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At least 523 records · Page 29

CRISPR-Cas9 Circular Permutants as Programmable Scaffolds for Genome Modification

The ability to engineer natural proteins is pivotal to a future, pragmatic biology. CRISPR proteins have revolutionized genome modification, yet the CRISPR-Cas9 scaffold is not ideal for fusions or activation by cellular triggers. Here in this paper, we show that a topological rearrangement of Cas9 using circular permutation provides an advanced platform for RNA-guided genome modification and protection. Through systematic interrogation, we find that protein termini can be positioned adjacent to bound DNA, offering a straightforward mechanism for strategically fusing functional domains. Additionally, circular permutation enabled protease-sensing Cas9s (ProCas9s), a unique class of single-molecule effectors possessing programmable inputs and outputs. ProCas9s can sense a wide range of proteases, and we demonstrate that ProCas9 can orchestrate a cellular response to pathogen-associated protease activity. Together, these results provide a toolkit of safer and more efficient genome-modifying enzymes and molecular recorders for the advancement of precision genome engineering in research, agriculture, and biomedicine.

59 BASIC BIOLOGICAL SCIENCES↗

Simulation of the TAEs’ saturation phase in the Large Helical Device: MHD burst

Here, the aim of the present study is to analyze the saturation regime of the toroidal Alfven eigenmodes (TAE) in the Large Helical Device plasma, particularly the MHD burst. The linear and nonlinear evolution of the TAEs are simulated by the FAR3d code that uses a reduced MHD model for the thermal plasma coupled with a gyrofluid model for the energetic particle (EP) species. The linear simulations indicate the overlapping of 1/2–1/1, 2/3–2/4 and 3/5–3/6 TAEs in the inner-middle plasma region and frequency range of 45–75 kHz, triggered by EPs with an energy of T f = 45 keV and EP β = 0.022. The nonlinear simulations show that 2/3–2/4 and 3/4–3/5 TAEs are further destabilized due to the energy transfer from the 1/1–1/2 TAE, leading to broad TAE radial overlapping and triggering of the MHD burst. The energy of the 1/1–1/2 TAE is also nonlinearly transferred to the thermal plasma destabilizing the 0/0 and 0/1 modes, inducing the generation of shear flows and zonal currents, as well as large deformations in the thermal pressure and EP density radial profiles. The nonlinear simulation reproduces the same succession of instabilities and the same frequency range with respect to the experiment. The instability propagates outward during the bursting phase, showing a large decrease of the EP density profile between the middle-outer plasma, indicating the loss of part of the EP population that explains the decrease in the plasma heating efficiency observed during the MHD burst.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Integrated Pest Management (IPM) for Early Detection Algal Crop Protection. Final Report

During large-scale, outdoor algal biomass growth, production strain(s) are subject to attack by pathogens, predators, and non-productive competitors, compromising the biomass yield. The project team at UCSD developed and demonstrated the effectiveness of Volatile Organic Compound, VOC, analysis via mass spectrometry (MS) as an early detection system for the presence of production algal ponds infection. The MS detection can then trigger high-resolution melt analysis (HRMA) and enhanced quantitative PCR (qPCR) to identify predatory or pathogenic species precisely. This study gathered the foundational data informing how wholly automated systems monitor the health of production ponds. By detecting the presence of low molecular weight VOCs in the air space above ponds, the instrument was able to mimic “sniffing” the health of the algae pond. This early warning system will be free growers from time-consuming and costly regular surveillance of ponds with the current techniques, such as qPCR and flow-cam assays, which are slower, less sensitive, and not easily fully automated, resulting in increased production efficiency through the reduction of crop loss. This project demonstrated that Chemical Ionization Mass Spectrometry, CIMS, could serve as a real-time monitor of ponds health tracking up to 100 different VOCs simultaneously for continuous periods up to 60 days without interruption, signaling infection within an algal crop 24 to 36 hours prior to techniques such as qPCR and microscopy. While mass spectrometry is an expensive tool, this simple VOC sampling system proved not only to be sensitive and robust but could to multiplexed to monitor several ponds, lowering the overall cost serially. This technology demonstrated a reduction in biomass production cost by approximately 50% compared to growers not employing any detection methodology.

09 BIOMASS FUELS↗

Particle detection through the quantum counter concept in YAG:Er{sup 3+}

We report on a scheme for particle detection based on the infrared quantum counter concept. Its operation consists of a two-step excitation process of a four level system, which can be realized in rare earth-doped crystals when a cw pump laser is tuned to the transition from the second to the fourth level. The incident particle raises the atoms of the active material into a low lying, metastable energy state, triggering the absorption of the pump laser to a higher level. Following a rapid non-radiative decay to a fluorescent level, an optical signal is observed with a conventional detector. In order to demonstrate the feasibility of such a scheme, we have investigated the emission from the fluorescent level {sup 4}S{sub 3∕2} (540 nm band) in an Er{sup 3+}-doped YAG crystal pumped by a tunable titanium sapphire laser when it is irradiated with 60 keV electrons delivered by an electron gun. We have obtained a clear signature that this excitation increases the {sup 4}I{sub 13∕2} metastable level population that can efficiently be exploited to generate a detectable optical signal.

71 CLASSICAL AND QUANTUM MECHANICS, GENERAL PHYSIC↗

Grid Impact Studies from Dynamic Wireless Charging in Smart Automated Highways

Autonomous and electrified mobility are two key developments expected in the next decade to improve the efficiency and reduce carbon footprint of transportation. As electric vehicles (EVs) increase on the roads, one of the issues that needs to be addressed is range anxiety. To mitigate this problem and for seamless integration of EVs, dynamic wireless charging is an attractive solution. In this paper, a few case studies are considered in a smart autonomous highway to understand the impact of dynamic wireless charging on grid dynamics. The studies show that the grid voltages vary significantly due to the dynamic wireless power transfers (DWPTs), if connected to the existing grid. The variations in the grid voltage can reduce power transfers, increase grid instability, and cause inadvertent protection triggers. The inadvertent protection triggers can reduce the reliability of the connected grid. These problems highlight the need for modern grid infrastructure to support DWPT systems.

Debnath, Suman↗

Extent of MHC Clustering Regulates Selectivity and Effectiveness of T Cell Responses

MHC proteins that present peptide ligands for recognition by T-cell antigen receptor (TCR) form nano-scale clusters on the cell membrane of antigen-presenting cells. How the extent of MHC clustering controls productive TCR engagement and TCR-mediated signaling has not been systematically studied. To evaluate the role of MHC clustering, we exploited nano-scale discoidal membrane mimetics (nanolipoprotein particles, or NLPs) to capture and present pMHC ligands at various densities. We examined the binding of these model membrane clusters to the surface of live CD8 + T cells and the subsequent triggering of intracellular signaling. The data demonstrate that the proximity of pMHC ligands, high association rate of CD8-MHC interactions, and relatively long lifetime of cognate TCRpMHC complexes emerge as essential parameters explaining the significance of MHC clustering. Rapid rebinding of CD8 to MHC suggested a dual role of CD8 in facilitating the T cells’ hunt for a rare foreign pMHC ligand and the induction of rapid T-cell response. Thus, our findings provide a new understanding of how MHC clustering influences multivalent interactions of pMHC ligands with CD8 and TCR on live T cells that regulate antigen recognition, kinetics of intracellular signaling, and the selectivity and efficiency of T-cell responses.

60 APPLIED LIFE SCIENCES↗

Electrochemically Triggered Chain Reactions for the Conversion of Furan Derivatives

Abstract We report an electrochemical method for coupling biomass‐derived C5/C6 compounds to value‐added fuel precursors. Using only 2 % of equivalent charges, 2‐methylfuran (2‐MF) was oxidized to yield a cation radical, which readily reacted with 3‐hexene‐2,5‐dione, a derivate of 2,5‐dimethylfuran, to produce 3‐(5‐methylfuran‐2‐yl)hexane‐2,5‐dione. The product was converted to 4‐ethylnonane (a component of biodiesel/jet fuel) in a single step in excellent yield. Importantly, the reaction was not sensitive to oxygen, and a trace amount of water was found to promote the reaction. Detailed mechanistic studies confirmed the proposed reaction pathways. Key to the mechanism is the radical generation that is enabled by electrochemistry. The radical is regenerated at the end of a reaction cycle to ensure chain propagation for an average of ca. 47 times, resulting in an apparent Faradaic efficiency of 4700 %.

Chen, Rong↗

Manipulating Na/TM Ratio‐Driven Structural Heterogeneity of O3‐NaNi 1/3 Fe 1/3 Mn 1/3 O 2 Cathode for High‐Voltage Sodium‐Ion Batteries

The stability of O3-type NaNi 1/3 Fe 1/3 Mn 1/3 O 2 under high-voltage cycling is dictated by how synthesis encodes lattice strain and redox heterogeneity. Here, in this study, the role of Na:TM stoichiometry is systematically resolved by tuning the NaOH:precursor ratio during solid-state synthesis. The stoichiometric condition (Na:TM = 1.00) yields minimized microstrain, enabling uniform O3–P3 phase evolution and homogeneous multi-metal redox with preserved octahedral symmetry. In contrast, Na-excess compositions inherit disordered intermediates and heterogeneous distortion fields that trigger abrupt multiphase transitions and promote localized charge redistribution. In situ XRD captures the divergence in phase-transition pathways, TXM resolves particle-level redox heterogeneity, and XANES corroborates a stronger and more reversible Fe redox contribution at stoichiometry, shifting to diminished Fe participation and spatially inhomogeneous redox at higher Na content. These results establish Na:TM stoichiometry as a critical synthesis parameter controlling both structural coherence and redox stability. Electrochemically, the stoichiometric composition exhibits smooth voltage profiles with minimal polarization growth and retains nearly 80% of its initial capacity after 100 cycles even at an extended 4.2 V cutoff, whereas Na-excess compositions show significantly reduced initial coulombic efficiency and rapid voltage fade. Precise stoichiometric tuning provides a scalable route to defect-suppressed O3 frameworks, enabling structurally resilient, high-voltage sodium-layered cathodes.

36 MATERIALS SCIENCE↗

Liraglutide attenuates NLRP3 inflammasome-dependent pyroptosis via regulating SIRT1/NOX4/ROS pathway in H9c2 cells

Highlights: • TNF-α and hypoxia triggers NLRP3 inflammasome-dependent pyroptosis in H9c2 cardiomyoblasts. • Liraglutide attenuates TNF-α and hypoxia-induced pyroptosis. • SIRT1/NOX4/ROS pathway is involved in the anti-pyroptosis effect of liraglutide. The glucagon-like peptide-1 analog liraglutide has been proved to exert cardioprotective role via activating prosurvival pathways and suppressing inflammation. The activation of NLRP3 inflammasome plays an important role in ischemic injury. The effect of liraglutide on NLRP3 inflammasome-dependent pyroptosis remains unclear. In this study, we established a double stimulation model with TNF-α and hypoxia to mimic ischemic environment and to induce NLRP3 inflammasome activation in H9c2 cardiomyoblasts. Pretreatment with 100 nM liraglutide could efficiently inhibit TNF-α and hypoxia-induced inflammasome activation, as evidenced by the decreased expression of NLRP3, caspase-1 p20 and Gasdermin D N-terminal fragment. Meanwhile, the pyroptosis was also demonstrated to be suppressed, indicated by the increased cell viability and decreased lactate dehydrogenase release in the cells. Mechanistically, liraglutide reversed the level of SIRT1 and the selective SIRT1 inhibitor EX 527 significantly abolished the anti-pyroptosis role of liraglutide. Furthermore, liraglutide diminished the levels of ROS generation and NOX4 expression, which could also be blocked by EX 527. Our results uncovered the anti-pyroptosis role of liraglutide in TNF-α and hypoxia-stimulated H9c2 cells, which was associated with SIRT1/NOX4/ROS pathway.

60 APPLIED LIFE SCIENCES↗

Patchy Particle Model of the Hierarchical Self-Assembly of π-Conjugated Optoelectronic Peptides

Self-assembling peptides containing aromatic groups are an attractive target for bioelectronic materials design because of their ease of manufacture, biocompatibility, aqueous solubility, and chemical tunability. Microscopic understanding of the properties that control assembly is a prerequisite for rational design. In this work, we study the assembly of a family of DXXX-Π–XXXD oligopeptides possessing a π-conjugated core flanked by Asp-terminated tetrapeptide wings that display pH-triggered assembly into supramolecular aggregates. We develop a coarse-grained patchy particle model to conduct molecular dynamics simulations of the assembly of ten thousand oligopeptides over hundreds of nanometers and hundreds of microseconds. We study the effects of core and side chain interaction strength and side chain steric volume upon the morphology and kinetics of assembly. By characterizing the rate and fractal dimension of hierarchical nanoaggregate growth, we identify parameter regimes that favor rapid assembly of linear aggregates and map these regimes to sequence-defined candidate peptides for experimental synthesis and testing. Here, this work establishes new understanding of assembly on previously unexplored time and length scales and presents an efficient and extensible protocol for computational screening and prediction of promising peptide chemistries to assemble nanostructures with desirable optoelectronic properties.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

SU-G-IeP4-06: Feasibility of External Beam Treatment Field Verification Using Cherenkov Imaging

Purpose: Cherenkov light emission has been shown to correlate with ionizing radiation (IR) dose delivery in solid tissue. In order to properly correlate Cherenkov light images with real time dose delivery in a patient, we must account for geometric and intensity distortions arising from observation angle, as well as the effect of monitor units (MU) and field size on Cherenkov light emission. To test the feasibility of treatment field verification, we first focused on Cherenkov light emission efficiency based on MU and known field size (FS). Methods: Cherenkov light emission was captured using a PI-MAX4 intensified charge coupled device(ICCD) system (Princeton Instruments), positioned at a fixed angle of 40° relative to the beam central axis. A Varian TrueBeam linear accelerator (linac) was operated at 6MV and 600MU/min to deliver an Anterior-Posterior beam to a 5cm thick block phantom positioned at 100cm Source-to-Surface-Distance(SSD). FS of 10×10, 5×5, and 2×2cm{sup 2} were used. Before beam delivery projected light field images were acquired, ensuring that geometric distortions were consistent when measuring Cherenkov field discrepancies. Cherenkov image acquisition was triggered by linac target current. 500 frames were acquired for each FS. Composite images were created through summation of frames and background subtraction. MU per image was calculated based on linac pulse delay of 2.8ms. Cherenkov and projected light FS were evaluated using ImageJ software. Results: Mean Cherenkov FS discrepancies compared to light field were <0.5cm for 5.6, 2.8, and 8.6 MU for 10×10, 5×5, and 2×2cm{sup 2} FS, respectably. Discrepancies were reduced with increasing field size and MU. We predict a minimum of 100 frames is needed for reliable confirmation of delivered FS. Conclusion: Current discrepancies in Cherenkov field sizes are within a usable range to confirm treatment delivery in standard and respiratory gated clinical scenarios at MU levels appropriate to standard MLC position segments.

60 APPLIED LIFE SCIENCES↗

Dislocation Patterning in Deforming Crystals: Theory, Computational Predictions and Validation (Final Technical Report)

This project was awarded for an initial period of three years, followed by a no-cost extension for one year and a funded one-year renewal. During the first four years, the project focused on investigating the role of dislocation reactions and dislocation correlation in dislocation patterning in FCC metals. During the fifth year, the scope of research was expanded to investigate the effects of composition inhomogeneity on the mesoscale plastic response of Body-Centered Cubic (BCC) alloys. In addition to its impact on metal hardening during deformation, dislocation patterning provides the microstructure information required to understand phenomena like fracture and recrystallization in metals. The Continuum Dislocation Dynamics (CDD) framework was the methodology used during the first four years, followed by the use of Discrete Dislocation Dynamics (DDD) during the fifth year. CDD is a density-based formalism of dislocation dynamics in which the plastic deformation of crystals is predicted together with the mesoscale dislocation patterns by tracking the space-time evolution of dislocations as driven by the applied stress, short-range and long-range interactions of dislocations, and cross slip. CDD is a crystal mechanics approach in which the plastic constitutive part is replaced with the equations of dislocation dynamics, which is driven by the internal stress via a mobility laws, while the evolution of the density gives the eigenstrain required to update the internal stress itself. The governing equations are thus those of crystal mechanics cast as an eigenstrain problem and those of dislocation transport and reactions. Our investigations during the first four years were driven by the hypothesis that that dislocation patterning is triggered by spatiotemporal dislocation density and internal stress fluctuations, and that such fluctuations influence the collective dislocation dynamic through their effects on the short-range reaction rates and the collective dislocation mobility. This hypothesis was tested by modeling the influence of the dislocation reactions and dislocation correlations on collective dislocation dynamics. The main research components during the first four years were: 1) Reformulation of the CDD framework to integrate the dislocation correlations and dislocation reactions. 2) Simulation of the dislocation correlations and quantifying their contribution to the long-range stress of complex dislocation systems. 3) Computational implementation of the updated CDD model for FCC single crystals and development of an efficient CDD code. 4) Investigation of dislocation patterning in FCC crystals based on the updated CDD model. Some key findings from these investigations were: 1) The patterning of dislocations is initiated by cross slip and internal stress fluctuations, and the refinement of the pattern results from junction formation. 2) Patterning is more prominent under high stress. 3) The correlation stress was found to be a significant part of the mean field stress in continuum representations of dislocation dynamics. During the last year of the project, we have established a method for performing dislocation dynamics in inhomogeneous alloys and demonstrated the impact of composition inhomogeneity on the characteristics of initial yielding and dislocation character in BCC alloys. We also tested this method using an irradiated ferritic alloy in which the composition and dislocation loops effects are both present. In doing so, we have considered two aspects of the role of inhomogeneity, the creation of internal coherency stress due to the dependence of the lattice parameter on the local composition, and the dependence of the dislocation mobility on the local composition. These two aspects resulted in an unexpected behavior of the dislocation system, and, in turn, the yielding behavior of BCC alloys. Key findings include: 1) The composition inhomogeneity in BCC alloys alters the well-known role of screw dislocations by forcing a level of waviness on the average dislocation character, thus destroying the screw character dominance in the yielding observed in pure or homogeneous BCC metals. 2) In the case of irradiated alloys, while composition inhomogeneity by itself and dislocation loops by themselves result in some hardening, the superposition of the two mechanisms does not result in the sum of the two contributions via any known rule. The latter result contradicts the classical works related hardening via multiple mechanisms, which state that various hardening mechanisms can be added linearly or using some Pythagorean additive rule. We were able to rationalize this unexpected result by a closer loop at the origin of the hardening mechanisms themselves, which both involved long-range elastic interactions with dislocations. We reached the conclusion that the hardening resulting from the total stress associated with these two mechanisms (current work) differs from the sum of the effects of the individual stress fields (classical literature). We have also found a major flaw in the classical theory of spinodal hardening. The latter theory never considered the impact of composition undulation on the solute hardening. We have built a new general theory accounting for the effect of solute friction together with the composition undulations on the dislocation configuration at Critical Resolved Shear Stress (CRSS), which is yielding a new definition of the spinodal hardening and new different results. This work is the first to recognize the lack of the role of solute in spinodal hardening theory of alloys.

36 MATERIALS SCIENCE↗

SPREADING LAYERS IN ACCRETING OBJECTS: ROLE OF ACOUSTIC WAVES FOR ANGULAR MOMENTUM TRANSPORT, MIXING, AND THERMODYNAMICS

Disk accretion at a high rate onto a white dwarf (WD) or a neutron star has been suggested to result in the formation of a spreading layer (SL)—a belt-like structure on the object's surface, in which the accreted matter steadily spreads in the poleward (meridional) direction while spinning down. To assess its basic characteristics, we perform two-dimensional hydrodynamic simulations of supersonic SLs in the relevant morphology with a simple prescription for cooling. We demonstrate that supersonic shear naturally present at the base of the SL inevitably drives sonic instability that gives rise to large-scale acoustic modes governing the evolution of the SL. These modes dominate the transport of momentum and energy, which is intrinsically global and cannot be characterized via some form of local effective viscosity (e.g., α-viscosity). The global nature of the wave-driven transport should have important implications for triggering Type I X-ray bursts in low-mass X-ray binaries. The nonlinear evolution of waves into a system of shocks drives effective rearrangement (sensitively depending on thermodynamical properties of the flow) and deceleration of the SL, which ultimately becomes transonic and susceptible to regular Kelvin–Helmholtz instability. We interpret this evolution in terms of the global structure of the SL and suggest that mixing of the SL material with the underlying stellar fluid should become effective only at intermediate latitudes on the accreting object's surface, where the flow has decelerated appreciably. In the near-equatorial regions the transport is dominated by acoustic waves and mixing is less efficient. We speculate that this latitudinal nonuniformity of mixing in accreting WDs may be linked to the observed bipolar morphology of classical nova ejecta.

79 ASTRONOMY AND ASTROPHYSICS↗

JAMES WEBB SPACE TELESCOPE CAN DETECT KILONOVAE IN GRAVITATIONAL WAVE FOLLOW-UP SEARCH

Kilonovae represent an important electromagnetic counterpart for compact binary mergers, which could become the most commonly detected gravitational-wave (GW) source. Follow-up observations of kilonovae, triggered by GW events, are nevertheless difficult due to poor localization by GW detectors and due to their faint near-infrared peak emission, which has limited observational capability. We show that the Near-Infrared Camera (NIRCam) on the James Webb Space Telescope will be able to detect kilonovae within the relevant GW-detection range of ∼200 Mpc in short (≲12-s) exposure times for a week following the merger. Despite this sensitivity, a kilonova search fully covering a fiducial localized area of 10 deg{sup 2} will not be viable with NIRCam due to its limited field of view. However, targeted surveys may be developed to optimize the likelihood of discovering kilonovae efficiently within limited observing time. We estimate that a survey of 10 deg{sup 2} focused on galaxies within 200 Mpc would require about 13 hr, dominated by overhead times; a survey further focused on galaxies exhibiting high star formation rates would require ∼5 hr. The characteristic time may be reduced to as little as ∼4 hr, without compromising the likelihood of detecting kilonovae, by surveying sky areas associated with 50%, rather than 90%, confidence regions of 3 GW events, rather than a single event. Upon the detection and identification of a kilonova, a limited number of NIRCam follow-up observations could constrain the properties of matter ejected by the binary and the equation of state of dense nuclear matter.

79 ASTRONOMY AND ASTROPHYSICS↗

Triggering collapse of the presolar dense cloud core and injecting short-lived radioisotopes with a shock wave. IV. effects of rotational axis orientation

Both astronomical observations of the interaction of Type II supernova remnants (SNRs) with dense interstellar clouds as well as cosmochemical studies of the abundances of daughter products of short-lived radioisotopes (SLRIs) formed by supernova nucleosynthesis support the hypothesis that the Solar System's SLRIs may have been derived from a supernova. This paper continues a series devoted to examining whether or not such a shock wave could have triggered the dynamical collapse of a dense, presolar cloud core and simultaneously injected sufficient abundances of SLRIs to explain the cosmochemical evidence. Here, we examine the effects of shock waves striking clouds whose spin axes are oriented perpendicular, rather than parallel, to the direction of propagation of the shock front. The models start with 2.2 M{sub ⊙} cloud cores and shock speeds of 20 or 40 km s{sup −1}. Central protostars and protoplanetary disks form in all models, although with their disk spin axes aligned somewhat randomly. The disks derive most of their angular momentum not from the initial cloud rotation, but from the Rayleigh-Taylor fingers that also inject shock wave SLRIs. Injection efficiencies, f{sub i}, the fraction of the incident shock wave material injected into the collapsing cloud core, are ∼0.04–0.1 in these models, similar to when the rotation axis is parallel to the shock propagation direction. Evidently, altering the rotation axis orientation has only a minor effect on the outcome, strengthening the case for this scenario as an explanation for the Solar System's SLRIs.

79 ASTRONOMY AND ASTROPHYSICS↗

Shotgun Immunoproteomic Approach for the Discovery of Linear B-Cell Epitopes in Biothreat Agents Francisella tularensis and Burkholderia pseudomallei

Peptide-based subunit vaccines are coming to the forefront of current vaccine approaches, with safety and cost-effective production among their top advantages. Peptide vaccine formulations consist of multiple synthetic linear epitopes that together trigger desired immune responses that can result in robust immune memory. The advantages of linear compared to conformational epitopes are their simple structure, ease of synthesis, and ability to stimulate immune responses by means that do not require complex 3D conformation. Prediction of linear epitopes through use of computational tools is fast and cost-effective, but typically of low accuracy, necessitating extensive experimentation to verify results. On the other hand, identification of linear epitopes through experimental screening has been an inefficient process that requires thorough characterization of previously identified full-length protein antigens, or laborious techniques involving genetic manipulation of organisms. In this study, we apply a newly developed generalizable screening method that enables efficient identification of B-cell epitopes in the proteomes of pathogenic bacteria. As a test case, we used this method to identify epitopes in the proteome of Francisella tularensis (Ft), a Select Agent with a well-characterized immunoproteome. Our screen identified many peptides that map to known antigens, including verified and predicted outer membrane proteins and extracellular proteins, validating the utility of this approach. We then used the method to identify seroreactive peptides in the less characterized immunoproteome of Select Agent Burkholderia pseudomallei (Bp). This screen revealed known Bp antigens as well as proteins that have not been previously identified as antigens. Although B-cell epitope prediction tools Bepipred 2.0 and iBCE-EL classified many of our seroreactive peptides as epitopes, they did not score them significantly higher than the non-reactive tryptic peptides in our study, nor did they assign higher scores to seroreactive peptides from known Ft or Bp antigens, highlighting the need for experimental data instead of relying on computational epitope predictions alone. The present workflow is easily adaptable to detecting peptide targets relevant to the immune systems of other mammalian species, including humans (depending upon the availability of convalescent sera from patients), and could aid in accelerating the discovery of B-cell epitopes and development of vaccines to counter emerging biological threats.

60 APPLIED LIFE SCIENCES↗

CACTUS: A depleted monolithic active timing sensor using a CMOS radiation hard technology

The planned luminosity increase at the Large Hadron Collider in the coming years has triggered interest in the use of the particles' time of arrival as additional information in specialized detectors to mitigate the impact of pile-up. The required time resolution is of the order of tens of picoseconds, with a spatial granularity of the order of 1 mm. A time measurement at this precision level will also be of interest beyond the LHC and beyond high energy particle physics. We present in this paper the first developments towards a radiation hard Depleted Monolithic Active Pixel Sensor (DMAPS), with high-resolution time measurement capability. The technology chosen is a standard high voltage CMOS process, in conjunction with a high resistivity detector material, which has already proven to efficiently detect particles in tracking applications after several hundred of Mrad of irradiation.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗