor of such admissibility. The thesis presented in the article is that the restriction of exclusion of pre-emptive right of current shareholders is de lege lata admissible in the procedure of “simplified increase of share capital.&rdquo

Conditional share capital increase

Przedmiotem pracy jest jeden ze szczególnych trybów podwyższenia kapitału zakładowego w spółkach akcyjnych, jakim jest warunkowe podwyższenie kapitału zakładowego. Został on wprowadzony wraz z wejściem w życie ustawy z dnia 15 września 2000 r. - Kodeks Spółek Handlowych (Dz.U. Nr 94, poz. 1037 ze zm.) i jest ściśle powiązany z hybrydowymi papierami wartościowymi, do których w polskim systemie prawnym należą obligacje zamienne, obligacje z prawem pierwszeństwa oraz warranty subskrypcyjne. Cechą wspólną obligacji zamiennych, obligacji z prawem pierwszeństwa oraz subskrypcyjnych jest to, że przez inkorporację w nich prawa do objęcia akcji zostały one konstrukcyjnie powiązane z instytucją warunkowego podwyższenia kapitału zakładowego. Instytucja ta jest ramą, w obrębie której prawo do objęcia akcji może powstać oraz być wykonywane. Poszczególne elementy warunkowego podwyższenia kapitału zakładowego determinują zatem powstanie, trwanie oraz wygaśnięcie tego prawa. Elementy kapitału warunkowego pozostają ze sobą w określonej relacji oraz wzajemnie na siebie wpływają a decyzje podjęte przez uczestników podwyższenia (akcjonariuszy, spółkę oraz wierzycieli spółki) decydują o jego dalszych losach. Z tego względu praca eksponuje proceduralny charakter instytucji warunkowego podwyższenia kapitału zakładowego, rozumianej jako pewien ciąg czynności prawnych i faktycznych, nakierowanych na powstanie oraz wygaśnięcie prawa do objęcia akcji oraz finalne wykreowanie praw udziałowych w spółce akcyjnej. Analiza obejmuje etapy od kreacji podstawy prawnej dla warunkowego podwyższenia kapitału zakładowego, przez powstanie prawa do objęcia akcji, jego wykonanie, zawarcie umowy objęcia akcji w kapitale warunkowo podwyższonym, wniesienie wkładów na kapitał zakładowy, wydanie akcji, aż do chwili zgłoszenia do sądu rejestrowego wykazu wydanych akcji. Wielopłaszczyznowy charakter omawianej instytucji spowodował, że w zakres analizy włączona została nie tylko materia Kodeksu Spółek Handlowych, lecz również ustawy z dnia 23 kwietnia 1964 r. – Kodeks Cywilny (Dz.U. Nr 16, poz. 93 ze zm.), ustawy z dnia 15 stycznia 2015 r. o obligacjach (Dz.U. z 2015 r. poz. 238 ze zm.) jak również, w ograniczonym zakresie, problematyka prawa rynku kapitałowego. Zastosowano w niej standardowe narzędzia wykładni prawa, tj. wykładnię językową, systemową oraz funkcjonalną, w ramach której uwzględniono również wykładnię proeuropejską omawianych przepisów. Praca zawiera także liczne odniesienia prawno-porównawcze, jako że polski model warunkowego podwyższenia kapitału zakładowego jest wprost wzorowany na rozwiązaniu niemieckim. W końcowej części została podjęta próba opisu polskiego systemu ochrony wierzycieli z tytułu prawa do objęcia akcji przed rozwodnieniem ich praw.Conditional share capital increase The summary - English language version The subject of this work is one of the special modes to increase the share capital in joint-stock companies, which is a conditional increase in share capital. It was introduced with the entry into force of the Act of 15 September 2000 - Commercial Code (OJ # 94, item. 1037 as amended) and is closely linked with hybrid securities, which in the Polish legal system include convertible bonds, bonds with warrants and subscription warrants. A common feature of convertible bonds, bonds with warrants and subscription warrants is that through the incorporation of the rights to subscribe for shares they are structurally related to the institution of the conditional share capital increase. This institution is the frame within which the right to subscribe for shares may arise and be executed. The individual elements of the conditional share capital determine therefore rise, duration and termination of this right. Elements of the contingent capital remain in a particular relationship and affect each other and the decisions taken by the participants of an increase (of the shareholders, the company and the creditors of the company) decide on its further fate. Due to this aspect the aim of this work is to highlight the procedural nature of the conditional share capital increase, perceived as a string of legal and factual actions aimed to create and terminate the right to subscribe for shares resulting in creation of final equity rights in the joint-stock company. The analysis begins with a creation of a legal basis for the conditional share capital increase, then moves to the following aspects: the rise of the rights to subscribe for shares, its execution, conclusion of the contract to subscribe for shares in the capital conditionally heightened, transfer of the contribution to the share capital and the notification to the court the list of issued shares. As a result of a complicated nature of this institution the scope of the analysis encompasses not only the content of the commercial companies code, but also the Act of 23 April 1964 - Civil Code (OJ # 16, item. 93 as amended), the Act of 15 January 2015 on bonds (Journal of laws of 2015 r. item 238 as amended) as well as, to a limited extent, the matters relating to capital market law. It features a standard tool of construing the law: linguistic, systemic and a functional method, which also includes the pro-european analysis of law. The work contains numerous comparative references, as the Polish model of the conditional share capital increase is directly derives from the German solution. This work is concluded with an attempt to describe the Polish system of protection of creditors in respect of the right to subscribe for shares against a dilution of their rights

Characterization of the molecular mechanisms for p53-mediated differentiation

The p53 tumor suppressor protein can induce both apoptosis and cell cycle arrest. Moreover, we and others have shown previously that p53 is a potent mediator of differentiation. For example, expression of ptsp53, a temperature-inducible form of p53, induces differentiation of leukemic monoblastic U-937 cells. The functions of p53 have for long been believed to be dependent on the transactivating capacity of p53. However, recent data show that both p53-induced cell cycle arrest and apoptosis can be induced independently of p53-mediated transcriptional activation, indicating alternative pathways for p53-induced apoptosis and cell cycle arrest. The bcl-2 proto-oncogene contributes to the development of certain malignancies, probably by inhibition of apoptosis. Interestingly, Bcl-2 has been shown to inhibit p53-mediated apoptosis as well as p53-mediated transcriptional activation. Asking whether Bcl-2 would interfere with the p53-mediated differentiation of U-937 cells, we stably transfected bcl-2 to U-937 cells inducibly expressing p53. Although the established Bcl-2-expressing clones were resistant to p53-mediated apoptosis, we did not observe any interference of Bcl-2 with the p53-mediated differentiation, suggesting separable pathways for p53 in mediating apoptosis and differentiation of U-937 cells. Neither did expression of Bcl-2 interfere with p53-induced expression of endogenous p21, suggesting that p53-induced differentiation might be dependent on the transcriptional activity of p53. To further investigate whether the p53-mediated differentiation of U-937 cells depends on the transcriptional activity of p53, we overexpressed transactivation-deficient p53, a transcriptionally inactive p53 mutant in these cells. However, in contrast to the effects of wild-type p53, expression of trans-activation-deficient p53 did neither induce signs of apoptosis nor of differentiation in U-937 cells. Our results indicate that the transcriptional activity of p53 is essential both for p53-mediated apoptosis and differentiation of U-937 cells

p53-mediated differentiation of the erythroleukemia cell line K562

The tumor suppressor gene p53 can mediate both apoptosis and cell cycle arrest. In addition, p53 also influences differentiation. To further characterize the differentiation inducing properties of p53, we overexpressed a temperature-inducible p53 mutant (ptsp53Val135) in the erythroleukemia cell line K562. The results show that wild-type p53 and hemin synergistically induce erythroid differentiation of K562 cells, indicating that p53 plays a role in the molecular regulation of differentiation. However, wild-type p53 did not affect phorbol 12-myristate 13-acetate-dependent appearance of the megakaryocyte-related cell surface antigens CD9 and CD61, suggesting that p53 does not generally affect phenotypic modulation. The cyclin-dependent kinase inhibitor p21, a transcriptional target of p53, halts the cell cycle in G1 and has also been implicated in the regulation of differentiation and apoptosis. However, transiently overexpressed p21 did neither induce differentiation nor affect the cell cycle distribution or viability of K562 cells, suggesting that targets downstream of p53 other than p21 are critical for the p53-mediated differentiation response