Targeting the adaptability of heterogeneous aneuploidy population

Aneuploid genomes, characterized by unbalanced and diverse chromosome stoichiometry (karyotype), are associated with cancer malignancy and drug-resistance of human pathogenic fungi. My PhD projects studied three aspects of aneuploidy that are logically linked to each other: the production of aneuploidy by environmental stress; the impact of the heterogeneous aneuploidy population generated by stress on adaptability; the potential therapeutic strategy towards these heterogeneous aneuploidy populations with high adaptability, a root for the clinical challenge in treating aneuploidy diseases such as cancer. We investigated whether pleiotropic stress could induce the production of aneuploidy in budding yeast. We showed that while diverse stresses can induce an increase in chromosome instability (CIN), proteotoxic stress, caused by transient Hsp90 inhibition or heat-shock, drastically elevated CIN to produce karyotypically mosaic cell population. The latter effect is linked to an evolutionarily conserved role for Hsp90 chaperon complexes in kinetochore assembly. We found the induction of aneuploidy population potentiates adaptability. Continued growth in the presence of Hsp90 inhibitor resulted in emergence of drug-resistant colonies with chromosome XV gain. This drug-resistance phenotype is a quantitative trait involving copy number increases of at least two genes located on chromosome XV. Short-term exposure to Hsp90 stress, which produced an aneuploidy population with heterogeneous karyotypes, potentiated fast adaptation to unrelated cyto-toxic compounds through different aneuploid chromosome stoichiometries. We designed an evolutionary trap to harness the adaptability of heterogeneous aneuploidy populations with high adaptability. Using a combination of experimental data and a general statistical model, we showed that the degree of phenotypic variation, thus evolvability, escalates with the degree of overall growth suppression irrespective of stress mechanisms. Such scaling explains the challenge of treating aneuploidy diseases with diverse different karyotypes by imposing a single mode of inhibition, yet specific karyotype features can be highly targetable. Motivated by this finding, we proposed an "evolutionary trap" targeting both karyotypic diversity and fitness of the population. This strategy entails a selective condition "channeling" a karyotypically divergent population into one with a predominant and drugable karyotypic feature. We provided a proof-of-principle test with mechanistic explanation in budding yeast and demonstrated the potential efficacy of this strategy toward aneuploidy-based azole resistance in the human pathogen Candida albicans. Karyotype channeling also happens naturally in tumors, which is resulted from adaptation to the tissue micro-environment and/or the need for oncogenic transformation. This natural karyotypic selection may be leveraged by drug treatment targeting the selected karyotype feature. Thus, the strategy proposed here may be utilized for designing a class of treatment regime distinct from current therapies

The radiation emitted from axion dark matter in a homogeneous magnetic field, and possibilities for detection

We study the direct radiation excited by oscillating axion (or axion-like particle) dark matter in a homogenous magnetic field and its detection scheme. We concretely derive the analytical expression of the axion-induced radiated power for a cylindrical uniform magnetic field. In the long wave limit, the radiation power is proportional to the square of the B-field volume and the axion mass $m_a$, whereas it oscillate as approaching the short wave limit and the peak powers are proportional to the side area of the cylindrical magnetic field and $m_a^{-2}$. The maximum power locates at mass $m_a\sim\frac{3\pi}{4R}$ for fixed radius $R$. Based on this characteristic of the power, we discuss a scheme to detect the axions in the mass range $1-10^4$\,neV, where four detectors of different bandwidths surround the B-field. The expected sensitivity for $m_a\lesssim1\,\mu$eV under typical-parameter values can far exceed the existing constraints.Comment: 10 pages, 9 figures, comments welcome

Understanding coupled factors that affect the modelling accuracy of typical planar compliant mechanisms

In order to accurately model compliant mechanism utilizing plate flexures, qualitative planar stress (Young’s modulus) and planar strain (plate modulus) assumptions are not feasible. This paper investigates a quantitative equivalent modulus using nonlinear finite element analysis (FEA) to reflect coupled factors in affecting the modelling accuracy of two typical distributed- compliance mechanisms. It has been shown that all parameters have influences on the equivalent modulus with different degrees; that the presence of large load-stiffening effect makes the equivalent modulus significantly deviate from the planar assumptions in two ideal scenarios; and that a plate modulus assumption is more reasonable for a very large out-of-plane thickness if the beam length is large

Determining the range of allowable axial force for the third-order Beam Constraint Mode

The Beam Constraint Model (BCM) was developed for the purpose of accurately and analytically modeling nonlinear behaviors of a planar beam flexure over an intermediate range of transverse deflections (10% of the beam length). The BCM is expressed in the form of Taylor's expansion associated with the axial force. It has been found that the BCM may yield large predicting errors (> 5 %) when the applied axial force goes beyond a certain boundary, even the deflection is still in the intermediate range. However, this boundary has not been clearly identified so far. In this work, we mathematically determine the non-dimensional boundary of the axial force by the condition that the strain energy expression of the BCM is a positive definite quadratic form, and by the buckling condition relate to compressing axial force. Several examples are analyzed to demonstrate the effects of the axial force on the modeling errors of the BCM. When using the BCM for modeling, it is always suggested to check if the axial force is within this boundary to avoid large modeling errors. If the axial force is beyond the boundary, the Chained Beam Constraint Model (CBCM) can be used instead

Compound optimal control of harmonic drive considering hysteresis characteristic

Hysteresis behavior widely exists in the transmission process of harmonic drives. Eliminating the hysteresis effect is highly desired in the high-precision mechanical transmission, which results in challenges in the control design. This paper aims to improve the tracking accuracy of the motor-harmonic drive serial system. Firstly, a modified Bouc-Wen model based on uniform smooth approximating function is applied to describe the hysteresis behavior of the harmonic drive. By using coordinate transformation and accurate state feedback linearization, we then obtain the mathematical model of the serial system of the motor-harmonic drive. Finally, the reference trajectory is tracked by a compound optimal controller that is based on a linear quadratic regulator. Simulation results show that compared with the disturbance observer-based control (DOBC) using a linear observer, the new compound optimal controller in this paper presents a smoother control signal with the elimination of large amount of high-frequency oscillations. Furthermore, the relative error in the steady state tracking tends to approach to zero and no cyclic fluctuations appears. With the employing of optimal control, the output of the harmonic drive can trace more complex trajectory

Increased concentrations of soluble B7-H3 and interleukin 36 in bronchoalveolar lavage fluid of Children with Mycoplasma pneumoniae pneumonia

Supporting data. (XLS 58 kb

Tuning electrochemical catalytic activity of defective 2D terrace MoSe2 heterogeneous catalyst via Co doping

This study presents successful growth of defective 2D terrace MoSe2/CoMoSe lateral heterostructures (LH), bilayer and multilayer MoSe2/CoMoSe LH, and vertical heterostructures (VH) nanolayers by doping metal Co (cobalt) element into MoSe2 atomic layers to form a CoMoSe alloy at the high temperature (~900 °C). After the successful introduction of metal Co heterogeneity in the MoSe2 thin layers, more active sites can be created to enhance hydrogen evolution reaction (HER) activities combining with metal Co catalysis, through the mechanisms including (1) atomic arrangement distortion in CoMoSe alloy nanolayers, (2) atomic level coarsening in LH interfaces and terrace edge layer architecture in VH, (3) formation of defective 2D terrace MoSe2 nanolayers heterogeneous catalyst via metal Co doping. The HER investigations indicated that the obtained products with LH and VH exhibited an improved HER activity in comparison with those from the pristine 2D MoSe2 electrocatalyst and LH type MoSe2/CoMoSe. The present work shows a facile yet reliable route to introduce metal ions into ultrathin 2D transition metal dichalcogenides (TMDCS) and produce defective 2D alloy atomic layers for exposing active sites, and thus eventually improve their electrocatalytic performance

Deficiency of N-linked glycosylation impairs immune function of B7-H6

B7-H6 is a novel immune checkpoint molecule that triggers NK cell cytotoxicity, but the role of N-glycosylation in B7-H6 is poorly understood. We here identified the existence of N-glycosylation of B7-H6 in different cell lines and exogenous expression cells by PNGase F digestion and tunicamycin blockage. Subsequently, we demonstrated that B7-H6 contains 6 functional N-linked glycosylation sites by single site mutation and electrophoresis. Phylogenetical and structural analysis revealed that N43 and N208 glycan are conserved in jawed vertebrates and may thus contribute more to the biological functions. We further demonstrated that N43 and N208 glycosylation are essential for B7-H6 to trigger NK cell activation. Mechanistically, we found that N43 and N208 glycan contributed to the stability and membrane expression of B7-H6 protein. Lack of N208 glycosylation led to membrane B7-H6 shedding, while N43 mutation resulted in impaired B7-H6/NKp30 binding affinity. Together, our findings highlight the significance of N-linked glycosylation in B7-H6 biological functions and suggest potential targets for modulating NK cell-mediated immunity

Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells

TET2 is a dioxygenase that catalyses multiple steps of 5-methylcytosine oxidation. Although TET2 mutations frequently occur in various types of haematological malignancies, the mechanism by which they increase risk for these cancers remains poorly understood. Here we show that Tet2?/? mice develop spontaneous myeloid, T- and B-cell malignancies after long latencies. Exome sequencing of Tet2?/? tumours reveals accumulation of numerous mutations, including Apc, Nf1, Flt3, Cbl, Notch1 and Mll2, which are recurrently deleted/mutated in human haematological malignancies. Single-cell-targeted sequencing of wild-type and premalignant Tet2?/? Lin?c-Kit+ cells shows higher mutation frequencies in Tet2?/? cells. We further show that the increased mutational burden is particularly high at genomic sites that gained 5-hydroxymethylcytosine, where TET2 normally binds. Furthermore, TET2-mutated myeloid malignancy patients have significantly more mutational events than patients with wild-type TET2. Thus, Tet2 loss leads to hypermutagenicity in haematopoietic stem/progenitor cells, suggesting a novel TET2 loss-mediated mechanism of haematological malignancy pathogenesis