Defects in mitochondrial fatty acid synthesis result in failure of multiple aspects of mitochondrial biogenesis in Saccharomyces cerevisiae

Mitochondrial fatty acid synthesis (mtFAS) shares acetyl‐CoA with the Krebs cycle as a common substrate and is required for the production of octanoic acid (C8) precursors of lipoic acid (LA) in mitochondria. MtFAS is a conserved pathway essential for respiration. In a genetic screen in Saccharomyces cerevisiae designed to further elucidate the physiological role of mtFAS, we isolated mutants with defects in mitochondrial post‐translational gene expression processes, indicating a novel link to mitochondrial gene expression and respiratory chain biogenesis. In our ensuing analysis, we show that mtFAS, but not lipoylation per se, is required for respiratory competence. We demonstrate that mtFAS is required for mRNA splicing, mitochondrial translation and respiratory complex assembly, and provide evidence that not LA per se, but fatty acids longer than C8 play a role in these processes. We also show that mtFAS‐ and LA‐deficient strains suffer from a mild haem deficiency that may contribute to the respiratory complex assembly defect. Based on our data and previously published information, we propose a model implicating mtFAS as a sensor for mitochondrial acetyl‐CoA availability and a co‐ordinator of nuclear and mitochondrial gene expression by adapting the mitochondrial compartment to changes in the metabolic status of the cell.     

Effects of potassium and gibberellic acid on stem growth of whole sunflower plants

Abstract The effects of gibberellic acid (GA₃) on whole sunflower (Helianthus annuus L.) plants grown at three potassium (K) levels (0.0, 0.5 and 5.0 mM) were studied. A tenfold increase in the length of the first internode was observed when plants grown without K were treated with GA₃. The uneven K distribution along the plant (higher K content in the higher internodes) was enhanced by GA₃ treatment. Gibberellic acid increased the content of reducing sugars, especially in K-deficient plants. An increase in the K level in the nutrient solution resulted in a decrease of the osmotic potential of stem segments. Osmotic potential differences within the elongating first internode were increased by GA₃ treatment.     

A taxonomic revision of the Hilara maura-group (Diptera: Empididae) in Europe

Abstract. The European species of the Hilara maura-group are revised. Three species are described as new to science, namely, H.nitidorella sp.n., H.discalis sp.n. (both temperate Central and Western Europe) and H.mauroides sp.n. (Caucasus, male only). A further five species, H.hybrida Collin, H.femorella Zetterstedt, H.sulcitarsis Strobl, H.tyrolensis Strobl and H.bartaki Straka are redescribed, and H.eumera Loew, 1873 becomes a new synonym of H.nitidula Zetterstedt, 1838. Seven lectotypes are designated. All IS European species are keyed, the main differential characters are illustrated, and additional data on biology and distribution are given. The Hilara maura-group is recognized as a monophyletic group within the genus, characterized by a set of apomorphous characters, and the hypothetical phylogenetic relationships of the species, classified into four natural complexes, are demonstrated.     

Systemic Monocytic-MDSCs Are Generated from Monocytes and Correlate with Disease Progression in Breast Cancer Patients

Myeloid-derived suppressor cells (MDSCs) are highly immunosuppressive myeloid cells, which increase in cancer patients. The molecular mechanism behind their generation and function is unclear. Whereas granulocytic-MDSCs correlate with poor overall survival in breast cancer, the presence and relevance of monocytic-MDSCs (Mo-MDSCs) is unknown. Here we report for the first time an enrichment of functional blood Mo-MDSCs in breast cancer patients before they acquire a typical Mo-MDSC surface phenotype. A clear population of Mo-MDSCs with the typical cell surface phenotype (CD14⁺HLA-DR^low/-CD86^low/-CD80^low/-CD163^low/-) increased significantly first during disease progression and correlated to metastasis to lymph nodes and visceral organs. Furthermore, monocytes, comprising the Mo-MDSC population, from patients with metastatic breast cancer resemble the reprogrammed immunosuppressive monocytes in patients with severe infections, both by their surface and functional phenotype but also at their molecular gene expression profile. Our data suggest that monitoring the Mo-MDSC levels in breast cancer patients may represent a novel and simple biomarker for assessing disease progression.     

Vestiges of an ancestral host plant: preference and performance in the butterfly Polygonia faunus and its sister species P. c‐album

1. In the study of the evolution of insect–host plant interactions, important information is provided by host ranking correspondences among female preference, offspring preference, and offspring performance. Here, we contrast such patterns in two polyphagous sister species in the butterfly family Nymphalidae, the Nearctic Polygonia faunus, and the Palearctic P. c‐album. 2. These two species have similar host ranges, but according to the literature P. faunus does not use the ancestral host plant clade – the ‘urticalean rosids’. Comparisons of the species can thus test the effects of a change in insect–plant associations over a long time scale. Cage experiments confirmed that P. faunus females avoid laying eggs on Urtica dioica (the preferred host of P. c‐album), instead preferring Salix, Betula, and Ribes. 3. However, newly hatched larvae of both species readily accept and grow well on U. dioica, supporting the general theory that evolutionary changes in host range are initiated through shifts in female host preferences, whereas larvae are more conservative and also can retain the capacity to perform well on ancestral hosts over long time spans. 4. Similar rankings of host plants among female preference, offspring preference, and offspring performance were observed in P. c‐album but not in P. faunus. This is probably a result of vestiges of larval adaptations to the lost ancestral host taxon in the latter species. 5. Female and larval preferences seem to be largely free to evolve independently, and consequently larval preferences warrant more attention.     

Eleven Candidate Susceptibility Genes for Common Familial Colorectal Cancer

Hereditary factors are presumed to play a role in one third of colorectal cancer (CRC) cases. However, in the majority of familial CRC cases the genetic basis of predisposition remains unexplained. This is particularly true for families with few affected individuals. To identify susceptibility genes for this common phenotype, we examined familial cases derived from a consecutive series of 1514 Finnish CRC patients. Ninety-six familial CRC patients with no previous diagnosis of a hereditary CRC syndrome were included in the analysis. Eighty-six patients had one affected first-degree relative, and ten patients had two or more. Exome sequencing was utilized to search for genes harboring putative loss-of-function variants, because such alterations are likely candidates for disease-causing mutations. Eleven genes with rare truncating variants in two or three familial CRC cases were identified: UACA, SFXN4, TWSG1, PSPH, NUDT7, ZNF490, PRSS37, CCDC18, PRADC1, MRPL3, and AKR1C4. Loss of heterozygosity was examined in all respective cancer samples, and was detected in seven occasions involving four of the candidate genes. In all seven occasions the wild-type allele was lost (P = 0.0078) providing additional evidence that these eleven genes are likely to include true culprits. The study provides a set of candidate predisposition genes which may explain a subset of common familial CRC. Additional genetic validation in other populations is required to provide firm evidence for causality, as well as to characterize the natural history of the respective phenotypes.     

Anti-tumor effects of rigosertib in high-risk neuroblastoma

High-risk neuroblastoma has a poor prognosis despite intense treatment, demonstrating the need for new therapeutic strategies. Here we evaluated the effects of rigosertib (ON-01910.Na) in preclinical models of high-risk neuroblastoma. Among several hundred cancer cell lines representing 24 tumor types, neuroblastoma was the most sensitive to rigosertib. Treatment of MYCN-amplified neuroblastoma organoids resulted in organoid disintegration, decreased cell viability, and increased apoptotic cell death. Neuroblastoma response to rigosertib involved G2M cell cycle arrest and decreased phosphorylation of AKT (Ser473) and ERK1/2 (Thr202/Tyr204). Rigosertib delayed tumor growth and prolonged survival of mice carrying neuroblastoma MYCN-amplified PDX tumors (median survival: 31 days, treated; 22 days, vehicle) accompanied with increased apoptosis in treated tumors. We further identified vincristine and rigosertib as a potential promising drug combination treatment. Our results show that rigosertib might be a useful therapeutic agent for MYCN-amplified neuroblastomas, especially in combination with existing agents.     

Allatostatin-like peptide in the brain-retrocerebral complex of the earwig Labidura riparia: cyclic variations related to the reproductive cycle

Summary

A polyclonal antibody raised against allatostatin-3 of Blattella germanica (BLAST-3) has been used to immunolocalize allatostatin-like peptides in the brain-retrocerebral complex of Labidura riparia adult females. Strongly stained immunoreactive cells are observed in the pars intercerebralis (14 cells) and mainly in the pars lateralis (32 cells). Fibres leading to the corpus allatum are also stained. In the deutocerebrum, one cell is immunostained at the root of each antennal nerve. In the tritocerebmm two cells in each brain hemisphere are weakly immunostained. During the reproductive cycle, these cells and their axons show immunoreactivity at previtellogenic, ovulation and ovarian arrest periods. During vitellogenesis, immunoreactivity is restricted to only four perikarya in the pars intercerebralis.

When young vitellogenic females are injected with 20-hydroxyecdysone (20E), which inhibits vitellogenesis, full immunoreactivity reappears, suggesting sensibility of these cells to 20E as is expected for a negative feed-back loop (Sayah et al., 1995).

These results show that BLAST-3-like material is produced periodically in Labidura in correlation with low levels of juvenile hormone and the absence of vitellogenesis. This study contributes to provide information on the degree of homology of allatostatins across various insects.     

Barriers and facilitators to implement shared decision making in multidisciplinary sciatica care: a qualitative study

Background

Venous thromboembolism (VTE) is a common preventable cause of mortality in hospitalized medical patients. Despite rigorous randomized trials generating strong recommendations for anticoagulant use to prevent VTE, nearly 40% of medical patients receive inappropriate thromboprophylaxis. Knowledge-translation strategies are needed to bridge this gap.

Methods

We conducted a 16-week pilot cluster randomized controlled trial (RCT) to determine the proportion of medical patients that were appropriately managed for thromboprophylaxis (according to the American College of Chest Physician guidelines) within 24 hours of admission, through the use of a multicomponent knowledge-translation intervention. Our primary goal was to determine the feasibility of conducting this study on a larger scale. The intervention comprised clinician education, a paper-based VTE risk assessment algorithm, printed physicians’ orders, and audit and feedback sessions. Medical wards at six hospitals (representing clusters) in Ontario, Canada were included; three were randomized to the multicomponent intervention and three to usual care (i.e., no active strategies for thromboprophylaxis in place). Blinding was not used.

Results

A total of 2,611 patients (1,154 in the intervention and 1,457 in the control group) were eligible and included in the analysis. This multicomponent intervention did not lead to a significant difference in appropriate VTE prophylaxis rates between intervention and control hospitals (appropriate management rate odds ratio = 0.80; 95% confidence interval: 0.50, 1.28; p = 0.36; intra-class correlation coefficient: 0.022), and thus was not considered feasible. Major barriers to effective knowledge translation were poor attendance by clinical staff at education and feedback sessions, difficulty locating preprinted orders, and lack of involvement by clinical and administrative leaders. We identified several factors that may increase uptake of a VTE prophylaxis strategy, including local champions, support from clinical and administrative leaders, mandatory use, and a simple, clinically relevant risk assessment tool.

Conclusions

Hospitals allocated to our multicomponent intervention did not have a higher rate of medical inpatients appropriately managed for thromboprophylaxis than did hospitals that were not allocated to this strategy.