Covering: 2008 to August 2020
Polyketides are a family of natural products constructed from simple building blocks to generate a diverse range of often complex chemical structures with biological ...activities of both pharmaceutical and agrochemical importance. Their biosynthesis is controlled by polyketide synthases (PKSs) which catalyse the condensation of thioesters to assemble a functionalised linear carbon chain. Alkyl-branches may be installed at the nucleophilic α- or electrophilic β-carbon of the growing chain. Polyketide β-branching is a fascinating biosynthetic modification that allows for the conversion of a β-ketone into a β-alkyl group or functionalised side-chain. The overall transformation is catalysed by a multi-protein 3-hydroxy-3-methylglutaryl synthase (HMGS) cassette and is reminiscent of the mevalonate pathway in terpene biosynthesis. The first step most commonly involves the aldol addition of acetate to the electrophilic carbon of the β-ketothioester catalysed by a 3-hydroxy-3-methylglutaryl synthase (HMGS). Subsequent dehydration and decarboxylation selectively generates either α,β- or β,γ-unsaturated β-alkyl branches which may be further modified. This review covers 2008 to August 2020 and summarises the diversity of β-branch incorporation and the mechanistic details of each catalytic step. This is extended to discussion of polyketides containing multiple β-branches and the selectivity exerted by the PKS to ensure β-branching fidelity. Finally, the application of HMGS in data mining, additional β-branching mechanisms and current knowledge of the role of β-branches in this important class of biologically active natural products is discussed.
The structural diversity of newly discovered polyketides continues to grow. This review summarises the range of structures with single and multiple β-branches and the mechanistic details of each catalytic step, covering literature from 2008 to August 2020.
The Alternative Lengthening of Telomeres (ALT) pathway is a telomerase-independent pathway for telomere maintenance that is active in a significant subset of human cancers and in vitro immortalized ...cell lines. ALT is thought to involve templated extension of telomeres through homologous recombination, but the genetic or epigenetic changes that unleash ALT are not known. Recently, mutations in the ATRX/DAXX chromatin remodeling complex and histone H3.3 were found to correlate with features of ALT in pancreatic neuroendocrine cancers, pediatric glioblastomas, and other tumors of the central nervous system, suggesting that these mutations might contribute to the activation of the ALT pathway in these cancers. We have taken a comprehensive approach to deciphering ALT by applying genomic, molecular biological, and cell biological approaches to a panel of 22 ALT cell lines, including cell lines derived in vitro. Here we show that loss of ATRX protein and mutations in the ATRX gene are hallmarks of ALT-immortalized cell lines. In addition, ALT is associated with extensive genome rearrangements, marked micronucleation, defects in the G2/M checkpoint, and altered double-strand break (DSB) repair. These attributes will facilitate the diagnosis and treatment of ALT positive human cancers.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The CRISPR-Cas9 system has revolutionized gene editing both at single genes and in multiplexed loss-of-function screens, thus enabling precise genome-scale identification of genes essential for ...proliferation and survival of cancer cells. However, previous studies have reported that a gene-independent antiproliferative effect of Cas9-mediated DNA cleavage confounds such measurement of genetic dependency, thereby leading to false-positive results in copy number-amplified regions. We developed CERES, a computational method to estimate gene-dependency levels from CRISPR-Cas9 essentiality screens while accounting for the copy number-specific effect. In our efforts to define a cancer dependency map, we performed genome-scale CRISPR-Cas9 essentiality screens across 342 cancer cell lines and applied CERES to this data set. We found that CERES decreased false-positive results and estimated sgRNA activity for both this data set and previously published screens performed with different sgRNA libraries. We further demonstrate the utility of this collection of screens, after CERES correction, for identifying cancer-type-specific vulnerabilities.
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IJS, NUK, SBMB, UL, UM, UPUK
We describe a computational method that infers tumor purity and malignant cell ploidy directly from analysis of somatic DNA alterations. The method, named ABSOLUTE, can detect subclonal heterogeneity ...and somatic homozygosity, and it can calculate statistical sensitivity for detection of specific aberrations. We used ABSOLUTE to analyze exome sequencing data from 214 ovarian carcinoma tumor-normal pairs. This analysis identified both pervasive subclonal somatic point-mutations and a small subset of predominantly clonal and homozygous mutations, which were overrepresented in the tumor suppressor genes TP53 and NF1 and in a candidate tumor suppressor gene CDK12. We also used ABSOLUTE to infer absolute allelic copy-number profiles from 3,155 diverse cancer specimens, revealing that genome-doubling events are common in human cancer, likely occur in cells that are already aneuploid, and influence pathways of tumor progression (for example, with recessive inactivation of NF1 being less common after genome doubling). ABSOLUTE will facilitate the design of clinical sequencing studies and studies of cancer genome evolution and intra-tumor heterogeneity.
Wnt/β-catenin signaling plays a key role in the pathogenesis of colon and other cancers; emerging evidence indicates that oncogenic β-catenin regulates several biological processes essential for ...cancer initiation and progression. To decipher the role of β-catenin in transformation, we classified β-catenin activity in 85 cancer cell lines in which we performed genome-scale loss-of-function screens and found that β-catenin active cancers are dependent on a signaling pathway involving the transcriptional regulator YAP1. Specifically, we found that YAP1 and the transcription factor TBX5 form a complex with β-catenin. Phosphorylation of YAP1 by the tyrosine kinase YES1 leads to localization of this complex to the promoters of antiapoptotic genes, including BCL2L1 and BIRC5. A small-molecule inhibitor of YES1 impeded the proliferation of β-catenin-dependent cancers in both cell lines and animal models. These observations define a β-catenin-YAP1-TBX5 complex essential to the transformation and survival of β-catenin-driven cancers.
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► β-catenin-dependent cancers require YAP1 expression for survival ► β-catenin, YAP1, and TBX5 form a complex that drives expression of BIRC5 and BCL2L1 ► YES1 regulates the activity of the β-catenin-YAP1-TBX5 complex ► The YES1 inhibitor dasatinib inhibits the proliferation of β-catenin-active cells
Loss-of-function screens and β-catenin activity profiling in 85 cancer cell lines identified a transcriptional complex composed of YAP1, a known mediator of Hippo signaling, the transcription factor TBX5, and β-catenin. This complex is essential for the proliferation and tumorigenicity of β-catenin-active cell lines.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Efforts to draw inferences about species occurrence frequently account for false negatives, the common situation when individuals of a species are not detected even when a site is occupied. However, ...recent studies suggest the need to also deal with false positives, which occur when species are misidentified so that a species is recorded as detected when a site is unoccupied. Bias in estimators of occupancy, colonization, and extinction can be severe when false positives occur. Accordingly, we propose models that simultaneously account for both types of error. Our approach can be used to improve estimates of occupancy for study designs where a subset of detections is of a type or method for which false positives can be assumed to not occur. We illustrate properties of the estimators with simulations and data for three species of frogs. We show that models that account for possible misidentification have greater support (lower AIC for two species) and can yield substantially different occupancy estimates than those that do not. When the potential for misidentification exists, researchers should consider analytical techniques that can account for this source of error, such as those presented here.
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BFBNIB, FZAB, GIS, IJS, INZLJ, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZRSKP
This study sought to assess, for the first time, the relationship between serum concentrations of the soluble interleukin-1 receptor family member ST2 (sST2) and serial change in left ventricular ...(LV) function after acute myocardial infarction (AMI).
Serum sST2 levels are elevated early after AMI and are associated with lower pre-discharge LV ejection fraction and adverse cardiovascular outcomes.
The sST2 levels were measured in 100 patients (mean age 58.9 +/- 12.0 years; 77% male), admitted with AMI with resultant LV systolic dysfunction, at baseline and at 12 and 24 weeks. Patients underwent cardiac magnetic resonance imaging and measurement of N-terminal pro-brain natriuretic peptide, norepinephrine, and aldosterone at each time point.
Median sST2 decreased from 263.3 pg/ml at baseline to 140.0 pg/ml at 24 weeks (p < 0.001). Serum sST2 correlated significantly with LV ejection fraction at baseline (r = -0.30, p = 0.002) and 24 weeks (r = -0.23, p = 0.026); change in sST2 correlated with change in LV end-diastolic volume index (r = -0.24, p = 0.023). Level of sST2 was positively associated with infarct volume index at baseline (r = 0.26, p = 0.005) and 24 weeks (r = 0.22, p = 0.037), and with change in infarct volume index (r = -0.28, p = 0.001). Level of sST2 was significantly higher in patients with greater infarct transmurality and endocardial extent, and in the presence of microvascular obstruction. Level of sST2 correlated significantly with norepinephrine and aldosterone, but not with N-terminal pro-brain natriuretic peptide.
Measurement of sST2 early after AMI assists in the prediction of medium-term LV functional recovery. Novel relationships were observed between sST2, infarct magnitude/evolution, and aldosterone. Serum sST2 may be of pathophysiological importance in ventricular and infarct remodeling after AMI. (Effects of Eplerenone on Left Ventricular Remodelling Following Heart Attack; NCT00132093).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The evolutionary success of beetles and numerous other terrestrial insects is generally attributed to co-radiation with flowering plants but most studies have focused on herbivorous or pollinating ...insects. Non-herbivores represent a significant proportion of beetle diversity yet potential factors that influence their diversification have been largely unexamined. In the present study, we examine the factors driving diversification within the Scarabaeidae, a speciose beetle family with a range of both herbivorous and non-herbivorous ecologies. In particular, it has been long debated whether the key event in the evolution of dung beetles (Scarabaeidae: Scarabaeinae) was an adaptation to feeding on dinosaur or mammalian dung. Here we present molecular evidence to show that the origin of dung beetles occurred in the middle of the Cretaceous, likely in association with dinosaur dung, but more surprisingly the timing is consistent with the rise of the angiosperms. We hypothesize that the switch in dinosaur diet to incorporate more nutritious and less fibrous angiosperm foliage provided a palatable dung source that ultimately created a new niche for diversification. Given the well-accepted mass extinction of non-avian dinosaurs at the Cretaceous-Paleogene boundary, we examine a potential co-extinction of dung beetles due to the loss of an important evolutionary resource, i.e., dinosaur dung. The biogeography of dung beetles is also examined to explore the previously proposed "out of Africa" hypothesis. Given the inferred age of Scarabaeinae as originating in the Lower Cretaceous, the major radiation of dung feeders prior to the Cenomanian, and the early divergence of both African and Gondwanan lineages, we hypothesise that that faunal exchange between Africa and Gondwanaland occurred during the earliest evolution of the Scarabaeinae. Therefore we propose that both Gondwanan vicariance and dispersal of African lineages is responsible for present day distribution of scarabaeine dung beetles and provide examples.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Using tools to act on non-food objects--for example, to make other tools--is considered to be a hallmark of human intelligence, and may have been a crucial step in our evolution. One form of this ...behaviour, 'sequential tool use', has been observed in a number of non-human primates and even in one bird, the New Caledonian crow (Corvus moneduloides). While sequential tool use has often been interpreted as evidence for advanced cognitive abilities, such as planning and analogical reasoning, the behaviour itself can be underpinned by a range of different cognitive mechanisms, which have never been explicitly examined. Here, we present experiments that not only demonstrate new tool-using capabilities in New Caledonian crows, but allow examination of the extent to which crows understand the physical interactions involved.
In two experiments, we tested seven captive New Caledonian crows in six tasks requiring the use of up to three different tools in a sequence to retrieve food. Our study incorporated several novel features: (i) we tested crows on a three-tool problem (subjects were required to use a tool to retrieve a second tool, then use the second tool to retrieve a third one, and finally use the third one to reach for food); (ii) we presented tasks of different complexity in random rather than progressive order; (iii) we included a number of control conditions to test whether tool retrieval was goal-directed; and (iv) we manipulated the subjects' pre-testing experience. Five subjects successfully used tools in a sequence (four from their first trial), and four subjects repeatedly solved the three-tool condition. Sequential tool use did not require, but was enhanced by, pre-training on each element in the sequence ('chaining'), an explanation that could not be ruled out in earlier studies. By analyzing tool choice, tool swapping and improvement over time, we show that successful subjects did not use a random probing strategy. However, we find no firm evidence to support previous claims that sequential tool use demonstrates analogical reasoning or human-like planning.
While the ability of subjects to use three tools in sequence reveals a competence beyond that observed in any other species, our study also emphasises the importance of parsimony in comparative cognitive science: seemingly intelligent behaviour can be achieved without the involvement of high-level mental faculties, and detailed analyses are necessary before accepting claims for complex cognitive abilities.
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