Renewing Felsenstein’s phylogenetic bootstrap in the era of big data

Content introduction：

• A randomized trial of normothermic preservation in liver transplantation


• SAMHD1 acts at stalled replication forks to prevent interferon induction


• Renewing Felsenstein’s phylogenetic bootstrap in the era of big data


• Laser spectroscopic characterization of the nuclear-clock isomer ^229mTh


• Identification of the tumour transition states occurring during EMT

1. A randomized trial of normothermic preservation in liver transplantation

Liver transplantation is a highly successful treatment, but is severely limited by the shortage in donor organs. However, many potential donor organs cannot be used; this is because sub-optimal livers do not tolerate conventional cold storage and there is no reliable way to assess organ viability preoperatively. Normothermic machine perfusion maintains the liver in a physiological state, avoids cooling and allows recovery and functional testing. Here David Nasralla at University of Oxford in Oxford, UK and his colleagues show that, in a randomized trial with 220 liver transplantations, compared to conventional static cold storage, normothermic preservation is associated with a 50% lower level of graft injury, measured by hepatocellular enzyme release, despite a 50% lower rate of organ discard and a 54% longer mean preservation time. There was no significant difference in bile duct complications, graft survival or survival of the patient. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality.

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2. SAMHD1 acts at stalled replication forks to prevent interferon induction

SAMHD1 was previously characterized as a dNTPase that protects cells from viral infections. Mutations in SAMHD1 are implicated in cancer development and in a severe congenital inflammatory disease known as Aicardi–Goutières syndrome. The mechanism by which SAMHD1 protects against cancer and chronic inflammation is unknown. Here Flavie Coquel at University of Montpellier in Montpellier, France and his colleagues show that SAMHD1 promotes degradation of nascent DNA at stalled replication forks in human cell lines by stimulating the exonuclease activity of MRE11. This function activates the ATR–CHK1 checkpoint and allows the forks to restart replication. In SAMHD1-depleted cells, single-stranded DNA fragments are released from stalled forks and accumulate in the cytosol, where they activate the cGAS–STING pathway to induce expression of pro-inflammatory type I interferons. SAMHD1 is thus an important player in the replication stress response, which prevents chronic inflammation by limiting the release of single-stranded DNA from stalled replication forks.

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3. Renewing Felsenstein’s phylogenetic bootstrap in the era of big data

Felsenstein’s application of the bootstrap method to evolutionary trees is one of the most cited scientific papers of all time. The bootstrap method, which is based on resampling and replications, is used extensively to assess the robustness of phylogenetic inferences. However, increasing numbers of sequences are now available for a wide variety of species, and phylogenies based on hundreds or thousands of taxa are becoming routine. With phylogenies of this size Felsenstein’s bootstrap tends to yield very low supports, especially on deep branches. Here F. Lemoine at Institut Pasteur & CNRS in Paris, France and his colleagues propose a new version of the phylogenetic bootstrap in which the presence of inferred branches in replications is measured using a gradual ‘transfer’ distance rather than the binary presence or absence index used in Felsenstein’s original version. The resulting supports are higher and do not induce falsely supported branches. The application of their method to large mammal, HIV and simulated datasets reveals their phylogenetic signals, whereas Felsenstein’s bootstrap fails to do so.



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4. Laser spectroscopic characterization of the nuclear-clock isomer 229mTh

The isotope 229Th is the only nucleus known to possess an excited state 229mTh in the energy range of a few electronvolts—a transition energy typical for electrons in the valence shell of atoms, but about four orders of magnitude lower than typical nuclear excitation energies. Of the many applications that have been proposed for this nuclear system, which is accessible by optical methods, the most promising is a highly precise nuclear clock that outperforms existing atomic timekeepers. Here Johannes Thielking at Physikalisch-Technische Bundesanstalt in Braunschweig, Germany and his colleagues present the laser spectroscopic investigation of the hyperfine structure of the doubly charged 229mTh ion and the determination of the fundamental nuclear properties of the isomer, namely, its magnetic dipole and electric quadrupole moments, as well as its nuclear charge radius. Following the recent direct detection of this long-sought isomer, they provide detailed insight into its nuclear structure and present a method for its non-destructive optical detection.

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5. Identification of the tumour transition states occurring during EMT

In cancer, the epithelial-to-mesenchymal transition (EMT) is associated with tumour stemness, metastasis and resistance to therapy. It has recently been proposed that, rather than being a binary process, EMT occurs through distinct intermediate states. However, there is no direct in vivo evidence for this idea. Here Ievgenia Pastushenko at Université Libre de Buxelles in Brussels, Belgium and his colleagues screen a large panel of cell surface markers in skin and mammary primary tumours, and identify the existence of multiple tumour subpopulations associated with different EMT stages: from epithelial to completely mesenchymal states, passing through intermediate hybrid states. Although all EMT subpopulations presented similar tumour-propagating cell capacity, they displayed differences in cellular plasticity, invasiveness and metastatic potential. Their transcriptional and epigenetic landscapes identify the underlying gene regulatory networks, transcription factors and signalling pathways that control these different EMT transition states. Finally, these tumour subpopulations are localized in different niches that differentially regulate EMT transition states.

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