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Mutation signature correlation graph

Seven supplementary tables. Table S1. Data yield and Duplex Sequencing statistics. Table S2. Mutation contexts significantly differ between normal stem cells and transformed cells. Table S3. Homoplasmic variants in the whole mtDNA identified using Duplex Sequencing. Table S4. Rare variants in the whole mtDNA of HBEC identified using Duplex Sequencing. Table S5. Mutations that are clonally expanded or negatively selected toward tumorigenesis. Table S6. Distribution of nonsynonymous mutations of rare variants in the whole mtDNA and within mtDNA coding regions. Table S7. The number of non-synonymous mutations of rare variants in mitochondrial protein-coding regions.

g Score sum graph

Supplementary methods

Figure legends for Supplementary figures 1, 2, and 3

Rare stochastic mutations may accumulate during dormancy of stem-like cells, but technical limitations in DNA sequencing have limited exploring this possibility. In this study, we employed a recently established deep-sequencing method termed Duplex Sequencing to conduct a genome-wide analysis of mitochondrial (mt) DNA mutations in a human breast stem cell model that recapitulates the sequential stages of breast carcinogenesis. Using this method, we found significant differences in mtDNA among normal stem cells, immortal/preneoplastic cells, and tumorigenic cells. Putative cancer stem-like cell (CSC) populations and mtDNA copy numbers increased as normal stem cells become tumorigenic cells. Transformed cells exhibited lower rare mutation frequencies of whole mtDNA than did normal stem cells. The predicted mtDNA rare mutation pathogenicity was significantly lower in tumorigenic cells than normal stem cells. Major rare mutation types in normal stem cells are C>T/G>A and T>C/A>G transitions, while only C>T/G>A are major types in transformed cells. We detected a total of 1,220 rare point mutations, 678 of which were unreported previously. With only one possible exception (m10342T>C), we did not find specific mutations characterizing mtDNA in human breast CSCs; rather, the mitochondrial genome of CSCs displayed an overall decrease in rare mutations. On the basis of our work, we suggest that this decrease (in particular T>C/A>G transitions), rather than the presence of specific mitochondrial mutations, may constitute an early biomarker for breast cancer detection. Our findings support the hypothesis that the mitochondrial genome is altered greatly as a result of the transformation of normal stem cells to CSCs, and that mtDNA mutation signatures may aid in delineating normal stem cells from CSCs. Cancer Res; 76(15); 4569–78. ©2016 AACR.

Rare and low heteroplasmic mutations frequency and mutation (%) fraction graphs

Advances in understanding the temperature effect on water dynamics in cellular respiration are important for the modeling of integrated energy processes and metabolic rates. For more than half a century, experimental studies have contributed to the understanding of the catalytic role of water in respiration combustion, yet the detailed water dynamics remains elusive. We combine a super-Arrhenius model that links the temperature-dependent exponential growth rate of a population of plant cells to respiration, and an experiment on isotope labeled 18O2 uptake to H218O transport role and to a rate-limiting step of cellular respiration. We use Phosphofructokinase (PFK-1) as a prototype because this enzyme is known to be a pacemaker (a rate-limiting enzyme) in the glycolysis process of respiration. The characterization shows that PFK-1 water matrix dynamics are crucial for examining how respiration (PFK-1 tetramer complex breathing) rates respond to temperature change through a water and nano-channel network created by the enzyme folding surfaces, at both short and long (evolutionary) timescales. We not only reveal the nano-channel water network of PFK-1 tetramer hydration topography but also clarify how temperature drives the underlying respiration rates by mapping the channels of water diffusion with distinct dynamics in space and time. The results show that the PFK-1 assembly tetramer possesses a sustainable capacity in the regulation of the water network toward metabolic rates. The implications and limitations of the reciprocal-activation–reciprocal-temperature relationship for interpreting PFK-1 tetramer mechanisms are briefly discussed.

Lattice QCD calculations of two-nucleon interactions have been underway for about a decade, but still haven't reached the pion mass regime necessary for matching onto effective field theories and extrapolating to the physical point. Furthermore, results from different methods, including the use of the Luscher formalism with different types of operators, as well as the HALQCD potential method, do not agree even qualitatively at very heavy pion mass. We investigate the role that different operators employed in the literature may play on the extraction of spectra for use within the Luscher method. We first explore expectations from Effective Field Theory solved within a finite volume, for which the exact spectrum may be computed given different physical scenarios. We then present preliminary lattice QCD results for two-nucleon spectra calculated using different operators on a common lattice ensemble., 11 pages, 7 figures, proceeding for The 38th International Symposium on Lattice Field Theory, LATTICE2021, 26th-30th July, 2021, Zoom/Gather@Massachusetts Institute of Technology

Polyimide (PI) has been adopted to protect the Cu from oxidation in the packaging industry. Electromigration (EM) of Cu redistribution layers (RDLs) capped with PI was investigated at 160 °C under 1.0 ×106 A/cm2. The results indicated that failure of fine-pitched (2-µm) is different from that of 10-µm RDLs, which is void formation. The failure of the 2-µm RDLs is mainly caused by severe oxidation during EM. To analyze the EM failure of the Cu RDLs with different pitches, the oxidation area of nanotwinned copper (nt-Cu) and regular Cu RDLs during EM was compared. We propose an oxidation equation to estimate the resistance increase of RDLs with various widths.

We present a new lossy compression algorithm for statistical floating-point data through a representation learning with binary variables. The algorithm finds a set of basis vectors and their binary coefficients that precisely reconstruct the original data. The optimization for the basis vectors is performed classically, while binary coefficients are retrieved through both simulated and quantum annealing for comparison. A bias correction procedure is also presented to estimate and eliminate the error and bias introduced from the inexact reconstruction of the lossy compression for statistical data analyses. The compression algorithm is demonstrated on two different datasets of lattice quantum chromodynamics simulations. The results obtained using simulated annealing show 3.5 times better compression performance than the algorithms based on a neural-network autoencoder and principal component analysis. Calculations using quantum annealing also show promising results, but performance is limited by the integrated control error of the quantum processing unit, which yields large uncertainties in the biases and coupling parameters. Hardware comparison is further studied between the previous generation D-Wave 2000Q and the current D-Wave Advantage system. Our study shows that the Advantage system is more likely to obtain low-energy solutions for the problems than the 2000Q., 15 pages, 5 figures

Dome formation can occur in cultured tubular epithelial cells originating from various tissues, including the mammary gland and the kidney. The isolation and characterization of normal kidney epithelial stem cells that give rise to dome-forming tubular cells have never been reported. We attempted to isolate and characterize canine kidney epithelial stem cells using a simple cell culture method that we have previously used to isolate other adult human stem cells. Dome-forming kidney epithelial cells were derived from dissociated adult canine kidney tissues that were cultured in a modified keratinocyte serum-free medium supplemented with N-acetyl-l-cysteine, l-ascorbic acid 2-phosphate, nicotinamide, and fetal bovine serum. These cells exhibited high self-renewal capacity in long-term culture (growth for >13 months and 30 cumulative population doublings) and exhibited characteristics of stem cells, including (1) deficiency in gap junctional intercellular communication, (2) anchorage-independent growth, (3) expression of stem cell markers octamer-binding transcription factor 4 and SRY (sex determining region Y)-box 2, (4) expression of cell surface markers CD24 and CD133, and (5) multipotent differentiation into osteoblasts, adipocytes, chondrocytes, and dome-forming tubular cells. Most of these characteristics are shared by the well-known canine renal tubule-derived immortalized Madin-Darby Canine Kidney cell line. Furthermore, the putative canine kidney stem cells developed in this study formed budding tubule-like organoids on Matrigel and required high cell density (>4,000 cells/cm2) for sustained growth and confluency for dome formation. The signal transducer and activator of transcription-3 (STAT3) phosphorylation inhibitor, AG490, inhibited colony-forming efficiency and dome formation, whereas lipopolysaccharide, an activator of STAT3, increased colony-forming efficiency in a dose-dependent manner. These results are consistent with the hypothesis that high cell density induces STAT3 expression, which promotes both stem cell self-renewal and differentiation into tubular cells. Our novel cell culture method should be useful for the future development of normal human kidney stem cells for clinical applications and for studying mechanisms of nephrotoxicity.

Because Cu-Cu bonding is the key technique in 3D IC packaging, its reliabilities will become issues in the future. In this study, Cu-Cu joints with underfill was fabricated by using instant bonding process, in which bonding conditions were under 31∼90 MPa at 300 °C for 10∼30 s. Several samples underwent two reliability tests: temperature cycling test (TCT) and electromigration (EM) test. These samples passed 1000 cycles TCT, and the measured EM life time was least 3 times longer than that of solder joints with similar dimension. Failure mechanisms of reliability tests were examined by cross-section images and finite element analysis. In TCT, cracks were formed at bonding interface because it is relative weak compared to the neighboring structures. For EM tests, voids were formed at passivation opening of joints with current crowding. The current study provides a fundamental understanding in the reliabilities of Cu/organic dielectric hybrid bonding structures.

We report on a subpercent scale determination using the omega baryon mass and gradient-flow methods. The calculations are performed on 22 ensembles of ${N}_{f}=2+1+1$ highly improved, rooted staggered sea-quark configurations generated by the MILC and CalLat Collaborations. The valence quark action used is M\"obius domain wall fermions solved on these configurations after a gradient-flow smearing is applied with a flowtime of ${t}_{\mathrm{gf}}=1$ in lattice units. The ensembles span four lattice spacings in the range $0.06\ensuremath{\lesssim}a\ensuremath{\lesssim}0.15\text{ }\text{ }\mathrm{fm}$, six pion masses in the range $130\ensuremath{\lesssim}{m}_{\ensuremath{\pi}}\ensuremath{\lesssim}400\text{ }\text{ }\mathrm{MeV}$ and multiple lattice volumes. On each ensemble, the gradient-flow scales ${t}_{0}/{a}^{2}$ and ${w}_{0}/a$ and the omega baryon mass $a{m}_{\mathrm{\ensuremath{\Omega}}}$ are computed. The dimensionless product of these quantities is then extrapolated to the continuum and infinite volume limits and interpolated to the physical light, strange and charm quark mass point in the isospin limit, resulting in the determination of $\sqrt{{t}_{0}}=0.1422(14)\text{ }\text{ }\mathrm{fm}$ and ${w}_{0}=0.1709(11)\text{ }\text{ }\mathrm{fm}$ with all sources of statistical and systematic uncertainty accounted for. The dominant uncertainty in both results is the stochastic uncertainty, though for $\sqrt{{t}_{0}}$ there are comparable continuum extrapolation uncertainties. For ${w}_{0}$, there is a clear path for a few-per-mille uncertainty just through improved stochastic precision, as recently obtained by the Budapest-Marseille-Wuppertal Collaboration.

We reformulate the continuous space Schr\"odinger equation in terms of spin Hamiltonians. For the kinetic energy operator, the critical concept facilitating the reduction in model complexity is the idea of position encoding. Binary encoding of position produces a Heisenberg-like model and yields exponential improvement in space complexity when compared to classical computing. Encoding with a binary reflected Gray code, and a Hamming distance 2 Gray code yields the additional effect of reducing the spin model down to the XZ and transverse Ising model respectively. We also identify the bijective mapping between diagonal unitaries and the Walsh series, producing the mapping of any real potential to a series of $k$-local Ising models through the fast Walsh transform. Finally, in a finite volume, we provide some numerical evidence to support the claim that the total time needed for adiabatic evolution is protected by the infrared cutoff of the system. As a result, initial state preparation from a free-field wavefunction to an interacting system is expected to exhibit polynomial time complexity with volume and constant scaling with respect to lattice discretization for all encodings. For the Hamming distance 2 Gray code, the evolution starts with the transverse Hamiltonian before introducing penalties such that the low lying spectrum reproduces the energy levels of the Laplacian. The adiabatic evolution of the penalty Hamiltonian is therefore sensitive to the ultraviolet scale. It is expected to exhibit polynomial time complexity with lattice discretization, or exponential time complexity with respect to the number of qubits given a fixed volume., Comment: 21 pages, 18 figures, Updated with final edits. Accepted to PRX Quantum https://journals.aps.org/prxquantum/accepted/8707fD5cQ401d60fc06f24d6027827488a2532127

Author(s): Horz, B; Howarth, D; Rinaldi, E; Hanlon, A; Chang, CC; Korber, C; Berkowitz, E; Bulava, J; Clark, MA; Lee, WT; Morningstar, C; Nicholson, A; Vranas, P; Walker-Loud, A | Abstract: We report on the first application of the stochastic Laplacian Heaviside method for computing multiparticle interactions with lattice QCD to the two-nucleon system. Like the Laplacian Heaviside method, this method allows for the construction of interpolating operators which can be used to construct a set of positive-definite two-nucleon correlation functions, unlike nearly all other applications of lattice QCD to two nucleons in the literature. It also allows for a variational analysis in which optimal linear combinations of the interpolating operators are formed that couple predominantly to the eigenstates of the system. Utilizing such methods has become of paramount importance to help resolve the discrepancy in the literature on whether two nucleons in either isospin channel form a bound state at pion masses heavier than physical, with the discrepancy persisting even in the SU(3)-flavor-symmetric point with all quark masses near the physical strange quark mass. This is the first in a series of papers aimed at resolving this discrepancy. In the present work, we employ the stochastic Laplacian Heaviside method without a hexaquark operator in the basis at a lattice spacing of a≈0.086 fm, lattice volume of L=48a≈4.1 fm and pion mass mπ≈714 MeV. With this setup, the observed spectrum of two-nucleon energy levels strongly disfavors the presence of a bound state in either the deuteron or dineutron channel.

Recently, the requirements of commercial electronic products continue to increase and the package sizes continue to decrease. The redistribution lines (RDLs) in fan-out packages and three dimensional integrated circuit (3D IC) become narrower, resulting in the high current density in the RDLs. The three dimensional integrated circuits which can stack chips vertically and decrease RCdelay. As the scaling of large-scale ICs faced the physical limit, the IC industry is trying to follow the Moore’s law to fulfill the needs of customers. By using the 3D IC, which not only reduce the form factor, but also enhance the power efficiency. The input/output pin numbers increasing while the size of the solder joints shrinking. It is inevitably leads to higher current densities and operating temperatures in the joints. It raises severe reliability issues such as electromigration and thermomigration. Furthermore, the RDLs need carry higher current density than before. As the volume of 3D ICs getting smaller, copper is the critical material in interconnects. Copper has low resistivity of 1.7 μΩ, high conductivity 401 W m.1 K.1, and excellent ability to resist electromigration. Recently, highly preferred orientation nanotwinned copper has been studied extensively. The highly (111) oriented nanotwinned copper (nt-Cu) possesses excellent mechanical strength and high ductility. The conductivity of nt-Cu is almost the same comparing to bulk copper. It is reported that the nano-scale twins in the copper contribute to high resistance of the electromigration. Therefore, we use nt-Cu as the material of RDL and observe destruction mechanism of electromigration tests. We also compare the electromigration lifetimes of nt-Cu RDL lines to randomly oriented Cu.

We report the results of a lattice quantum chromodynamics calculation of ${F}_{K}/{F}_{\ensuremath{\pi}}$ using M\"obius domain-wall fermions computed on gradient-flowed ${N}_{f}=2+1+1$ highly improved staggered quark (HISQ) ensembles. The calculation is performed with five values of the pion mass ranging from $130\ensuremath{\lesssim}{m}_{\ensuremath{\pi}}\ensuremath{\lesssim}400\text{ }\text{ }\mathrm{MeV}$, four lattice spacings of $a\ensuremath{\sim}0.15$, 0.12, 0.09 and 0.06 fm and multiple values of the lattice volume. The interpolation/extrapolation to the physical pion and kaon mass point, the continuum, and infinite volume limits are performed with a variety of different extrapolation functions utilizing both the relevant mixed-action effective field theory expressions as well as discretization-enhanced continuum chiral perturbation theory formulas. We find that the $a\ensuremath{\sim}0.06\text{ }\text{ }\mathrm{fm}$ ensemble is helpful, but not necessary to achieve a subpercent determination of ${F}_{K}/{F}_{\ensuremath{\pi}}$. We also include an estimate of the strong isospin breaking corrections and arrive at a final result of ${F}_{{\stackrel{^}{K}}^{+}}/{F}_{{\stackrel{^}{\ensuremath{\pi}}}^{+}}=1.1942(45)$ with all sources of statistical and systematic uncertainty included. This is consistent with the Flavour Lattice Averaging Group average value, providing an important benchmark for our lattice action. Combining our result with experimental measurements of the pion and kaon leptonic decays leads to a determination of $|{V}_{us}|/|{V}_{ud}|=0.2311(10)$.

This study investigates the toughness of 40-μm-wide nanotwinned Cu lines before and after annealing. The toughness of Cu lines was measured by tensile test, and different annealing temperatures and durations were used to examine the thermal stability of the nt-Cu films. The initial and post-annealed microstructures was analyzed, and initial surface orientation of Cu lines was examined. The tensile test results showed the mechanical properties of nt-Cu lines is better than that of regular Cu lines. In addition, the toughness of nt-Cu lines significantly increased after annealing, although the ultimate tensile strength slightly dropped. The nanotwinned Cu is very suitable For application as redistribution lines in Fan-Out Wafer-Level Packaging (FO-WLP), because the toughness of nt-Cu lines increased after the annealing at 250°C for 3 h, which is close to the curing process of polyimide capping.

Adipose-derived mesenchymal stem cells (ADMSCs) are easily accessible and are attractive mesenchymal stem cells for use in regenerative medicine; however their application is frequently restricted due to various challenges present in the environment they are administered. Therefore ADMSCs are preferably preconditioned with various stimulating factors to overcome the barriers developed in any pathological conditions. Here we used ADMSCs from rat adipose based on the abundance of positive markers and preconditioned the cells with extracts from Alpinate Oxyphyllae Fructus (AOF), a traditional Chinese herb used for antiaging, associated various health benefits. The preconditioned stem cells were tested for their potential to drive H9c2 from doxorubicin (Dox)-induced aging. The AOF-treated stem cells enriched stemness in ADMSCs with respect to their stem cells' positive marker, and enhanced their longevity mechanism and elevated the stem cell homing-associated C-X-C chemokine receptor type 7 (CXCR7). The AOF preconditioned stem cells, when cocultured with H9c2 cells, showed effective protection to Dox-induced senescence and stem cell homing to damaged H9c2 cells. The presence of AOF provided greater protective effects in the Dox environment. In addition, AOF-pretreated ADMSCs showed enhanced migration than those treated with AOF in Dox environment. Therefore, our results show that administration of AOF preconditioned stem cells is potentially an effective strategy in the management of aging-associated cardiac disorders.

Background: Intraventricular tumors can generally result in obstructive hydrocephalus as they grow. Rarely, however, some intraventricular tumors develop superficial siderosis (SS) and trigger hydrocephalus, even though the tumor has hardly grown. Here, we present an illustrative case of SS and nonocclusive hydrocephalus caused by subependymoma of the lateral ventricles. Case Description: A 78-year-old man with an intraventricular tumor diagnosed 7 years ago had been suffering from gait disturbance for 2 years. He also developed cognitive impairment. Intraventricular tumors showed little growth on annual magnetic resonance imaging (MRI). MRI T2-star weighted images (T2*WI) captured small intratumoral hemorrhages from the beginning of the follow-up. Three years before, at the same time as the onset of ventricular enlargement, T2*WI revealed low intensity in the whole tumor and cerebral surface. Subsequent follow-up revealed that this hemosiderin deposition had spread to the brain stem and cerebellar surface, and the ventricles had expanded further. Cerebrospinal fluid (CSF) examination revealed xanthochromia. The tumor was completely removed en bloc. Histopathological findings were consistent with those of subependymoma. Although CSF findings improved, SS and hydrocephalus did not improve. Therefore, the patient underwent a lumboperitoneal shunt for CSF diversion after tumor resection. Conclusion: Some intraventricular tumors cause SS and nonobstructive hydrocephalus due to microbleeding, even in the absence of tumor growth. T2*WI and, if necessary, timely CSF examination can allow identification of presymptomatic SS. This follow-up strategy may provide a favorable course by facilitating early intervention in patients with intraventricular lesions, not just subependymomas.

The nucleon axial coupling, $g_A$, is a fundamental property of protons and neutrons, dictating the strength with which the weak axial current of the Standard Model couples to nucleons, and hence, the lifetime of a free neutron. The prominence of $g_A$ in nuclear physics has made it a benchmark quantity with which to calibrate lattice QCD calculations of nucleon structure and more complex calculations of electroweak matrix elements in one and few nucleon systems. There were a number of significant challenges in determining $g_A$, notably the notorious exponentially-bad signal-to-noise problem and the requirement for hundreds of thousands of stochastic samples, that rendered this goal more difficult to obtain than originally thought. I will describe the use of an unconventional computation method, coupled with ``ludicrously'' fast GPU code, access to publicly available lattice QCD configurations from MILC and access to leadership computing that have allowed these challenges to be overcome resulting in a determination of $g_A$ with 1\% precision and all sources of systematic uncertainty controlled. I will discuss the implications of these results for the convergence of SU(2) Chiral Perturbation theory for nucleons, as well as prospects for further improvements to $g_A$ (sub-percent precision, for which we have preliminary results) which is part of a more comprehensive application of lattice QCD to nuclear physics. This is particularly exciting in light of the new CORAL supercomputers coming online, Sierra and Summit, for which our lattice QCD codes achieve a machine-to-machine speed up over Titan of an order of magnitude.

Many microelectromechanical systems (MEMS) devices generate large deflections and stresses under some severe loads, and this cumulative stress often causes structural fatigue when applying high cyclic loads. It affects the reliability and quality of the product and can easily damage structures in harsh environments. For example, accelerometers and gyroscopes in motion sensors always combine a movable mass component with a bending or torsion spring, which can severely deform their structure at some large accelerations or angular accelerations. After this high cycle of deformation, the spring structure will be damaged and cause device failure, we call this failure mode high cycle fatigue (HCF). This is very common for MEMS products, but it is difficult for designers to predict it at design stage. To prevent early fatigue problems and reduce product development time, we developed a simulation process and empirical prediction model to help designers predict HCF and improve fatigue strength of moving structures used in MEMS devices. In this study, a bending and a torsion beam are used as test vehicles. A combination of dynamic and electromechanical coupling simulations was developed and applied to analyze the effects of frequency under HCF testing. The test structures were fabricated using silicon-on-insulator (SOI) MEMS technique and these test structures were used to validate empirical life prediction equation developed in this research. The frequency effect of HCF was also to be included in the developed prediction model. Based on the test results, the accuracy of the empirical prediction equation is improved by including frequency effect.

Anchoring the nuclear interaction in QCD is a long-outstanding problem in nuclear physics. While the lattice community has made enormous progress in mesonic physics and single nucleon physics, continuum-limit physical-point multi-nucleon physics has remained out of reach. I will review CalLat's strategy for multi-nucleon spectroscopy and our latest results., Proceedings of the 36th Annual International Symposium on Lattice Field Theory, 22-28 July, 2018, Michigan State University, East Lansing, Michigan

The search for neutrinoless double beta decay of nuclei is believed to be one of the most promising means to search for new physics. Observation of this very rare nuclear process, which violates Lepton Number conservation, would imply the neutrino sector has a Majorana mass component and may also provide an explanation for the universe matter-antimatter asymmetry of the universe. In the case where a heavy intermediate particle is exchanged in this process, QCD contributions from short range interactions become relevant and the calculation of matrix elements with four-quark operators becomes necessary. In these proceedings we will discuss our current progress in the calculation of these four-quark operators from LQCD., Comment: Proceedings of the 36th Annual International Symposium on Lattice Field Theory, 22-28 July, 2018, Michigan State University, East Lansing, Michigan

Fan out wafer level packaging is a potential solution for combining high electrical performance and low cost. However, with the shrinkage of the package, the mechanical reliability of the copper redistribution layer becomes an important issue. However, based on the processing of fan out packaging, the copper lines were annealed several times during the process. The annealing process is harmful to traditional strengthen mechanisms but not to columnar grains with high-density twinning structure. In this study, the technology of electroplating highly -oriented copper lines was introduced to solve the reliability issue in copper RDLs. By the nature of nano-twinned Cu, the performance of thermal cycling test (TCT) lifetime is much better than normal copper, and the failure mechanisms were discussed in this study.

In this paper, we measured the electromigration lifetimes for nanotwinned copper (nt-Cu) and regular copper redistribution lines (RDLs) for 3D-ICs packaging. The width of the RDLs is 10µm in width and 5µm in thickness, and the lines were coated by polyimide. The average lifetime of the nt-Cu RDL copper line is 445 hours to reach 1.2 times of its initial resistance. However, it takes 160 hours to reach the same resistance increase for regular copper RDL line. The nt-Cu has better EM lifetime than regular copper.

In the present paper, the nt-Cu were electroplated on the InFO test vehicles with 5 μm line width to compare the reliability with the normal electroplated copper. The temperature of the TCT ranges from -55 to 125°C. The microstructure of the copper traces after 200 cycles and 1000 cycles was shown in the results. The nt-Cu RDL is much stronger than the normal Cu in the thermal cycling test. In order to understand the mechanical property of the nt-Cu and the normal Cu, tensile tests of electroplated copper foils was employed. After annealing at 250°C for 3 hours, the toughness of nt-Cu (about 60MJ/m3) is much higher than normal copper (about 30MJ/m3). In addition, the simulation results shows that the maximum stress on the copper trace during the TCT is about 200MPa which is much lower than the yield point of nt-Cu. In other word, the nt-Cu would return to original size when the stress removed without strain accumulation. In summary, we observed that the nt-Cu performs much better than normal copper in TCT. From the tensile test and simulation, we can understand the mechanical behavior and the typical reason for the high reliability of nt-Cu.

Although, titanium dioxide nanoparticles (TiO2NPs) are nanomaterials commonly used in consumer products, little is known about their hazardous effects, especially on central nervous systems. To examine this issue, ALT astrocyte-like, BV-2 microglia and differentiated N2a neuroblastoma cells were exposed to 6 nm of 100% anatase TiO2NPs. A lipopolysaccharide (LPS) was pre-treated to activate glial cells before NP treatment for mimicking NP exposure under brain injury. We found that ALT and BV-2 cells took up more NPs than N2a cells and caused lower cell viability. TiO2NPs induced IL-1β in the three cell lines and IL-6 in N2a. LPS-activated BV-2 took up more TiO2NPs than normal BV-2 and released more intra/extracellular reactive oxygen species (ROS), IL-1β, IL-6 and MCP-1 than did activated BV-2. Involvement of clathrin- and caveolae-dependent endocytosis in ALT and clathrin-dependent endocytosis and phagocytosis in BV-2 both had a slow NP translocation rate to lysosome, which may cause slow ROS production (after 24 h). Although TiO2NPs did not directly cause N2a viability loss, by indirect NP exposure to the bottom chamber of LPS-activated BV-2 in the Transwell system, they caused late apoptosis and loss of cell viability in the upper N2a chamber due to H2O2 and/or TNF-α release from BV-2. However, none of the adverse effects in N2a or BV-2 cells was observed when TiO2NPs were exposed to ALT-N2a or ALT-BV-2 co-culture. These results demonstrate that neuron damage can result from TiO2NP-mediated ROS and/or cytokines release from microglia, but not from astrocytes.

Leadership computing facilities around the world support cutting-edge scientific research across a broad spectrum of disciplines including understanding climate change, combating opioid addiction, or simulating the decay of a neutron. While the increase in computational power has allowed scientists to better evaluate the underlying model, the size of these computational projects have grown to a point where a framework is desired to facilitate managing the workflow. A typical scientific computing workflow includes: Defining all input parameters for every step of the computation; Defining dependencies of computational tasks; Storing some of the output data; Post-processing these data files; Performing data analysis on output. EspressoDB is a programmatic object-relational data management framework implemented in Python and based on the Django web framework. EspressoDB was developed to streamline data management workflows, centralize and guarantee data integrity, while providing domain flexibility and ease of use. The framework provided by EspressoDB aims to support the ever increasing complexity of workflows of scientific computing at leadership computing facilities, with the goal of reducing the amount of human time required to manage the jobs, thus giving scientists more time to focus on science., Comment: Repository: https://github.com/callat-qcd/espressodb, use case: https://github.com/callat-qcd/lattedb; published version

Numerous scientific and engineering applications require numerically solving systems of equations. Classically solving a general set of polynomial equations requires iterative solvers, while linear equations may be solved either by direct matrix inversion or iteratively with judicious preconditioning. However, the convergence of iterative algorithms is highly variable and depends, in part, on the condition number. We present a direct method for solving general systems of polynomial equations based on quantum annealing, and we validate this method using a system of second-order polynomial equations solved on a commercially available quantum annealer. We then demonstrate applications for linear regression, and discuss in more detail the scaling behavior for general systems of linear equations with respect to problem size, condition number, and search precision. Finally, we define an iterative annealing process and demonstrate its efficacy in solving a linear system to a tolerance of $10^{-8}$., 11 pages, 4 figures. Added example for a system of quadratic equations. Supporting code is available at https://github.com/cchang5/quantum_poly_solver . This is a post-peer-review, pre-copyedit version of an article published in Scientific Reports. The final authenticated version is available online at: https://www.nature.com/articles/s41598-019-46729-0

The overall goal of the present study was to evaluate the chemotherapeutic and cancer‑protective properties of D‑erythro‑sphingosine (sphingosine) and C2‑ceramide using a human breast epithelial cell (HBEC) culture system, which represents multiple‑stages of breast carcinogenesis. The HBEC model includes Type I HBECs (normal stem), Type II HBECs (normal differentiated) and transformed cells (immortal/non‑tumorigenic cells and tumorigenic cells, which are transformed from the same parental normal stem cells). The results of the present study indicate that sphingosine preferentially inhibits proliferation and causes death of normal stem cells (Type I), tumorigenic cells, and MCF7 breast cancer cells, but not normal differentiated cells (Type II). In contrast to the selective anti‑proliferative effects of sphingosine, C2‑ceramide inhibits proliferation of normal differentiated cells as well as normal stem cells, tumorigenic cells, and MCF7 cancer cells with similar potency. Both sphingosine and C2‑ceramide induce apoptosis in tumorigenic cells. Among the sphingosine stereoisomers (D‑erythro, D‑threo, L‑erythro, and L‑threo) and sphinganine that were tested, L‑erythro‑sphingosine most potently inhibits proliferation of tumorigenic cells. The inhibition of breast tumorigenic/cancer cell proliferation by sphingosine was accompanied by inhibition of telomerase activity. Sphingosine at non‑cytotoxic concentrations, but not C2‑ceramide, induces differentiation of normal stem cells (Type I), thereby reducing the number of stem cells that are more susceptible to neoplastic transformation. To the best of our knowledge, the present study demonstrates one of the first results that sphingosine can be a potential chemotherapeutic and cancer‑protective agent, whereas C2‑ceramide is not an ideal chemotherapeutic and cancer‑protective agent due to its anti‑proliferative effects on Type II HBECs and its inability to induce the differentiation of Type I to Type II HBECs.