The App-Runx1 Region Is Critical for Birth Defects and Electrocardiographic Dysfunctions Observed in a Down Syndrome Mouse Model

Down syndrome (DS) leads to complex phenotypes and is the main genetic cause of birth defects and heart diseases. The Ts65Dn DS mouse model is trisomic for the distal part of mouse chromosome 16 and displays similar features with post-natal lethality and cardiovascular defects. In order to better understand these defects, we defined electrocardiogram (ECG) with a precordial set-up, and we found conduction defects and modifications in wave shape, amplitudes, and durations in Ts65Dn mice. By using a genetic approach consisting of crossing Ts65Dn mice with Ms5Yah mice monosomic for the App-Runx1 genetic interval, we showed that the Ts65Dn viability and ECG were improved by this reduction of gene copy number. Whole-genome expression studies confirmed gene dosage effect in Ts65Dn, Ms5Yah, and Ts65Dn/Ms5Yah hearts and showed an overall perturbation of pathways connected to post-natal lethality (Coq7, Dyrk1a, F5, Gabpa, Hmgn1, Pde10a, Morc3, Slc5a3, and Vwf) and heart function (Tfb1m, Adam19, Slc8a1/Ncx1, and Rcan1). In addition cardiac connexins (Cx40, Cx43) and sodium channel sub-units (Scn5a, Scn1b, Scn10a) were found down-regulated in Ts65Dn atria with additional down-regulation of Cx40 in Ts65Dn ventricles and were likely contributing to conduction defects. All these data pinpoint new cardiac phenotypes in the Ts65Dn, mimicking aspects of human DS features and pathways altered in the mouse model. In addition they highlight the role of the App-Runx1 interval, including Sod1 and Tiam1, in the induction of post-natal lethality and of the cardiac conduction defects in Ts65Dn. These results might lead to new therapeutic strategies to improve the care of DS people

The clinical and functional significance of c-Met in breast cancer: a review

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.CMH-Y is funded by a Cancer Research UK Clinical Research Fellowship. JLJ is funded by the Breast Cancer Campaign Tissue Bank

Regulation and functional role of the Runt-related transcription factor-2 in pancreatic cancer

Recent evidence suggests that Runt-related transcription factors play a role in different human tumours. In the present study, the localisation of the Runt-related transcription factor-2 (Runx2), its transcriptional activity, as well as its regulation of expression was analysed in human pancreatic ductal adenocarcinoma (PDAC). Quantitative real-time PCR and immunohistochemistry were used for Runx2 expression and localisation analysis. Runt-related transcription factor-2 expression was silenced using specific siRNA oligonucleotides in pancreatic cancer cells (Panc-1) and immortalised pancreatic stellate cells (IPSCs). Overexpression of Runx2 was achieved using a full-length expression vector. TGF-β1, BMP2, and other cytokines were assessed for their potential to regulate Runx2 expression. There was a 6.1-fold increase in median Runx2 mRNA levels in PDAC tissues compared to normal pancreatic tissues (P<0.0001). Runt-related transcription factor-2 was localised in pancreatic cancer cells, tubular complexes, and PanIN lesions of PDAC tissues as well as in tumour-associated fibroblasts/stellate cells. Coculture of IPSCs and Panc-1 cells, as well as treatment with TGF-β1 and BMP2, led to increased Runx2 expression in Panc-1 cells. Runt-related transcription factor-2 overexpression was associated with decreased MMP1 release as well as decreased growth and invasion of Panc-1 cells. These effects were reversed by Runx2 silencing. In conclusion, Runx2 is overexpressed in PDAC, where it is regulated by certain cytokines such as TGF-β1 and BMP2 in an auto- and paracrine manner. In addition, Runx2 has the potential to regulate the transcription of extracellular matrix modulators such as SPARC and MMP1, thereby influencing the tumour microenvironment

How firms respond to financial restatement: CEO successors and external reactions

Although past studies have paid considerable attention to firms' reputations, few have investigated the actions that firms take following a reputation-damaging event. We identify firms involved in financial earnings restatements and examine whether naming a successor CEO with specific qualities serves to signal the seriousness of a firm's efforts to restore its reputation. Using theories of market signaling, we argue that attributes of successor CEOs significantly influence the reactions of key external constituencies. In particular, firms with more severe restatement tend to name successors who have prior CEO or turnaround experience and a more elite education. The naming of such successors results in more positive reactions from the stock market, financial analysts, and mass media. We argue that these attributes send messages to stakeholders and the broader public about the CEO's credibility and the firm's efforts

Run Away or Stick Together? The Impact of Organization-Specific Adverse Events on Alliance Partner Defection

Alliances are inter-organizational relationships wherein partners agree to engage in joint action and share benefits and burdens. But when might an adverse event that strikes one partner become too burdensome for another partner? Extant theories of alliance instability provide incomplete answers, which is problematic: for stricken organizations, anticipating whether their non-stricken partners will remain in the alliance can be essential for survival. Integrating insights from alliance dynamics and organizational stigma literatures, we theorize how an organization-specific adverse event affects a non-stricken partner's decision to continue with or defect from an alliance by considering factors that shift the balance between cohesive and disruptive forces. We propose that high stigmatization risk will increase the probability of partner defection through two disruptive mechanisms: relational uncertainty and stigma anxiety. Building on the idea that the same factors contributing to alliance formation may also condition partner defection, we theorize about the roles of partner resource interdependencies, relational embeddedness, and perceived partner similarity in amplifying or attenuating disruptive mechanisms triggered by an adverse event. We extend the research on partner defection and alliance instability by advancing an event-based view of alliance instability and specifying the conditions under which an alliance partner might defect

DEVELOPMENT OF HIGHLY EFFICIENT TECHNOLOGICAL EQUIPMENT

The article discusses the problems associated with processing buckwheat on roller deck machines and reducing the amount of crushed kernel. Recently, there has been a tendency to increase the number of processed fractions of buckwheat grain, which significantly improves the quality of the output product. At the same time, this requires more precise adjustment to the working gaps and obtaining the correct shape of the working area (crescent-shaped when processing buckwheat) between the abrasive roller and the deck. The designs of roller deck machines used in the cereal industry and their installation mechanisms are analyzed. The mechanisms used for installing the deck on rolling deck machines do not allow one to accurately set the shape of the working gap and its dimensions. A more advanced mechanism for removing the deck from the abrasive roller and a mechanism for installing the deck on a wedge shape between the deck and the abrasive roller (usually used when processing millet or sorghum) have been proposed. The calculations of working gaps confirm the correct choice of geometric parameters of the abrasive roller, deck and installation mechanisms. The dependences of the minimum working gap on the magnitude of the parallel movement of the deck are determined. The dependences of the difference in working gaps between the deck and the abrasive roller when changing the structural height of the deck were also found. It is shown that asthe deck height is reduced by half, the difference between the maximum working gap and the minimum decreases by four times. This significantly affects the shape of the processing zone and the working dimensions in the active zones of buckwheat peeling. Reducing the deck height under production conditions leads to an increase in the amount of broken grain, due to an increase in the number of grains passes through the hulling machines. Based on the obtained calculation data, the roller deck machine was modernized, and in fact, a new mdel was developed in which the process flow is stabilized, the conditions for feeding grain into the working area are improved, and the working gaps are adjusted optimally in two active zones of buckwheat grain processing. The design of the roller deck machine allows you to select the husks from the kernel and send them to waste bins

Unwinding of the third strand of a DNA triple helix, a novel activity of the SV40 large T-antigen helicase.

We present experiments indicating that the SV40 large T-antigen (T-ag) helicase is capable of unwinding the third strand of DNA triple helices. Intermolecular d(TC)(20)d(GA)(20)d(TC)(20) triplexes were generated by annealing, at pH 5.5, a linearized double-stranded plasmid containing a d(TC)(27).d(GA)27 tract with a (32)P-labeled oligonucleotide consisting of a d(TC)(20) tract flanked by a sequence of 15 nt at the 3'-end. The triplexes remained stable at pH 7.2, as determined by agarose gel electrophoresis and dimethyl sulfate footprinting. Incubation with the T-ag helicase caused unwinding of the d(TC)(20) tract and consequent release of the oligonucleotide, while the plasmid molecules remained double-stranded. ATP was required for this reaction and could not be replaced by the non-hydrolyzable ATP analog AMP-PNP. T-ag did not unwind similar triplexes formed with oligonucleotides containing a d(TC)(20) tract and a 5' flanking sequence or no flanking sequence. These data indicate that unwinding of DNA triplexes by the T-ag helicase must be preceded by binding of the helicase to a single-stranded 3' flanking sequence, then the enzyme migrates in a 3'--> 5' direction, using energy provided by ATP hydrolysis, and causes release of the third strand. Unwinding of DNA triplexes by helicases may be required for processes such as DNA replication, transcription, recombination and repair