The potato developer (D) locus encodes an R2R3 MYB transcription factor that regulates expression of multiple anthocyanin structural genes in tuber skin

A dominant allele at the D locus (also known as I in diploid potato) is required for the synthesis of red and purple anthocyanin pigments in tuber skin. It has previously been reported that D maps to a region of chromosome 10 that harbors one or more homologs of Petuniaan2, an R2R3 MYB transcription factor that coordinately regulates the expression of multiple anthocyanin biosynthetic genes in the floral limb. To test whether D acts similarly in tuber skin, RT-PCR was used to evaluate the expression of flavanone 3-hydroxylase (f3h), dihydroflavonol 4-reductase (dfr) and flavonoid 3′,5′-hydroxylase (f3′5′h). All three genes were expressed in the periderm of red- and purple-skinned clones, while dfr and f3′5′h were not expressed, and f3h was only weakly expressed, in white-skinned clones. A potato cDNA clone with similarity to an2 was isolated from an expression library prepared from red tuber skin, and an assay developed to distinguish the two alleles of this gene in a diploid potato clone known to be heterozygous Dd. One allele was observed to cosegregate with pigmented skin in an F1 population of 136 individuals. This allele was expressed in tuber skin of red- and purple-colored progeny, but not in white tubers, while other parental alleles were not expressed in white or colored tubers. The allele was placed under the control of a doubled 35S promoter and transformed into the light red-colored cultivar Désirée, the white-skinned cultivar Bintje, and two white diploid clones known to lack the functional allele of D. Transformants accumulated pigment in tuber skin, as well as in other tissues, including young foliage, flower petals, and tuber flesh

Unity between God and mind? A study on the relationship between panpsychism and pantheism

The author thanks the John Templeton Foundation and The Pantheism and Panentheism Project for sponsoring this paperA number of contemporary philosophers have suggested that the recent revival of interest in panpsychism within philosophy of mind could reinvigorate a pantheistic philosophy of religion. This project explores whether the combination and individuation problems, which have dominated recent scholarship within panpsychism, can aid the pantheist’s articulation a God/Universe Unity. Constitutive holistic panpsychism is seen to be the only type of panpsychism suited to aid pantheism in articulating this type of unity. There are currently no well-developed solutions to the individuation problem for this type of panpsychism. Moreover, the gestures towards a solution appear costly to the religious significance of pantheism. This article concludes that any hope that the contemporary panpsychism might aid pantheists in articulating Unity is premature and possibly misplaced.Publisher PDFPeer reviewe

Genetic regulation of MUC1 alternative splicing in human tissues

The membrane mucin MUC1 is aberrantly expressed in a variety of cancers, and in stomach, it is a ligand for Helicobacter pylori where it plays a role in gastric carcinogenesis. Splicing variation, leading to a 9-amino acid insertion in the signal peptide region, was proposed to be because of a single-nucleotide polymorphism (rs4072037) at the 5′ end of exon 2, but is also reported to be cancer-associated. However, the effect of rs4072037 on this splicing event in healthy non-cancer tissues and on the additional spliceoforms of MUC1, including those lacking the polymorphic tandem repeat (TR) domain, has never been investigated. Here we show that in both foetal and adult tissues of known genotype, there is clear evidence for the role of rs4072037 in controlling alternative splicing of the 5′ exon 2 region of both full-length transcripts and those lacking the TR domain. Although there is some evidence for additional genetic and epigenetic influences, there is no indication of an effect of the TR domain on the proportions of the spliceoforms. In conclusion, over-representation of certain transcripts in tumour material cannot be evaluated without information on the SNP genotype as well

Genetic and Chemical Modifiers of a CUG Toxicity Model in Drosophila

Non-coding CUG repeat expansions interfere with the activity of human Muscleblind-like (MBNL) proteins contributing to myotonic dystrophy 1 (DM1). To understand this toxic RNA gain-of-function mechanism we developed a Drosophila model expressing 60 pure and 480 interrupted CUG repeats in the context of a non-translatable RNA. These flies reproduced aspects of the DM1 pathology, most notably nuclear accumulation of CUG transcripts, muscle degeneration, splicing misregulation, and diminished Muscleblind function in vivo. Reduced Muscleblind activity was evident from the sensitivity of CUG-induced phenotypes to a decrease in muscleblind genetic dosage and rescue by MBNL1 expression, and further supported by the co-localization of Muscleblind and CUG repeat RNA in ribonuclear foci. Targeted expression of CUG repeats to the developing eye and brain mushroom bodies was toxic leading to rough eyes and semilethality, respectively. These phenotypes were utilized to identify genetic and chemical modifiers of the CUG-induced toxicity. 15 genetic modifiers of the rough eye phenotype were isolated. These genes identify putative cellular processes unknown to be altered by CUG repeat RNA, and they include mRNA export factor Aly, apoptosis inhibitor Thread, chromatin remodelling factor Nurf-38, and extracellular matrix structural component Viking. Ten chemical compounds suppressed the semilethal phenotype. These compounds significantly improved viability of CUG expressing flies and included non-steroidal anti-inflammatory agents (ketoprofen), muscarinic, cholinergic and histamine receptor inhibitors (orphenadrine), and drugs that can affect sodium and calcium metabolism such as clenbuterol and spironolactone. These findings provide new insights into the DM1 phenotype, and suggest novel candidates for DM1 treatments

Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme

BACKGROUND: The relevance of angiogenesis inhibition in the treatment of glioblastoma multiforme (GBM) should be considered in the unique context of malignant brain tumours. Although patients benefit greatly from reduced cerebral oedema and intracranial pressure, this important clinical improvement on its own may not be considered as an anti-tumour effect. DISCUSSION: GBM can be roughly separated into an angiogenic component, and an invasive or migratory component. Although this latter component seems inert to anti-angiogenic therapy, it is of major importance for disease progression and survival. We reviewed all relevant literature. Published data support that clinical symptoms are tempered by anti-angiogenic treatment, but that tumour invasion continues. Unfortunately, current imaging modalities are affected by anti-angiogenic treatment too, making it even harder to define tumour margins. To illustrate this we present MRI, biopsy and autopsy specimens from bevacizumab-treated patients. Moreover, while treatment of other tumour types may be improved by combining chemotherapy with anti-angiogenic drugs, inhibiting angiogenesis in GBM may antagonise the efficacy of chemotherapeutic drugs by normalising the blood-brain barrier function. SUMMARY: Although angiogenesis inhibition is of considerable value for symptom reduction in GBM patients, lack of proof of a true anti-tumour effect raises concerns about the place of this type of therapy in the treatment of GBM

A Template-Dependent Dislocation Mechanism Potentiates K65R Reverse Transcriptase Mutation Development in Subtype C Variants of HIV-1

Numerous studies have suggested that the K65R reverse transcriptase (RT) mutation develops more readily in subtype C than subtype B HIV-1. We recently showed that this discrepancy lies partly in the subtype C template coding sequence that predisposes RT to pause at the site of K65R mutagenesis. However, the mechanism underlying this observation and the elevated rates of K65R development remained unknown. Here, we report that DNA synthesis performed with subtype C templates consistently produced more K65R-containing transcripts than subtype B templates, regardless of the subtype-origin of the RT enzymes employed. These findings confirm that the mechanism involved is template-specific and RT-independent. In addition, a pattern of DNA synthesis characteristic of site-specific primer/template slippage and dislocation was only observed with the subtype C sequence. Analysis of RNA secondary structure suggested that the latter was unlikely to impact on K65R development between subtypes and that Streisinger strand slippage during DNA synthesis at the homopolymeric nucleotide stretch of the subtype C K65 region might occur, resulting in misalignment of the primer and template. Consequently, slippage would lead to a deletion of the middle adenine of codon K65 and the production of a -1 frameshift mutation, which upon dislocation and realignment of the primer and template, would lead to development of the K65R mutation. These findings provide additional mechanistic evidence for the facilitated development of the K65R mutation in subtype C HIV-1

PCNA levels in neuroblastoma are increased in tumors with an amplified N- myc gene and in metastatic stage tumors

N- myc oncogene amplification in neuroblastoma has been found to be significantly associated with advanced stage disease and tumor progression. However, there is a lack of data on tumors, regarding the relationship between N- myc gene amplification and proliferation activity. Proliferating cell nuclear antigen (PCNA) is a proliferation-induced 36 kD nuclear protein that is the auxiliary component of DNA polymerase δ. PCNA levels in tissues have been found to correlate with proliferative activity. We have examined PCNA levels in neuroblastomas in relation to N- myc gene amplification and tumor stage. Statistically, significantly higher levels of PCNA were observed in tumors with an amplified N- myc gene relative to tumors with a single gene copy. The highest levels of PCNA were observed in advanced stage tumors with an amplified N- myc gene. Treatment of neuroblastoma cells in culture with retinoic acid, which induces differentiation, resulted in a substantial decrease in PCNA. Our results suggest that PCNA levels may reflect differences in proliferative activity between neuroblastomas, related to stage of the disease and to N- myc gene copy number.[/p ]Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42581/1/10585_2004_Article_BF00880069.pd

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Whiting–related sediment export along the Middle Miocene carbonate ramp of Great Bahama Bank.

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