Evolutionary history of histone demethylase families: distinct evolutionary patterns suggest functional divergence

<p>Abstract</p> <p>Background</p> <p>Histone methylation can dramatically affect chromatin structure and gene expression and was considered irreversible until recent discoveries of two families of histone demethylases, the KDM1 (previously LSD1) and JmjC domain-containing proteins. These two types of proteins have different functional domains and distinct substrate specificities. Although more and more KDM1 and JmjC proteins have been shown to have histone demethylase activity, our knowledge about their evolution history is limited.</p> <p>Results</p> <p>We performed systematic phylogenetic analysis of these histone demethylase families and uncovered different evolutionary patterns. The <it>KDM1 </it>genes have been maintained with a stable low copy number in most organisms except for a few duplication events in flowering plants. In contrast, multiple genes for JmjC proteins with distinct domain architectures were present before the split of major eukaryotic groups, and experienced subsequent birth-and-death evolution. In addition, distinct evolutionary patterns can also be observed between animal and plant histone demethylases in both families. Furthermore, our results showed that some <it>JmjC </it>subfamilies contain only animal genes with specific demethylase activities, but do not have plant members.</p> <p>Conclusion</p> <p>Our study improves the understanding about the evolutionary history of <it>KDM1 </it>and <it>JmjC </it>genes and provides valuable insights into their functions. Based on the phylogenetic relationship, we discussed possible histone demethylase activities for several plant JmjC proteins. Finally, we proposed that the observed differences in evolutionary pattern imply functional divergence between animal and plant histone demethylases.</p

Phylogenetic detection of numerous gene duplications shared by animals, fungi and plants

BACKGROUND: Gene duplication is considered a major driving force for evolution of genetic novelty, thereby facilitating functional divergence and organismal diversity, including the process of speciation. Animals, fungi and plants are major eukaryotic kingdoms and the divergences between them are some of the most significant evolutionary events. Although gene duplications in each lineage have been studied extensively in various contexts, the extent of gene duplication prior to the split of plants and animals/fungi is not clear. RESULTS: Here, we have studied gene duplications in early eukaryotes by phylogenetic relative dating. We have reconstructed gene families (with one or more orthogroups) with members from both animals/fungi and plants by using two different clustering strategies. Extensive phylogenetic analyses of the gene families show that, among nearly 2,600 orthogroups identified, at least 300 of them still retain duplication that occurred before the divergence of the three kingdoms. We further found evidence that such duplications were also detected in some highly divergent protists, suggesting that these duplication events occurred in the ancestors of most major extant eukaryotic groups. CONCLUSIONS: Our phylogenetic analyses show that numerous gene duplications happened at the early stage of eukaryotic evolution, probably before the separation of known major eukaryotic lineages. We discuss the implication of our results in the contexts of different models of eukaryotic phylogeny. One possible explanation for the large number of gene duplication events is one or more large-scale duplications, possibly whole genome or segmental duplication(s), which provides a genomic basis for the successful radiation of early eukaryotes

Controlling multiple returnings in non-sequential double ionization with orthogonal two-color laser pulses

With the three-dimensional semi-classical ensemble model, we studied the non-sequential double ionization by orthogonal two-color laser pulses. Our calculations show that the proportion of events experiencing multiple returnings, the sum of the final energies of two electrons, and the ion momentum distribution depend on the relative phase of the two-color fields, exhibiting oscillatory behavior with a period of π. Back analysis of these trajectories reveals that we can control the recollision energy of the electron by changing the relative phase of the two-color laser pulse. As a consequence, the trajectories of multiple-returning ions change with the relative phase, resulting in relative-phase-dependent ion momentum distributions. The result shows that the momentum distribution of the ions in the trajectories of multiple returnings is clearly wider than that for the case of single returning. For the multiple-returning events, the binary recollision leads to a smaller scattering angle of the first electron

The emerging role of deubiquitylating enzymes as therapeutic targets in cancer metabolism.

Cancer cells must rewire cellular metabolism to satisfy the unbridled proliferation, and metabolic reprogramming provides not only the advantage for cancer cell proliferation but also new targets for cancer treatment. However, the plasticity of the metabolic pathways makes them very difficult to target. Deubiquitylating enzymes (DUBs) are proteases that cleave ubiquitin from the substrate proteins and process ubiquitin precursors. While the molecular mechanisms are not fully understood, many DUBs have been shown to be involved in tumorigenesis and progression via controlling the dysregulated cancer metabolism, and consequently recognized as potential drug targets for cancer treatment. In this article, we summarized the significant progress in understanding the key roles of DUBs in cancer cell metabolic rewiring and the opportunities for the application of DUBs inhibitors in cancer treatment, intending to provide potential implications for both research purpose and clinical applications

Measurement and Prediction of Coupling Coordination Level of Economic Development, Social Stability and Ecological Environment in Qinghai—Thoughts on Sustainable Societal Safety

Societal safety is the result of the coordinated development of several subsystems; the coupling–coordination relationship among economic development (ED), social stability (SS), and ecological environment (EE) is the premise of realizing sustainable societal safety (SSS). Taking Qinghai Province as an example, this paper quantitatively evaluates the development index of each subsystem by constructing ED-SS-EE evaluation index system, then analyzes the spatio-temporal evolution of ED, SS, and EE coupling coordination levels based on the coupling coordination model, and finally predicts the coupling coordination level of ED, SS, and EE by using the GM(1.1) model. The findings are as follows: (1) The economy is developing rapidly, but the regional development is extremely uneven; ED is driving SS, and SS lags behind ED and slowly improves; EE is improving continuously, and the spatial pattern is relatively stable. (2) The ED, SS, and EE systems have a high degree of coupling, showing a fluctuating upward trend. Coordination level is low, showing a slow upward trend, and the regional differences are obvious. (3) In the future, the coordination level of ED, SS, and EE systems in different regions will be upgraded from the level of near imbalance and barely coordination to the level of intermediate coordination, good coordination, and even high-quality coordination. The spatio-temporal description of ED, SS, and EE coupling coordination level not only reveals the development trend and problems of SSS in Qinghai, it also proves the feasibility of evaluating societal safety level based on the coupling coordination level of sustainable social structure system.publishedVersionPeer reviewe

Novel laser triangulation measurement method for screw rotor profile under multi-factor constraints

Abstract(#br)In order to achieve optimal control of the screw rotor process, a novel measurement method using laser triangulation under multi-factor constraints was introduced to achieve online measurement of the screw rotor profile. This method involved the integration of a 4-axis motion system, which is used to adjust the laser probe, with a laser displacement sensor (LDS), which is used to measure the screw rotor profile. Firstly, the effect of laser beam positioning on measurement accuracy was analyzed experimentally in conjunction with an improved LDS error compensation model. Then, according to the characteristics of rotor profiles, a laser-measurement trajectory planning algorithm for the rotor profile under multi-factor constraints was developed. Finally, the comparison study between the traditional contact measurement (P65) and the proposed measurement demonstrates that the proposed method has not only kept the advantages of traditional contact measurement, but also shown good performances and high measuring precision

Error compensation and accuracy analysis of laser measurement system based on laser-beam calibration

Abstract(#br)In this paper, a novel measurement strategy, based on a 4D error-compensation model for the measurement of free-form surfaces in laser measurement systems, is presented. To improve the measurement accuracy, effects of the inclination angle and the azimuth angle (including the rotation angle and the deflection angle) on the measurement results are investigated experimentally. Considering the error compensation and the constructing iterative function, a calibration method for arbitrary positions and orientations of the laser-beam is presented, and a corresponding measurement strategy is presented. To verify the effectiveness and accuracy of the proposed measurement strategy, calibration schemes of a check bar geometry center are studied based on a 4-axis measuring platform. The obtained results demonstrate that the proposed strategy can greatly improve the measurement accuracy

A novel criterion of metabolically healthy obesity could effectively identify individuals with low cardiovascular risk among Chinese cohort

Background and objectiveObesity has become a serious public health problem and brings a heavy burden of cardiovascular disease. Metabolically healthy obesity (MHO) is defined as individuals with obesity with no or only minor metabolic complications. Whether individuals with MHO have a lower cardiovascular risk remains controversial. In this study, a new criterion was used to define MHO and assess its predictive value for cardiovascular events and death. At the same time, the new criterion and the traditional criterion are compared to analyze the differences between different diagnostic criteria.MethodsA prospective cohort was established in northeast rural China from 2012 to 2013. Follow-up was conducted in 2015 and 2018 to investigate the incidence of cardiovascular events and survival. Subjects were grouped according to the metabolic health and obesity status. Kaplan-Meier curves were drawn to describe the cumulative risk of endpoint events in the four groups. Cox regression analysis model was constructed to evaluate the risk of endpoint events. Analysis of variance and post hoc analyses were used to calculate and compare differences in metabolic markers between MHO subjects diagnosed by novel and traditional criteria.ResultsA total of 9345 participants 35 years of age or older without a history of cardiovascular disease were included in this study. After a median follow-up of 4.66 years, the data showed that participants in the MHO group had no significant increase in the risk of composite cardiovascular events and stroke, but had a 162% increase in the risk of coronary heart disease (HR: 2.62; 95%CI: 1.21-5.67). However, when using conventional criteria for metabolic health, mMHO group had a 52% increase in combined CVD risk (HR: 1.52; 95%CI: 1.14-2.03). By comparing the differences of metabolic indicators between MHO subjects diagnosed by the two criteria, MHO subjects diagnosed by the new criterion had higher WC, WHR, TG, FPG, and lower HDL-C levels except for lower blood pressure, showing more exposure to cardiovascular risk factors.ConclusionsThe risk of combined CVD and stroke was not increased in MHO subjects. The new metabolic health criterion is superior to the traditional criterion and can effectively identify individuals with obesity with a lower risk of combined CVD. Blood pressure levels may be responsible for the inconsistent risk of combined CVD in MHO subjects diagnosed with both criteria

Anti-PD-L1/TGF-βR fusion protein (SHR-1701) overcomes disrupted lymphocyte recovery-induced resistance to PD-1/PD-L1 inhibitors in lung cancer

Background Second-generation programmed cell death-protein 1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors, such as bintrafusp alfa (M7824), SHR-1701, and YM101, have been developed to simultaneously block PD-1/PD-L1 and transforming growth factor-beta/transforming growth factor-beta receptor (TGF-β/TGF-βR). Consequently, it is necessary to identify predictive factors of lung cancer patients who are not only resistant to PD-1/PD-L1 inhibitors but also sensitive to bifunctional drugs. The purpose of this study was to search for such predictors. Methods Multivariable Cox regression was used to study the association between the clinical outcome of treatment with PD-1/PD-L1 inhibitors and lymphocyte recovery after lymphopenia in lung cancer patients. Murine CMT167 lung cancer cells were engineered to express the firefly luciferase gene and implanted orthotopically in the lung of syngeneic mice. Bioluminescence imaging, flow cytometry, and immunohistochemistry were employed to determine response to immunotherapy and function of tumor-infiltrating immune cells. Results For lung cancer patients treated with anti-PD-1/PD-L1 antibodies, poor lymphocyte recovery was associated with a shorter progression-free survival (PFS; P < 0.001), an accumulation of regulatory T cells (Tregs), and an elimination of CD8+ T cells in the peripheral blood. Levels of CD8+ T cells and Treg cells were also imbalanced in the tumors and peripheral immune organs of mice with poor lymphocyte recovery after chemotherapy. Moreover, these mice failed to respond to anti-PD-1 antibodies but remained sensitive to the anti-PD-L1/TGF-βR fusion protein (SHR-1701). Consistently, SHR-1701 but not anti-PD-1 antibodies, markedly enhanced IFN-γ production and Ki-67 expression in peripheral CD8+ T cells from patients with impaired lymphocyte recovery. Conclusions Lung cancer patients with poor lymphocyte recovery and suffering from persistent lymphopenia after previous chemotherapy are resistant to anti-PD-1/PD-L1 antibodies but might be sensitive to second-generation agents such as SHR-1701.publishedVersio