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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 289 records · Page 16
All sourcesNASA NTRSDOE OSTI
DOE OSTI2022

AI-assisted optimization of the ECCE tracking system at the Electron Ion Collider

The Electron-Ion Collider (EIC) is a cutting-edge accelerator facility that will study the nature of the “glue” that binds the building blocks of the visible matter in the universe. The proposed experiment will be realized at Brookhaven National Laboratory in approximately 10 years from now, with detector design and R&D currently ongoing. Notably, EIC is one of the first large-scale facilities to leverage Artificial Intelligence (AI) already starting from the design and R&D phases. The EIC Comprehensive Chromodynamics Experiment (ECCE) is a consortium that proposed a detector design based on a 1.5 T solenoid. The EIC detector proposal review concluded that the ECCE design will serve as the reference design for an EIC detector. Herein we describe a comprehensive optimization of the ECCE tracker using AI. The work required a complex parametrization of the simulated detector system. Herein our approach dealt with an optimization problem in a multidimensional design space driven by multiple objectives that encode the detector performance, while satisfying several mechanical constraints. We describe our strategy and show results obtained for the ECCE tracking system. The AI-assisted design is agnostic to the simulation framework and can be extended to other sub-detectors or to a system of sub-detectors to further optimize the performance of the EIC detector.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗
DOE OSTI2019

Drugging an undruggable pocket on KRAS

The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different RAS proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations in RAS are among the most common oncogenic drivers in human cancers, with KRAS being the most frequently mutated oncogene. Although KRAS is an excellent drug discovery target for many cancers, and despite decades of research, no therapeutic agent directly targeting RAS has been clinically approved. Using structure-based drug design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with nanomolar affinity to a pocket, thus far perceived to be “undruggable,” between switch I and II on RAS; 1 is mechanistically distinct from covalent KRAS G12C inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, it blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These findings clearly demonstrate that this so-called switch I/II pocket is indeed druggable and provide the scientific community with a chemical probe that simultaneously targets the active and inactive forms of KRAS

60 APPLIED LIFE SCIENCES↗
DOE OSTI2019

Bxy‐fuca encoding α‐L‐fucosidase plays crucial roles in development and reproduction of the pathogenic pinewood nematode, Bursaphelenchus xylophilus

Abstract BACKGROUND The pine wood nematode (PWN) Bursaphelenchus xylophilus is the causal agent of pine wilt disease (PWD). This disease is a serious threat to pine forests globally. The fuca gene encodes α‐L‐fucosidase, which plays crucial roles in numerous biological and pathological processes in bacteria, fungi, plants and animals. To find promising control strategies against PWD, we investigated the expression and functions of Bxy‐fuca in B. xylophilus . RESULTS Bxy‐fuca encoding α‐L‐fucosidase is highly conserved within the deduced functional domains and key residues. It is expressed continuously across all developmental stages of B. xylophilus . mRNA in situ hybridization demonstrated that Bxy‐fuca was mainly localized in the body wall muscles and intestine. RNA interference indicated that the zygotic expression of Bxy‐fuca was indispensable for embryogenesis. The rate of B. xylophilus egg hatch was significantly decreased after Bxy‐fuca was interfered. Postembryonic silence of Bxy‐fuca resulted in a dramatic decrease in the longevity of and the total number of eggs produced by B. xylophilus . In addition, the motility of the nematode was greatly hampered with a significant drop in head thrashing frequency. CONCLUSION Bxy‐fuca plays crucial roles in development, lifespan and reproduction of B. xylophilus . Our results provide promising hints for control of PWD by blocking embryogenesis and ontogenesis, decreasing nematode fecundity, and disrupting the connection between B. xylophilus and its vector beetle by preventing nematode movement into the tracheal system. © 2019 Society of Chemical Industry

Tang, Jia↗
DOE OSTI2012

Two Translation Products of Yersinia yscQ Assemble To Form a Complex Essential to Type III Secretion

The bacterial flagellar C-ring is composed of two essential proteins, FliM and FliN. The smaller protein, FliN, is similar to the C-terminus of the larger protein, FliM, both being composed of SpoA domains. While bacterial type III secretion (T3S) systems encode many proteins in common with the flagellum, they mostly have a single protein in place of FliM and FliN. This protein resembles FliM at its N-terminus and is as large as FliM but is more like FliN at its C-terminal SpoA domain. We have discovered that a FliN-sized cognate indeed exists in the Yersinia T3S system to accompany the FliM-sized cognate. The FliN-sized cognate, YscQ-C, is the product of an internal translation initiation site within the locus encoding the FliM-sized cognate YscQ. Both intact YscQ and YscQ-C were found to be required for T3S, indicating that the internal translation initiation site, which is conserved in some but not all YscQ orthologs, is crucial for function. The crystal structure of YscQ-C revealed a SpoA domain that forms a highly intertwined, domain-swapped homodimer, similar to those observed in FliN and the YscQ ortholog HrcQ{sub B}. A single YscQ-C homodimer associated reversibly with a single molecule of intact YscQ, indicating conformational differences between the SpoA domains of intact YscQ and YscQ-C. A 'snap-back' mechanism suggested by the structure can account for this. The 1:2 YscQ-YscQ-C complex is a close mimic of the 1:4 FliM-FliN complex and the likely building block of the putative Yersinia T3S system C-ring.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2022

Human sperm TMEM95 binds eggs and facilitates membrane fusion

Tmem95 encodes a sperm acrosomal membrane protein, whose knockout has a male-specific sterility phenotype in mice. Tmem95 knockout murine sperm can bind to, but do not fuse with, eggs. How TMEM95 plays a role in membrane fusion of sperm and eggs has remained elusive. Here, we utilize a sperm penetration assay as a model system to investigate the function of human TMEM95. We show that human TMEM95 binds to hamster egg membranes, providing evidence for a TMEM95 receptor on eggs. Using X-ray crystallography, we reveal an evolutionarily conserved, positively charged region of TMEM95 as a putative receptor-binding surface. Amino acid substitutions within this region of TMEM95 ablate egg-binding activity. We identify monoclonal antibodies against TMEM95 that reduce the number of human sperm fused with hamster eggs in sperm penetration assays. Strikingly, these antibodies do not block binding of sperm to eggs. Taken together, these results provide strong evidence for a specific, receptor-mediated interaction of sperm TMEM95 with eggs and suggest that this interaction may have a role in facilitating membrane fusion during fertilization.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2018

Crystal structure of WA352 provides insight into cytoplasmic male sterility in rice

Highlights: • Identification of a C-terminal structural and functional core domain of WA352. • The crystal structure of C-terminus of WA352 was determined at 1.3 Å resolution. • Molecular mechanism whereby WA352 perturbs COX11 function to cause CMS is proposed. Plant cytoplasmic male sterility (CMS) is an important phenomenon and is widely utilized in hybrid crop breeding. The Wild Abortive CMS (CMS-WA), a well-known CMS type, has been successfully applied in the commercial production of hybrid rice seeds for more than 40 years. The CMS-WA causal gene WA352 encodes a novel transmenbrane protein and the interacts with the mitochondrial copper chaperone COX11, triggering reactive oxygen species production and resulting in male sterility in CMS-WA lines. However, the structure of WA352 is currently unknown, and the structural mechanism whereby WA352 perturbs COX11 function to cause CMS remains largely unknown. Here, we report the crystal structure of the C-terminal functional domain of WA352 at 1.3 Å resolution. This functional domain, consisting of five α helices, is spindle-shaped with a length of 42 Å, and a diameter of 28 Å. Notably, the absence of any structural similarity to a known protein structure suggests that the WA352 functional domain is a novel fold. In addition, surface conservation analysis and structural modeling of the WA352-COX11 complex revealed details about the WA352-COX11 interaction. Further structural analysis suggested that the WA352-COX11 interaction blocks the copper ion transportation activity of COX11, which is essential for the assembly of cytochrome c oxidase, resulting in male sterility in CMS-WA lines. Our study paves the way toward structural determination of the WA352-COX11 complex and provides new insight into the mechanism of plant CMS.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2016

Expression of the small T antigen of Lymphotropic Papovavirus is sufficient to transform primary mouse embryo fibroblasts

Polyomaviruses induce cell proliferation and transformation through different oncoproteins encoded within the early region (ER): large T antigen (LT), small T antigen (sT) and, in some cases, additional components. Each virus utilizes different mechanisms to achieve transformation. For instance, the LTs of Simian virus 40 (SV40), BK and/or JC virus can induce transformation; but Merkel Cell Polyomavirus (MCPyV) requires expression of sT. Lymphotropic Papovavirus (LPV) is closely related to Human Polyomavirus 9 (HuPyV9) and, under similar conditions, mice expressing LPV.ER exhibit higher rates of tumor formation than mice expressing SV40.ER. We have investigated the contributions of individual LPV.ER components to cell transformation. In contrast to SV40, LPV.ER transforms mouse embryonic fibroblasts (MEFs), but expression of LPV LT is insufficient to transform MEFs. Furthermore, LPV sT induces immortalization and transformation of MEFs. Thus, in the case of LPV, sT is the main mediator of oncogenesis. - Highlights: • Characterization of early region products from the Lymphotropic Polyomavirus (LPV). • On its own, sT immortalizes and transforms mouse primary cells, and is able to block p53 activation. • Combined LT and sT expression induces a greater rate of proliferation than either LT or sT alone.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2013

Minimal Power Latch for Single-Slope ADCs

Column-parallel analog-to-digital converters (ADCs) for imagers involve simultaneous operation of many ADCs. Single-slope ADCs are well adapted to this use because of their simplicity. Each ADC contains a comparator, comparing its input signal level to an increasing reference signal (ramp). When the ramp is equal to the input, the comparator triggers a latch that captures an encoded counter value (code). Knowing the captured code, the ramp value and hence the input signal are determined. In a column-parallel ADC, each column contains only the comparator and the latches; the ramp and code generation are shared. In conventional latch or flip-flop circuits, there is an input stage that tracks the input signal, and this stage consumes switching current every time the input changes. With many columns, many bits, and high code rates, this switching current can be substantial. It will also generate noise that may corrupt the analog signals. A latch was designed that does not track the input, and consumes power only at the instant of latching the data value. The circuit consists of two S-R (set-reset) latches, gated by the comparator. One is set by high data values and the other by low data values. The latches are cross-coupled so that the first one to set blocks the other. In order that the input data not need an inversion, which would consume power, the two latches are made in complementary polarity. This requires complementary gates from the comparator, instead of complementary data values, but the comparator only triggers once per conversion, and usually has complementary outputs to begin with. An efficient CMOS (complementary metal oxide semiconductor) implementation of this circuit is shown in the figure, where C is the comparator output, D is the data (code), and Q0 and Q1 are the outputs indicating the capture of a zero or one value. The latch for Q0 has a negative-true set signal and output, and is implemented using OR-AND-INVERT logic, while the latch for Q1 uses positive- true signals and is implemented using AND-OR-INVERT logic. In this implementation, both latches are cleared when the comparator is reset. Two redundant transistors are removed from the reset side of each latch, making for a compact layout. CMOS imagers with column-parallel ADCs have demonstrated high performance for remote sensing applications. With this latch circuit, the power consumption and noise can be further reduced. This innovation can be used in CMOS imagers and very-low-power electronics

Hancock, Bruce R.↗
DOE OSTI2018

The role of Rho-GEF Trio in regulating tooth root development through the p38 MAPK pathway

Highlights: • We have determined the role of Trio, a GTP exchange factor, in tooth development. • The Wnt1-cre;Trio{sup fl/fl} mice were created for in vivo study. • P38 MAPK pathway was found to be involved in Trio related root deformity. Trio, the Rho guanine nucleotide exchange factor (Rho-GEF), plays diverse roles in cell migration, cell axon guidance and cytoskeleton reorganization. Conserved during evolution, Trio encodes two guanine nucleotide exchange factor domains (GEFs) and activates small GTPases. The Rho-family small GTPases RhoA and Rac1, which are target molecules of Trio, have been described to engage in craniofacial development and tooth formation. However, the exact role of Trio in tooth development remains elusive. In this study, we generated Wnt1-cre;Trio{sup fl/fl} mice to address the potential function of Trio in tooth development. Wnt1-cre;Trio{sup fl/fl} mice showed short root deformity as well as decreased expression of odontogenic makers such as RUNX2, OSX, OCN, and OPN. In vitro, Trio was silenced in human stem cells of dental papilla (SCAPs). Compared with the control group, the proliferation and migration ability in the experimental group was disrupted. After knocking down Trio in SCAPs, the cells showed phenotypes of poor odontogenic differentiation and weak mineralized nodules. To study the underlying mechanism, we investigated the p38 MAPK pathway and found that loss of Trio blocked the cascade transduction of p38 MAPK signaling. In conclusion, we identified Trio as a novel coordinator in regulating root development and clarified its relevant molecular events.

60 APPLIED LIFE SCIENCES↗
NASA NTRS2001

Streptococcus pneumoniae PstS production is phosphate responsive and enhanced during growth in the murine peritoneal cavity

Differential display-PCR (DDPCR) was used to identify a Streptococcus pneumoniae gene with enhanced transcription during growth in the murine peritoneal cavity. Northern dot blot analysis and comparative densitometry confirmed a 1.8-fold increase in expression of the encoded sequence following murine peritoneal culture (MPC) versus laboratory culture or control culture (CC). Sequencing and basic local alignment search tool analysis identified the DDPCR fragment as pstS, the phosphate-binding protein of a high-affinity phosphate uptake system. PCR amplification of the complete pstS gene followed by restriction analysis and sequencing suggests a high level of conservation between strains and serotypes. Quantitative immunodot blotting using antiserum to recombinant PstS (rPstS) demonstrated an approximately twofold increase in PstS production during MPC from that during CCs, a finding consistent with the low levels of phosphate observed in the peritoneum. Moreover, immunodot blot and Northern analysis demonstrated phosphate-dependent production of PstS in six of seven strains examined. These results identify pstS expression as responsive to the MPC environment and extracellular phosphate concentrations. Presently, it remains unclear if phosphate concentrations in vivo contribute to the regulation of pstS. Finally, polyclonal antiserum to rPstS did not inhibit growth of the pneumococcus in vitro, suggesting that antibodies do not block phosphate uptake; moreover, vaccination of mice with rPstS did not protect against intraperitoneal challenge as assessed by the 50% lethal dose.

Non-NASA Center↗
DOE OSTI2015

A Combination of Structural and Empirical Analyses Delineates the Key Contacts Mediating Stability and Affinity Increases in an Optimized Biotherapeutic Single-chain Fv (scFv)

Fully-human single-chain Fv (scFv) proteins are key potential building blocks of bispecific therapeutic antibodies, but they often suffer from manufacturability and clinical development limitations such as instability and aggregation. Here, the causes of these scFv instability problems, in proteins that should be theoretically stable, remains poorly understood. To inform the future development of such molecules, we carried out a comprehensive structural analysis of the highly stabilized anti-CXCL13 scFv E10. E10 was derived from the parental 3B4 using complementarity-determining region (CDR)-restricted mutagenesis and tailored selection and screening strategies, and carries four mutations in V L -CDR3. High-resolution crystal structures of parental 3B4 and optimized E10 scFvs were solved in the presence and absence of human CXCL13. In parallel, a series of scFv mutants was generated to interrogate the individual contribution of each of the four mutations to stability and affinity improvements. In combination, these analyses demonstrated that the optimization of E10 was primarily mediated by removing clashes between both the V L and the V H , and between the V L and CXCL13. Importantly, a single, germline-encoded V L -CDR3 residue mediated the key difference between the stable and unstable forms of the scFv. This work demonstrates that, aside from being the critical mediators of specificity and affinity, CDRs may also be the primary drivers of biotherapeutic developability.

59 BASIC BIOLOGICAL SCIENCES↗
NASA NTRS1999

Miniature EPSPs and sensory encoding in the primary afferents of the vestibular lagena of the toadfish, Opsanus tau

The synaptic activity transmitted from vestibular hair cells of the lagena to primary afferent neurons was recorded in vitro using sharp, intracellular microelectrodes. At rest, the activity was composed of miniature excitatory postsynaptic potentials (mEPSPs) at frequencies from 5 to 20/s and action potentials (APs) at frequencies betwen 0 and 10/s. mEPSPs recorded from a single fiber displayed a large variability. For mEPSPs not triggering APs, amplitudes exhibited an average coefficient of variance (CV) of 0.323 and rise times an average CV of 0.516. APs were only triggered by mEPSPs with larger amplitudes (estimated 4-6 mV) and/or steeper maximum rate of rise (10.9 mV/ms, +/- 3.7 SD, n=4 experiments) compared to (3.50 mV/ms, +/-0.07 SD, n=6 experiments) for nontriggering mEPSPs. The smallest mEPSPs showed a fast rise time (0.99 ms between 10% and 90% of peak amplitude) and limited variability across fibers (CV:0.18) confirming that they were not attenuated signals, but rather represented single-transmitter discharges (TDs). The mEPSP amplitude and rise-time relationship suggests that many mEPSPs represented several, rather than a single pulse of secretion of TDs. According to the estimated overall TD frequency, the coincidence of TDs contributing to the same mEPSP were not statistically independent, indicating a positive interaction between TDs that is reminiscent of the way subminiature signals group to form miniature signals at the neuromuscular junction. Depending on the duration and intensity of efferent stimulation, a complete block of AP initiation occurred either immediately or after a delay of a few seconds. Efferent stimulation did not significantly change AP threshold level, but abruptly decreased mEPSP frequency to a near-complete block that followed the block of APs. Maximum mEPSP rate of rise decreased during, and recovered progressively after, efferent stimulation. After termination of efferent stimulation, mEPSP amplitude did not recover instantly and for a few seconds the amplitude distribution of synaptic events showed fewer large-amplitude events than during the control period. This confirms that mEPSP amplitude and rate of rise properties, which are critical for triggering afferent APs, are modified by efferent activity. The depression of afferent AP firing during efferent stimulation corresponded to a decrease in mEPSP frequency and, to a lesser extent, a decrease in mEPSP amplitude and rate of rise, suggesting, a decrease in the level of interaction among TDs contibuting to a mEPSP.

Non-NASA Center↗
DOE OSTI2018

Nucleon Tomography Studies at Jefferson Lab

Protons and neutrons, are the building blocks of atomic nuclei. They constitute over 99 percent of the mass of the matter in the visible universe. A fundamental challenge of modern nuclear physics is to understand the structure of these constituents. The 12 GeV Upgrade of the Continuous Electron Beam Accelerator Facility (CEBAF) at Jefferson Lab and the construction of state-of-the-art detector systems make it a unique facility in the world to address this challenge. Electron scattering is a superb experimental tool to study the internal structure of nucleons at differing distance scales, as the resolving power of the probe can be varied. The CEBAF Upgrade was completed in September 2017 and the new generation of experiments has started. These experiments will enable a collaboration of scientists from around the world to perform precise experiments of exclusive processes covering a large range in kinematics to effectively engage in nuclear imaging, revealing hidden aspects of its internal structure, and providing insight into quark confinement forces in the nucleon, one of the greatest mysteries of modern physics. The Generalized Parton Distributions (GPDs) provide the theoretical framework to interpret the experimental data in terms of 3-dimensional imaging. In addition, recent development demonstrated that the GPD formalism enables access to the nucleon's Gravitational Form Factors that encode its mechanical properties. We will focus on the study of the Deeply Virtual Compton Scattering (DVCS), the most effective way to access GPDs. We will review the landscape of both theory and experiment, and discuss the latest results from Jefferson Lab at 6 GeV in comparison with results from other facilities, and present a first look at the new experiments with the 12 GeV Upgrade.

Elouadrhiri, Latifa↗
DOE OSTI2018

LL-37-induced human osteoblast cytotoxicity and permeability occurs independently of cellular LL-37 uptake through clathrin-mediated endocytosis

Highlights: • LL-37 reduces viability and increases permeability of human osteoblast-like cells. • Chlorpromazine, inhibitor of clathrin-mediated endocytosis, reduces LL-37 import. • LL-37-induced cytotoxicity is unaffected by clathrin-mediated endocytosis block. • Knockdown of clathrin heavy chain gene attenuates uptake of LL-37. • Knockdown of clathrin heavy chain gene has no impact on LL-37-induced cytotoxicity. The host defense peptide LL-37 is cytotoxic for bacteria but it has also been reported to reduce host cell viability through an intracellular mechanism. LL-37-evoked cytotoxicity may be involved in the loss of bone tissue in periodontitis which is an inflammatory disease characterized by high concentrations of LL-37 observed locally in the periodontal tissue at the inflammation process. Here, we showed that LL-37 reduced human osteoblast-like MG63 cell viability assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and increased plasma membrane permeability determined by measuring intracellular Ca{sup 2+} levels and lactate dehydrogenase (LDH) release. Treatment with chlorpromazine, a well-recognized inhibitor of clathrin-mediated endocytosis, reduced cellular uptake of synthesized LL-37 b y about 30% assessed by Western blotting and ELISA, while filipin, an inhibitor of caveolin-mediated endocytosis, had no effect. The chlorpromazine-induced attenuation of LL-37 uptake was not associated with modulation of LL-37-induced cytotoxicity and LL-37-evoked plasma membrane permeability. Clathrin heavy chain 2 is a major protein of the polyhedral coat of coated pits and vesicles encoded by clathrin heavy chain like 1 gene. Down-regulation of clathrin heavy chain like 1 gene activity by siRNA reduced uptake of LL-37 but did not affect LL-37-induced cytotoxicity and permeability. Thus, we show, using both a pharmacological approach and knockdown of clathrin heavy chain like 1 expression, that LL-37-induced MG63 cell cytotoxicity and permeability occurs independently of LL-37 uptake via clathrin-mediated endocytosis.

60 APPLIED LIFE SCIENCES↗
DOE OSTI2014

Uncovering the polymerase-induced cytotoxicity of an oxidized nucleotide

Oxidative stress promotes genomic instability and human diseases. A common oxidized nucleoside is 8-oxo-7,8-dihydro-2’-deoxyguanosine found both in DNA (8-oxo-G) and as a free nucleotide (8-oxo-dGTP). Nucleotide pools are especially vulnerable to oxidative damage. Therefore cells encode an enzyme (MutT/MTH1) that removes free oxidized nucleotides. This cleansing function is required for cancer cell survival and to modulate E. coli antibiotic sensitivity in a DNA polymerase (pol)-dependent manner. How polymerase discriminates between damaged and non-damaged nucleotides is not well understood. This analysis is essential given the role of oxidized nucleotides in mutagenesis, cancer therapeutics, and bacterial antibiotics. Even with cellular sanitizing activities, nucleotide pools contain enough 8-oxo-dGTP to promote mutagenesis. This arises from the dual coding potential where 8-oxo-dGTP(anti) base pairs with cytosine (Cy) and 8-oxodGTP(syn) utilizes its Hoogsteen edge to base pair with adenine (Ad). Here in this paper we utilized time-lapse crystallography to follow 8-oxo-dGTP insertion opposite Ad or Cy with human DNA pol β, to reveal that insertion is accommodated in either the syn- or anti-conformation, respectively. For 8-oxo-dGTP(anti) insertion, a novel divalent metal relieves repulsive interactions between the adducted guanine base and the triphosphate of the oxidized nucleotide. With either templating base, hydrogen bonding interactions between the bases are lost as the enzyme reopens after catalysis, leading to a cytotoxic nicked DNA repair intermediate. Combining structural snapshots with kinetic and computational analysis reveals how 8-oxodGTP utilizes charge modulation during insertion that can lead to a blocked DNA repair intermediate.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗
NASA NTRS2003

Block QCA Fault-Tolerant Logic Gates

Suitably patterned arrays (blocks) of quantum-dot cellular automata (QCA) have been proposed as fault-tolerant universal logic gates. These block QCA gates could be used to realize the potential of QCA for further miniaturization, reduction of power consumption, increase in switching speed, and increased degree of integration of very-large-scale integrated (VLSI) electronic circuits. The limitations of conventional VLSI circuitry, the basic principle of operation of QCA, and the potential advantages of QCA-based VLSI circuitry were described in several NASA Tech Briefs articles, namely Implementing Permutation Matrices by Use of Quantum Dots (NPO-20801), Vol. 25, No. 10 (October 2001), page 42; Compact Interconnection Networks Based on Quantum Dots (NPO-20855) Vol. 27, No. 1 (January 2003), page 32; Bit-Serial Adder Based on Quantum Dots (NPO-20869), Vol. 27, No. 1 (January 2003), page 35; and Hybrid VLSI/QCA Architecture for Computing FFTs (NPO-20923), which follows this article. To recapitulate the principle of operation (greatly oversimplified because of the limitation on space available for this article): A quantum-dot cellular automata contains four quantum dots positioned at or between the corners of a square cell. The cell contains two extra mobile electrons that can tunnel (in the quantummechanical sense) between neighboring dots within the cell. The Coulomb repulsion between the two electrons tends to make them occupy antipodal dots in the cell. For an isolated cell, there are two energetically equivalent arrangements (denoted polarization states) of the extra electrons. The cell polarization is used to encode binary information. Because the polarization of a nonisolated cell depends on Coulomb-repulsion interactions with neighboring cells, universal logic gates and binary wires could be constructed, in principle, by arraying QCA of suitable design in suitable patterns. Heretofore, researchers have recognized two major obstacles to realization of QCA-based logic gates: One is the need for (and the difficulty of attaining) operation of QCA circuitry at room temperature or, for that matter, at any temperature above a few Kelvins. It has been theorized that room-temperature operation could be made possible by constructing QCA as molecular-scale devices. However, in approaching the lower limit of miniaturization at the molecular level, it becomes increasingly imperative to overcome the second major obstacle, which is the need for (and the difficulty of attaining) high precision in the alignments of adjacent QCA in order to ensure the correct interactions among the quantum dots.

Firjany, Amir↗
DOE OSTI2013

The LMNA mutation p.Arg321Ter associated with dilated cardiomyopathy leads to reduced expression and a skewed ratio of lamin A and lamin C proteins

Dilated cardiomyopathy (DCM) is a disease of the heart muscle characterized by cardiac chamber enlargement and reduced systolic function of the left ventricle. Mutations in the LMNA gene represent the most frequent known genetic cause of DCM associated with disease of the conduction systems. The LMNA gene generates two major transcripts encoding the nuclear lamina major components lamin A and lamin C by alternative splicing. Both haploinsuffiency and dominant negative effects have been proposed as disease mechanism for premature termination codon (PTC) mutations in LMNA. These mechanisms however are still not clearly established. In this study, we used a representative LMNA nonsense mutation, p.Arg321Ter, to shed light on the molecular disease mechanisms. Cultured fibroblasts from three DCM patients carrying this mutation were analyzed. Quantitative reverse transcriptase PCR and sequencing of these PCR products indicated that transcripts from the mutant allele were degraded by the nonsense-mediated mRNA decay (NMD) mechanism. The fact that no truncated mutant protein was detectable in western blot (WB) analysis strengthens the notion that the mutant transcript is efficiently degraded. Furthermore, WB analysis showed that the expression of lamin C protein was reduced by the expected approximately 50%. Clearly decreased lamin A and lamin C levels were also observed by immunofluorescence microscopy analysis. However, results from both WB and nano-liquid chromatography/mass spectrometry demonstrated that the levels of lamin A protein were more reduced suggesting an effect on expression of lamin A from the wild type allele. PCR analysis of the ratio of lamin A to lamin C transcripts showed unchanged relative amounts of lamin A transcript suggesting that the effect on the wild type allele was operative at the protein level. Immunofluorescence microscopy analysis showed no abnormal nuclear morphology of patient fibroblast cells. Based on these data, we propose that heterozygosity for the nonsense mutation causes NMD degradation of the mutant transcripts blocking expression of the truncated mutant protein and an additional trans effect on lamin A protein levels expressed from the wild type allele. We discuss the possibility that skewing of the lamin A to lamin C ratio may contribute to ensuing processes that destabilize cardiomyocytes and trigger cardiomyopathy - Highlights: • We study disease mechanisms in DCM patients carrying PTC mutations in the LMNA gene. • The mutant transcript is degraded by the nonsense mediated mRNA decay system. • Skewed lamin A to lamin C protein ratio expressed from the wild type allele. • We suggest a combined pathomechanism: haploinsuffiency plus lamin A/C imbalance.

60 APPLIED LIFE SCIENCES↗