Interstitial deletion (2)(p13p15)

Summary A dysmorphic 5-year-old girl with severe growth and mental deficiency was studied. She presented a de novo interstitial 2p deletion. Karyotype: 46,XX,del(2)(p13p15).     

The breakthrough paradox: How focusing on one form of innovation jeopardizes the advancement of science

Research needs a balance of risk‐taking in “breakthrough projects” and gradual progress. For building a sustainable knowledge base, it is indispensable to provide support for both. Subject Categories: Careers, Economics, Law & Politics, Science Policy & Publishing

Science is about venturing into the unknown to find unexpected insights and establish new knowledge. Increasingly, academic institutions and funding agencies such as the European Research Council (ERC) explicitly encourage and support scientists to foster risky and hopefully ground‐breaking research. Such incentives are important and have been greatly appreciated by the scientific community. However, the success of the ERC has had its downsides, as other actors in the funding ecosystem have adopted the ERC’s focus on “breakthrough science” and respective notions of scientific excellence. We argue that these tendencies are concerning since disruptive breakthrough innovation is not the only form of innovation in research. While continuous, gradual innovation is often taken for granted, it could become endangered in a research and funding ecosystem that places ever higher value on breakthrough science. This is problematic since, paradoxically, breakthrough potential in science builds on gradual innovation. If the value of gradual innovation is not better recognized, the potential for breakthrough innovation may well be stifled.

While continuous, gradual innovation is often taken for granted, it could become endangered in a research and funding ecosystem that places ever higher value on breakthrough science.

Concerns that the hypercompetitive dynamics of the current scientific system may impede rather than spur innovative research have been voiced for many years (Alberts et al, 2014). As performance indicators continue to play a central role for promotions and grants, researchers are under pressure to publish extensively, quickly, and preferably in high‐ranking journals (Burrows, 2012). These dynamics increase the risk of mental health issues among scientists (Jaremka et al, 2020), dis‐incentivise relevant and important work (Benedictus et al, 2016), decrease the quality of scientific papers (Sarewitz, 2016) and induce conservative and short‐term thinking rather than risk‐taking and original thinking required for scientific innovation (Alberts et al, 2014; Fochler et al, 2016). Against this background, strong incentives for fostering innovative and daring research are indispensable.     

Top3α Is Required during the Convergent Migration Step of Double Holliday Junction Dissolution

Although Blm and Top3α are known to form a minimal dissolvasome that can uniquely undo a double Holliday junction structure, the details of the mechanism remain unknown. It was originally suggested that Blm acts first to create a hemicatenane structure from branch migration of the junctions, followed by Top3α performing strand passage to decatenate the interlocking single strands. Recent evidence suggests that Top3α may also be important for assisting in the migration of the junctions. Using a mismatch-dHJ substrate (MM-DHJS) and eukaryotic Top1 (in place of Top3α), we show that the presence of a topoisomerase is required for Blm to substantially migrate a topologically constrained Holliday junction. When investigated by electron microscopy, these migrated structures did not resemble a hemicatenane. However, when Blm is together with Top3α, the dissolution reaction is processive with no pausing at a partially migrated structure. Potential mechanisms are discussed.     

Biochemical evidence accumulates across neurons to drive a network-level eruption

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Targeting of malate synthase 1 to the peroxisomes of Saccharomyces cerevisiae cells depends on growth on oleic acid medium.

The eukaryotic glyoxylate cycle has been previously hypothesized to occur in the peroxisomal compartment, which in the yeast Saccharomyces cerevisiae additionally represents the sole site for fatty acid beta-oxidation. The subcellular location of the key glyoxylate-cycle enzyme malate synthase 1 (Mls1p), an SKL-terminated protein, was examined in yeast cells grown on different carbon sources. Immunoelectron microscopy in combination with cell fractionation showed that Mls1p was abundant in the peroxisomes of cells grown on oleic acid, whereas in ethanol-grown cells Mls1p was primarily cytosolic. This was reinforced using a green fluorescent protein (GFP)-Mls1p reporter, which entered peroxisomes solely in cells grown under oleic acid-medium conditions. Although growth of cells devoid of Mls1p on ethanol or acetate could be fully restored using a cytosolic Mls1p devoid of SKL, this construct could only partially alleviate the requirement for native Mls1p in cells grown on oleic acid. The combined results indicated that Mls1p remained in the cytosol of cells grown on ethanol, and that targeting of Mls1p to the peroxisomes was advantageous to cells grown on oleic acid as a sole carbon source.     

Systematic epistatic mapping of cellular processes

Genetic screens have identified many novel components of various biological processes, such as components required for cell cycle and cell division. While forward genetic screens typically generate unstructured ‘hit’ lists, genetic interaction mapping approaches can identify functional relations in a systematic fashion. Here, we discuss a recent study by our group demonstrating a two-step approach to first screen for regulators of the mitotic cell cycle, and subsequently guide hypothesis generation by using genetic interaction analysis. The screen used a high-content microscopy assay and automated image analysis to capture defects during mitotic progression and cytokinesis. Genetic interaction networks derived from process-specific features generate a snapshot of functional gene relations in those processes, which follow a temporal order during the cell cycle. This complements a recently published approach, which inferred directional genetic interactions reconstructing hierarchical relationships between genes across different phases during mitotic progression. In conclusion, this strategy leverages unbiased, genome-wide, yet highly sensitive and process-focused functional screening in cells.     

Rhipsalis (Cactaceae): loss and gain of floral rewards is mirrored in range sizes and distribution patterns of species

Autogamous species are usually distinguishable from xenogamous relatives by smaller flowers, fewer or even no floral rewards and lower pollen–ovule (P/O) ratios. Many Rhipsalis spp. are small flowered, selfing and include the most widespread species in Cactaceae. However, Rhipsalis also includes a large number of narrowly endemic species and is most diverse in the Atlantic rainforests of Brazil. To investigate the evolution of floral function and the correlation between floral function and range size, we analysed display size, floral reward and P/O ratios of Rhipsalis and its closest relatives, reconstructed ancestral traits and related these patterns to the distributions and range sizes of the species. Display size and sugar amount are reduced in subgenera Goniorhipsalis and Rhipsalis and secondarily increased in Phyllarthrorhipsalis, whereas the P/O ratio is decreased in subgenera Rhipsalis and Phyllarthrorhipsalis. We interpret this pattern as a switch from a predominantly xenogamous to an autogamous reproductive system, followed by a return to a predominantly xenogamous system. None of the floral parameters shows significant correlations with range size, except for display size. Nevertheless, those species with the smallest flowers, lowest sugar amounts per flower and lowest P/O ratios occur either outside southeastern Brazil and/or have comparatively large distribution ranges. Almost all Rhipsalis spp. occurring outside the Atlantic rainforests are restricted to the clade formed by subgenera Rhipsalis and Phyllarthrorhipsalis. Thus, we believe that the evolution of an autogamous reproduction system enabled this lineage of Rhipsalis to diversify and spread in the Atlantic rainforests, in the rest of the Neotropics and even spread to the Old World, where it is the only member of the family.     

Impact of miR-21, miR-126 and miR-221 as Prognostic Factors of Clear Cell Renal Cell Carcinoma with Tumor Thrombus of the Inferior Vena Cava

Clear cell renal cell carcinoma (ccRCC) characterized by a tumor thrombus (TT) extending into the inferior vena cava (IVC) generally indicates poor prognosis. Nevertheless, the risk for tumor recurrence after nephrectomy and thrombectomy varies. An applicable and accurate prediction system to select ccRCC patients with TT of the IVC (ccRCC/TT) at high risk after nephrectomy is urgently needed, but has not been established up to now. To our knowledge, a possible role of microRNAs (miRs) for the development of ccRCC/TT or their impact as prognostic markers in ccRCC/TT has not been explored yet. Therefore, we analyzed the expression of the previously described onco-miRs miR-200c, miR-210, miR-126, miR-221, let-7b, miR-21, miR-143 and miR-141 in a study collective of 74 ccRCC patients. Using the expression profiles of these eight miRs we developed classification systems that accurately differentiate ccRCC from non-cancerous renal tissue and ccRCC/TT from tumors without TT. In the subgroup of 37 ccRCC/TT cases we found that miR-21, miR-126, and miR-221 predicted cancer related death (CRD) accurately and independently from other clinico-pathological features. Furthermore, a combined risk score based on the expression of miR-21, miR-126 and miR-221 was developed and showed high sensitivity and specificity to predict cancer specific survival (CSS) in ccRCC/TT. Using the combined risk score we were able to classify ccRCC/TT patients correctly into high and low risk cases. The risk stratification by the combined risk score (CRS) will benefit from further cohort validation and might have potential for clinical application as a molecular prediction system to identify high- risk ccRCC/TT patients.