FISH mapping and molecular organization of the major repetitive sequences of tomato

This paper presents a bird's-eye view of the major repeats and chromatin types of tomato. Using fluorescence in-situ hybridization (FISH) with Cot-1, Cot-10 and Cot-100 DNA as probes we mapped repetitive sequences of different complexity on pachytene complements. Cot-100 was found to cover all heterochromatin regions, and could be used to identify repeat-rich clones in BAC filter hybridization. Next we established the chromosomal locations of the tandem and dispersed repeats with respect to euchromatin, nucleolar organizer regions (NORs), heterochromatin, and centromeres. The tomato genomic repeats TGRII and TGRIII appeared to be major components of the pericentromeres, whereas the newly discovered TGRIV repeat was found mainly in the structural centromeres. The highly methylated NOR of chromosome 2 is rich in [GACA](4), a microsatellite that also forms part of the pericentromeres, together with [GA](8), [GATA](4) and Ty1-copia. Based on the morphology of pachytene chromosomes and the distribution of repeats studied so far, we now propose six different chromatin classes for tomato: (1) euchromatin, (2) chromomeres, (3) distal heterochromatin and interstitial heterochromatic knobs, (4) pericentromere heterochromatin, (5) functional centromere heterochromatin and (6) nucleolar organizer regio

Processing DNA lesions during mitosis to prevent genomic instability

Failure of cells to process toxic double-strand breaks (DSBs) constitutes a major intrinsic source of genome instability, a hallmark of cancer. In contrast with interphase of the cell cycle, canonical repair pathways in response to DSBs are inactivated in mitosis. Although cell cycle checkpoints prevent transmission of DNA lesions into mitosis under physiological condition, cancer cells frequently display mitotic DNA lesions. In this review, we aim to provide an overview of how mitotic cells process lesions that escape checkpoint surveillance. We outline mechanisms that regulate the mitotic DNA damage response and the different types of lesions that are carried over to mitosis, with a focus on joint DNA molecules arising from under-replication and persistent recombination intermediates, as well as DNA catenanes. Additionally, we discuss the processing pathways that resolve each of these lesions in mitosis. Finally, we address the acute and long-term consequences of unresolved mitotic lesions on cellular fate and genome stability

Somatostatin in the rat periventricular nucleus: sex differences and effect of gonadal steroids

In the rat, the sexual dimorphism in growth hormone release is driven by sex steroids, and is suggested to result mainly from differences in somatostatin (SOM) release patterns from the median eminence. We studied the effect of gonadal steroids on SOM peptide-containing cells in the periventricular nucleus (PeVN) of ovariectomized (OVX) female rats, and compared these data with data from intact male rats. Adult female rats were treated with estradiol (E2) and/or progesterone (P), 3 months (long-term) or 2 weeks (short-term) after ovariectomy (OVX). Perfusion-fixed brains were sliced and stained, and the number of SOM-immunoreactive (-ir) cells and total SOM-ir area (in μm2) were determined using computer assisted analysis. SOM-ir cells in the PeVN showed a very characteristic rostro-caudal distribution and localization in relation to the third ventricle. Both the number of SOM-ir cells and total SOM-ir area in the PeVN were higher in male compared to OVX female rats. Neither the number of SOM-ir cells, nor the total SOM-ir area in the PeVN was affected by E2 or P treatment alone. Treatment with both gonadal steroids, however, did increase total SOM-immunoreactivity. This study is the first to describe SOM cell distribution within the rat PeVN in great detail. A clear sex difference exists in SOM peptide content in the rat PeVN. In addition, E2 and P may act synergistically to affect SOM cells in the female PeVN, suggesting that both gonadal steroids may be involved in the generation of the typical feminine SOM release pattern

Uptake and Effects of the e-Vita Personal Health Record with Self-Management Support and Coaching, for Type 2 Diabetes Patients Treated in Primary Care

We studied the use, uptake, and effects of e-Vita, a personal health record, with self-management support and personalized asynchronized coaching, for type 2 diabetes patients treated in primary care. Patients were invited by their practice nurse to join the study aimed at testing use and effects of a personal health record. Patients were followed up for 6 months. Uptake and usage were monitored using log data. Outcomes were self-reported diabetes self-care, diabetes-related distress, and emotional wellbeing. Patients’ health status was collected from their medical chart. 132 patients agreed to participate in the study of which less than half (46.1%) did not return to the personal health record after 1st login. Only 5 patients used the self-management support program within the personal health record, 3 of whom asked a coach for feedback. Low use of the personal health record was registered. No statistical significant differences on any of the outcome measures were found between baseline and 6 month follow-up. This study showed minimal impact of implementing a personal health record including self-management support in primary diabetes care. Successful adoption of web-based platforms, as ongoing patient centered care, is hard to achieve without additional strategies aimed at enhancing patient motivation and engaging professionals

Testicular cancer: Determinants of cisplatin sensitivity and novel therapeutic opportunities:Determinants of cisplatin sensitivity and novel therapeutic opportunities

Testicular cancer (TC) is the most common solid tumor among men aged between 15 and 40 years. TCs are highly aneuploid and the 12p isochromosome is the most frequent chromosomal abnormality. The mutation rate is of TC is low, with recurrent mutations in  KIT and  KRAS observed only at low frequency in seminomas. Overall cure rates are high, even in a metastatic setting, resulting from excellent cisplatin sensitivity of TCs. Factors contributing to the observed cisplatin sensitivity include defective DNA damage repair and a hypersensitive apoptotic response to DNA damage. Nonetheless, around 10–20% of TC patients with metastatic disease cannot be cured by cisplatin-based chemotherapy. Resistance mechanisms include downregulation of OCT4 and failure to induce PUMA and NOXA, elevated levels of MDM2, and hyperactivity of the PI3K/AKT/mTOR pathway. Several pre-clinical approaches have proven successful in overcoming cisplatin resistance, including specific targeting of PARP, MDM2 or AKT/mTOR combined with cisplatin. Finally, patient-derived xenograft models hold potential for mechanistic studies and pre-clinical validation of novel therapeutic strategies in TC. While clinical trials investigating targeted drugs have been disappointing, pre-clinical successes with chemotherapy and targeted drug combinations fuel the need for further investigation in clinical setting

A face for all seasons:searching for context-specific leadership traits and discovering a general preference for perceived health

Previous research indicates that followers tend to contingently match particular leader qualities to evolutionarily consistent situations requiring collective action (i.e., context-specific cognitive leadership prototypes) and information processing undergoes categorization which ranks certain qualities as first-order context-general and others as second-order context-specific. To further investigate this contingent categorization phenomenon we examined the “attractiveness halo”—a first-order facial cue which significantly biases leadership preferences. While controlling for facial attractiveness, we independently manipulated the underlying facial cues of health and intelligence and then primed participants with four distinct organizational dynamics requiring leadership (i.e., competition vs. cooperation between groups and exploratory change vs. stable exploitation). It was expected that the differing requirements of the four dynamics would contingently select for relatively healthier- or intelligent-looking leaders. We found perceived facial intelligence to be a second-order context-specific trait—for instance, in times requiring a leader to address between-group cooperation—whereas perceived health is significantly preferred across all contexts (i.e., a first-order trait). The results also indicate that facial health positively affects perceived masculinity while facial intelligence negatively affects perceived masculinity, which may partially explain leader choice in some of the environmental contexts. The limitations and a number of implications regarding leadership biases are discussed

Dual mTORC1/2 inhibition sensitizes testicular cancer models to cisplatin treatment

Testicular cancer is the most common cancer type among young men. Despite highly effective cisplatin-based chemotherapy, around 20% of patients with metastatic disease will still die from the disease. The aim of this study was to explore the use of kinase inhibitors to sensitize testicular cancer cells to cisplatin treatment. Activation of kinases, including receptor tyrosine kinases and downstream substrates, was studied in five cisplatin-sensitive or -resistant testicular cancer cell lines using phospho-kinase arrays and Western blotting. The phospho-kinase array showed AKT and S6 to be among the top phosphorylated proteins in testicular cancer cells, which are part of the PI3K/AKT/mTORC pathway. Inhibitors of most active kinases in the PI3K/AKT/mTORC pathway were tested using apoptosis assays and survival assays. Two mTORC1/2 inhibitors, AZD8055 and MLN0128, strongly enhanced cisplatin-induced apoptosis in all tested testicular cancer cell lines. Inhibition of mTORC1/2 blocked phosphorylation of the mTORC downstream proteins S6 and 4E-BP1. Combined treatment with AZD8055 and cisplatin led to reduced clonogenic survival of testicular cancer cells. Two testicular cancer patient-derived xenografts (PDX), either from a chemosensitive or -resistant patient, were treated with cisplatin in the absence or presence of kinase inhibitor. Combined AZD8055 and cisplatin treatment resulted in effective mTORC1/2 inhibition, increased caspase-3 activity, and enhanced tumor growth inhibition. In conclusion, we identified mTORC1/2 inhibition as an effective strategy to sensitize testicular cancer cell lines and PDX models to cisplatin treatment. Our results warrant further investigation of this combination therapy in the treatment of patients with testicular cancer with high-risk relapsed or refractory disease