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At least 55 records · Page 3

New Capability at ORNL: High Precision Uranium Titration

Destructive analytical measurements establish a nuclear facility’s nuclear material inventory and inventory differences for Nuclear Material Accountancy and Control. A nuclear laboratory’s ability to perform accurate high-precision analytical measurements is key for tracking large inventories within a facility’s material balance areas and during production to track material movement through dynamic processes. For uranium, these measurements are made by using several established high-precision measurement protocols. These include isotope dilution mass spectrometry, gravimetry, and potentiometric titrations. Whatever measurement technique a nuclear lab chooses to use, reference materials (RMs) with certified attributes and accompanying uncertainties are used to calibrate measurement systems, and are the cornerstone for accurate results. In addition to calibration, RMs provide for metrological traceability, are used for method development and validation, and thus provide critical evaluations of the appropriateness and performance of analytical processes used. Evaluations may include validation that a method is fit-for-purpose, quantification of systematic and random biases, and the evaluation of long-term and short-term performance metrics. High-precision measurement techniques require that measured attributes be certified to a high degree of precision in the RMs used—ultimately, to a higher degree than that of the measurement technique itself. The US authority on the production of special nuclear material Certified Reference Materials is the NBL Program Office (NBLPO), formally known as New Brunswick Laboratory (NBL). The NBLPO is responsible for the sales and distribution of existing NBL certified reference materials (CRMs) and for the production of the next generation of nuclear RMs. To accomplish its mission, NBLPO is establishing key base capabilities within the DOE laboratory complex that formerly existed at the NBL laboratory. The Nuclear Analytical Chemistry (NAC) section within the Chemical Sciences Division (CSD) at Oak Ridge National Laboratory (ORNL) is currently working with NBLPO to set up laboratory and measurement capabilities to provide measurements and capabilities for production and/or recertification of existing and future CRMs for uranium assay. The NBL-developed high-precision titration (HPT) method is a critically-evaluated, extremely precise and accurate primary method utilized for the determination of uranium content in a variety of uranium materials. The HPT method, combined with detailed balance weighing protocols, provides for an analytical methodology that is unsurpassed in precision and one in which all sources of error have been evaluated, a requirement of CRM certification. HPT capability within the United States was lost with the closure of the labs at NBL. The NAC has been collaborating with NBLPO to stand up and demonstrate the capability to perform uranium assay via HPT at ORNL. HPT can produce results with an expanded uncertainty of approximately 0.01% for pure uranium compounds, with typical precisions of <0.006%. The major tasks required to stand up the method at ORNL were the refurbishment of a dedicated lab and equipment setup, procedure development, analyst training, establishing method-specific quality assurance, and qualification of an analyst to perform the method. This report summarizes these tasks, outlines the documents drafted, and gives the outcome of the qualification titrations.

38 RADIATION CHEMISTRY, RADIOCHEMISTRY, AND NUCLEA↗

Kokes Awards for the 27th North American Catalysis Society Meeting

The Richard J. Kokes Travel Award program encourages student participation in the biennial North American Catalysis Society (NACS) Meetings. During NAM27 in 2022, 50 of the 111 students who received the Kokes Award were supported through this proposal, funded by the Department of Energy (DOE). The award covered a significant conference-related expense, that is the registration fees. Eligible students had to be enrolled in a North American university, present an oral or poster presentation, and contribute 2-4 hours to assist with meeting operations. While the program is open to undergraduate students, none were awarded in 2022. The selection process involved a comprehensive evaluation by external academic reviewers from NACS.

99 GENERAL AND MISCELLANEOUS↗

Neutral composition in the thermosphere.

Data obtained from the Ogo 6 neutral atmospheric composition (NAC) experiment for a period of more than 1 year are used to compare the average constituent composition at an altitude of 400 km with that predicted by the Jacchia 1971 and 1965 models. The comparison shows that the Jacchia 1971 model underestimates the molecular nitrogen densities at 400 km by a factor of 2. An atmosphere is constructed down to 120 km by means of the Stein and Walker technique. A fit is made with (1) the 400-km total densities from drag measurements and the composition from Ogo 6 NAC, (2) the 250-km measured molecular nitrogen densities, and (3) the 150-km total densities from drag. This fit shows that the Jacchia 1971 model overestimates the atomic oxygen content at 150 km.

Taeusch, D. R.↗

Pyroclastic Deposits in the Floor-fractured Crater Alphonsus

Alphonsus, the 118 km diameter floor-fractured crater, is located immediately east of Mare Nubium. Eleven pyroclastic deposits have been identified on the crater's floor. Early telescopic spectra suggest that the floor of Alphonsus is noritic, and that the pyroclastic deposits contain mixtures of floor material and a juvenile component including basaltic glass. Head and Wilson contend that Nubium lavas intruded the breccia zone beneath Alphonsus, forming dikes and fractures on the crater floor. In this model, the magma ascended to the level of the mare but cooled underground, and a portion broke thru to the surface in vulcanian (explosive) eruptions. Alternatively, the erupted material could be from a source unrelated to the mare, in the style of regional pyroclastic deposits. High-resolution images and spectroscopy from the Moon Mineralogy Mapper (M3), Diviner Lunar Radiometer, and Lunar Reconnaissance Orbiter Camera Narrow Angle Camera (NAC) provide data to test these formation models. Spectra from M3 confirm that the crater floor is primarily composed of noritic material, and that the Nubium lavas are basaltic. Spectra from the three largest pyroclastic deposits in Alphonsus are consistent with a minor low- Ca pyroxene component in a glass-rich matrix. The centers of the 2 micron absorption bands have wavelengths too short to be of the same origin as the Nubium basalts. Diviner Christiansen feature (CF) values were used to estimate FeO abundances for the crater floor, Nubium soil, and pyroclastic deposits. The estimated abundance for the crater floor (7.5 +/- 1.4 wt.%) is within the range of FeO values for Apollo norite samples. However, the estimated FeO abundance for Nubium soil (13.4 +/- 1.4 wt.%) is lower than those measured in most mare samples. The difference may reflect contamination of the mare soil by highland ejecta. The Diviner-derived FeO abundance for the western pyroclastic deposit is 13.8 +/- 3.3 wt.%. This is lower than the values for mare soil samples, but within the range of analyzed pyroclastic glasses. The NAC images of the pyroclastic vents highlight their bright wall materials. The M3 spectra of the southeastern vent indicate that this bright material is noritic, likely crater floor material exposed by explosive eruption. These observations address the hypothesis that Nubium lavas intruded the fracture network beneath Alphonsus, leading to localized vulcanian-style eruptions. This model implies that the eruption products should be dominated by crystalline basalt fragments similar in elemental composition and mineralogy to mare lavas. The bright noritic material exposed in the vent walls is consistent with explosive eruptions. The estimated FeO abundances for the pyroclastic deposits are too low to be consistent with FeO abundances measured in mare basalts, but are within the range of pyroclastic glass samples. The visible- to near-infrared (VIS-NIR) spectra of the pyroclastic deposits and Nubium soils are significantly different, suggesting that the pyroclastics are unrelated to the mare basalts. The pyroclastic spectra are consistent with Fe-bearing glass plus small amounts of noritic wall rock. Similar glassy materials dominate regional pyroclastic deposits, suggesting a deep source for the pyroclastics observed in Alphonsus.

Allen, Carlton C.↗

Coordinates of Anthropogenic Features on the Moon

High-resolution images from the Lunar Reconnaissance Orbiter Camera (LROC) Narrow Angle Camera (NAC) reveal the landing locations of recent and historic spacecraft and associated impact sites across the lunar surface. Using multiple images of each site acquired between 2009 and 2015, an improved Lunar Reconnaissance Orbiter (LRO) ephemeris, and a temperature-dependent camera orientation model, we derived accurate coordinates ( less than 12 meters) for each soft-landed spacecraft, rover, deployed scientific payload, and spacecraft impact crater that we have identified. Accurate coordinates enhance the scientific interpretations of data returned by the surface instruments and of returned samples of the Apollo and Luna sites. In addition, knowledge of the sizes and positions of craters formed as the result of impacting spacecraft provides key benchmarks into the relationship between energy and crater size, as well as calibration points for reanalyzing seismic measurements acquired during the Apollo program. We identified the impact craters for the three spacecraft that impacted the surface during the LRO mission by comparing before and after NAC images.

Moon↗

Frequency-Range Distribution of Boulders Around Cone Crater: Relevance to Landing Site Hazard Avoidance

Boulders represent a landing hazard that must be addressed in the planning of future landings on the Moon. A boulder under a landing leg can contribute to deck tilt and boulders can damage spacecraft during landing. Using orbital data to characterize boulder populations at locations where landers have safely touched down (Apollo, Luna, Surveyor, and Chang'e-3 sites) is important for determining landing hazard criteria for future missions. Additionally, assessing the distribution of boulders can address broader science issues, e.g., how far craters distribute boulders and how this distribution varies as a function of crater size and age. The availability of new Lunar Reconnaissance Orbiter Camera (LROC) Narrow Angle Camera (NAC) images [1] enables the use of boulder size- and range frequency distributions for a variety of purposes [2-6]. Boulders degrade over time and primarily occur around young or fresh craters that are large enough to excavate bedrock. Here we use NAC images to analyze boulder distributions around Cone crater (340 m diameter) at the Apollo 14 site. Cone crater (CC) was selected because it is the largest crater where astronaut surface photography is available for a radial traverse to the rim. Cone crater is young (approximately 29 Ma [7]) relative to the time required to break down boulders [3,8], giving us a data point for boulder range-frequency distributions (BRFDs) as a function of crater age.

Clegg-Watkins, R. N.↗

Boulder Distributions at Legacy Landing Sites: Assessing Regolith Production Rates and Landing Site Hazards

Understanding how the distribution of boulders on the lunar surface changes over time is key to understanding small-scale erosion processes and the rate at which rocks become regolith. Boulders degrade over time, primarily as a result of micrometeorite bombardment so their residence time at the surface can inform the rate at which rocks become regolith or become buried within regolith. Because of the gradual degradation of exposed boulders, we expect that the boulder population around an impact crater will decrease as crater age increases. Boulder distributions around craters of varying ages are needed to understand regolith production rates, and Lunar Reconnaissance Orbiter Camera (LROC) Narrow Angle Camera (NAC) images provide one of the best tools for conducting these studies. Using NAC images to assess how the distribution of boulders varies as a function of crater age provides key constraints for boulder erosion processes. Boulders also represent a potential hazard that must be addressed in the planning of future lunar landings. A boulder under a landing leg can contribute to deck tilt, and boulders can damage spacecraft during landing. Using orbital data to characterize boulder populations at locations where landers have safely touched down (Apollo, Luna, Surveyor, Chang'e-3) provides validation for landed mission hazard avoidance planning. Additionally, counting boulders at legacy landing sites is useful because: 1) LROC has extensive coverage of these sites at high resolutions (approximately 0.5 meters per pixel). 2) Returned samples from craters at these sites have been radiometrically dated, allowing assessment of how boulder distributions vary as a function of crater age. 3) Surface photos at these sites can be used to correlate with remote sensing measurements.

Watkins, R. N.↗

Precision Pointing Improvements for the Lunar Reconnaissance Orbiter Camera

The Lunar Reconnaissance Orbiter (LRO) was launched in 2009 and, with its seven science instruments, continues to make remarkable discoveries of the Moon. LRO is in a slightly elliptical, polar lunar orbit and nominally maintains a nadir orientation. In early 2018, the Miniature Inertial Measurement Unit (MIMU) was powered off following a fairly rapid decline in the laser intensity on the X axis. An algorithm combining star tracker quaternion differentiated rates and integrated control torque commands in a complementary filter, now provides the onboard rate estimate, replacing the MIMU. One of the science instruments, the LRO Camera(LROC) system, contains a Wide Angle Camera (WAC) and two Narrow Angle Cameras (NAC). The NACs suffer from larger attitude drifts during imaging of the Moon for stereo image processing, resulting from pointing stability degradation of the star tracker derived rates. The controller gains and structural filter were redesigned to attenuate the new disturbances while also maintaining adequate stability and modal suppression. This paper documents the development, testing, and operational implementation of the revised control system parameters, specifically targeted for use during LROC imaging. The new parameters improved pointing performance for LROC.

Julie Halverson↗

OPTIMUS{sup TM} Packaging for Intermediate Level Wastes and Spent Fuel - 20129

NAC's OPTIMUS{sup TM} packaging is a family of Type B(U)F transportation packages designed for maximum flexibility and cost-efficiency to support shipment of a wide range of challenging wastes and materials. They are small, modular packaging designs meeting DOT weight limits for road transport. OPTIMUS{sup TM} contents include low level waste, mixed low-level waste, irradiated fuel waste and intermediate level waste. Contents can also include aerosol cans with compressed gas and liquefied gas propellants and standard DOT 3E lecture bottles for shipment to treatment facilities. OPTIMUS{sup TM} packaging provides a cost-effective solution for challenging and unique waste contents combined with design simplicity and operational flexibility meeting the requirements of both SSR-6 and 10 CFR 71 for Type B(U)F packaging. The modular design of the packaging components combined with the flexibility to add modified internals for enhanced packaging performance makes OPTIMUS{sup TM} the preferred solution for many radioactive material transportation needs. The OPTIMUS{sup TM} product line currently includes two packaging designs; OPTIMUS{sup TM}-L and OPTIMUS{sup TM}-H. OPTIMUS{sup TM}-L is a lightweight transportation packaging intended for low-activity wastes, whereas OPTIMUS{sup TM}-H is a larger, heavier package intended for high-activities wastes. Due to its small size and weight, six (6) to ten (10) OPTIMUS{sup TM}-L packages can be accommodated on a single legal-weight truck shipment, depending on the weight of the contents. For typical payloads, two (2) OPTIMUS{sup TM}-H packages can be accommodated on a single legal-weight truck shipment. The OPTIMUS{sup TM} packaging share the same cask containment vessel (CCV) in the OPTIMUS{sup TM}-H and OPTIMUS{sup TM}-L. The large cavity size of the CCV, which can accommodate a 416-liter (110-gallon) drum, combined with the small size, low weight and modularity of the OPTIMUS{sup TM} packaging provides unmatched flexibility. In this paper, NAC provides a technical overview of the OPTIMUS{sup TM} packaging and identifies the design features and technology advancements making the OPTIMUS{sup TM} a readily adaptable and flexible solution for packaging processing facilities, reactor and decommissioning wastes. Optimized shielding performance through the addition of internal shielding components and alternative shipping configurations are discussed. In addition, an overview of the first major deployment of the OPTIMUS{sup TM} packaging for the Whiteshell Laboratories Closure Project (WLCP) is discussed. (authors)

12 MANAGEMENT OF RADIOACTIVE AND NON-RADIOACTIVE W↗

Recommended Actions to Improve Adapter Safety

With the rapid advancement and acceleration in the electric vehicle (EV) industry within the United States, major automakers and EV charging companies are increasingly adopting the North American Charging Standard (NACS) connector style, now officially known as J3400. This shift is expected to enhance charging infrastructure, providing a better customer experience by making it easier for all EV drivers to access a wider network of direct-current (DC) fast chargers (DCFCs). However, the adoption of the J3400 standard presents challenges for many EVs already on the roads and some currently coming off production lines that are equipped with the Combined Charging System (CCS) connector, which this report will refer to as the North American standard, CCS1. These vehicles will need adapters to use new or existing J3400 infrastructure. During this transition, several issues have emerged. Firstly, there is a need to standardize the new connector type to ensure it is interoperable, safe, and reliable. Second, existing CCS EV drivers need a way to access the J3400 network, which will require electric vehicle supply equipment (EVSE) or sites with both connector types, driver-provided adapters to physically convert from CCS to J3400, or EVSE with retained adapters designed for use with the EVSE. Third, adapter standards will need to be written to specify how they will be designed and what evaluations will be needed to ensure safe and reliable performance. To address these challenges, adapters that support different types of charging connectors will be essential. These adapters will play a crucial role in supporting the transition and ensuring continued service for legacy EVs with CCS inlets as the J3400 standard becomes the predominant one in the United States. Consequently, the National Charging Experience (ChargeX) Consortium has investigated and performed a teardown analysis on the different adapter versions on the market. The aim is to create a failure mode and effects analysis (FMEA) on what are expected to be the most common adapter types used in this transition. In order to support this work, we executed an FMEA exercise with the main goal of identifying gaps in the existing adapters' performance and conformance to the most common safety requirements of high-power and high-voltage devices. This effort focused on adapters provided by the driver, as these may present the highest safety and reliability risks. The recommendations made here apply to both retained and driver-provided adapters.

25 ENERGY STORAGE↗

Evaluations of Connectors, Inlets, and Adapters on Side-Load and Withstand Force

This report examines the mechanical forces that direct current fast charging (DCFC) electric vehicle supply equipment (EVSE) connectors and electric vehicle (EV) inlet ports experience during normal usage. As we witness the fast and growing variety of EVs, charge port locations, and bigger and more powerful EVSE configurations including the SAE J3400 North American Charging Standard (NACS), which has increased the use of adapters with J3400 and J1772 compatibility. These new conditions contribute to increased mechanical forces due to their size, weight and lever arm effect, which creates the need to study and compare these forces to the limits on UL2251 and IEC 62196-1 standards. This report focuses solely on high power DC charging EVSE connectors, EV inlets and adapters for the specific compatibility cases on J3400 with J1772. We first describe the details of the 100N and the 750N side-load evaluations as described in the standards, then present the data obtained by replicating these tests to finally go into more detail on the findings and our recommendations.

100N↗

Dimensional Stability of High Purity Invar 36

High performance requirements for the Imaging Science Subsystem (ISS)/Narrow Angle Camera (NAC) instrument on the NASA/Jet Propulsion Laboratory (JPL) Cassini spacecraft impose very stringent demands for dimensional stability of metering rods in the camera's athermalizing system.

imaging↗

Salt-Assisted 2H-to-1T' Phase Transformation of Transition Metal Dichalcogenides [plus supplemental information]

Phase engineering of nanomaterials (PEN) has demonstrated great potential in the fields of catalysis, electronics, energy storage and conversion, and condensed matter physics. Recently, transition metal dichalcogenides (TMDs) with unconventional metastable phases (e.g., 1T and 1T') have attracted increasing research interest due to their unique and appealing physicochemical properties. However, there is still a lack of a simple, universal, and controlled method for the preparation of large-scale and high-purity unconventional-phase TMD crystals, restricting their further fundamental study and practical applications. Here, a facile, one-step salt-assisted general strategy is reported for the controlled phase transformation of commercially available TMDs with conventional 2H phase, yielding a large amount of metastable 1T'-phase TMDs, including WS 2 , WSe 2 , MoS 2 , and MoSe 2 . It is found that the easily accessible metal salts, such as K 2 C 2 O 4 ·H 2 O, K 2 CO 3 , Na 2 CO 3 , Rb 2 CO 3 , Cs 2 CO 3 , KHCO 3 , NaHCO 3 , and NaC 2 O 4 , can be used to assist the 2H-to-1T' phase transformation, greatly simplifying the synthetic process for producing metastable 1T'-TMDs. Importantly, this method can also be used to prepare 1T'-TMD alloys, such as 1T'-WS 2x Se 2(1–x) . We report this newly developed strategy is robust and highly effective, which can also be used for the phase engineering of other materials with various polymorphs.

1T′ phase↗

PotLib 2023: New version of a potential energy surface library for chemical systems

POTLIB is a library of global and semiglobal potential energy surface subprograms. The library currently features 410 entries, including both single-state entries and multi-state entries. When one calls the routine of a single-state entry, it returns the ground-electronic-state adiabatic potential energy surface at the input geometry. In addition, some entries also return the gradient of the surface. Further, when one calls a multi-state entry, it returns a diabatic potential energy matrix (DPEM). If the entry also has the gradient of the DPEM, one can compute adiabatic surfaces, their gradients, and the nonadiabatic coupling vectors (NACs) from the DPEM and its gradient by diagonalization. Some but not all the routines conform to one of a set of standard interfaces. The goal is to facilitate chemical dynamics research by collecting and disseminating a comprehensive collection of state-of-the-art potential energy routines (developed by a wide, international group of researchers) with systematic and well-defined interfaces for use with chemical dynamics programs. Systems in the library include CHArO 2 , CHN 2 O + , CH 2 O, CH 2 O 2 , CH 3 N 2 , CH 3 O, CH 4 , CH 4 Br, CH 4 Cl, CH 4 F, CH 4 O, CH 4 OCl, CH 4 OF, CH 4 OH, CH 5 , CH$^{+}_{5}$, CH 5 N, CH 5 O 2 , CH 8 O 2 , C 2 H 2 N 2 O, C 2 H 2 O, C 2 H 4 N, C 2 H 4 O 4 , C 2 H 6 Cl, C 2 H 6 F, C 2 H 6 H, C 2 H 6 O, C 2 H 6 OH, C 2 H 7 , C 2 O 2 , C 3 H 4 O 2 , C 3 H 7 NO, C 6 H 6 O, C 6 H 6 S, C 7 H8S, HBrCl, HCl 2 , HF 2 , HI 2 , HLiF, HNaF, HO 2 , HO 3 , HOBr, HSiO, H 2 Br, H 2 ClO, H 2 F, H 2 F 2 , H 2 FO, H 2 Na, H 2 O, H 2 O 2 , H 2 OBr, H 3 , H 3 Cl, H 3 ClN, H 3 ClO, H 3 N, H 3 O, H 3 O 2 , H$^{+}_{3}$, H 3 S, H 4 ClSi, H 4 N, H 4 NO, H 4 O 2 , H 5 GeO, H 5 Si, H$^{+}_{7}$, Al m H n , Al n , Ar N O, K 2 Rb 2 , NO 2 , N 2 O, N 2 O 2 , N 3 , N 4 , O 3 , and O 4 .

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

A robust alloy design (RAD) strategy for next-generation (IV) nuclear fission reactors

Next-generation nuclear reactors demand structural materials capable of withstanding extreme conditions, including high temperatures, intense neutron flux, and corrosive environments. Multi-Principal Element Alloys (MPEAs) have emerged as promising candidates due to their exceptional radiation tolerance, thermal stability, and compositional flexibility. This study introduces a versatile and customizable Robust Alloy Design (RAD) strategy for systematically designing MPEAs for GEN-IV reactor fuel cladding. The RAD framework integrates nuclear-relevant selection criteria, empirical parameter assessments, and high-throughput CALPHAD simulations to efficiently narrow compositional space and identify stable alloys. A unified RAD score developed for the first time, combines key performance metrics, including fuel-clad chemical interaction (FCCI), neutron absorption cross-section (NAC), valence electron configuration (VEC), and melting point factor (MPF), into a flexible ranking system adaptable to reactor-specific priorities. Among 724 candidates, V555(5Al–5Cr–5Fe–85V) emerged as the top alloy, validated experimentally with a homogeneous single-phase BCC microstructure and superior mechanical properties (nano-indentation: 3.389 ± 0.258 GPa; Vickers hardness: 240 ± 6.7 HV), significantly outperforming Zircaloy-4 and V-4Cr-4Ti. Importantly, the RAD strategy is not limited to nuclear applications; its customizable weighting system enables scalability to other extreme environments. This adaptability positions RAD strategy as a versatile tool for advanced materials design across multiple industries.

Alloy design↗

Bortezomib activation of mTORC1 pathway mediated by NOX2-drived reactive oxygen species results in apoptosis in primary dorsal root ganglion neurons

Highlights: • Bort induces apoptosis in DRG neurons. • Bort activates mTORC1 pathway in DRG neurons. • Bort-activated mTORC1 pathway contributes to DRG neuronal apoptosis. • Bort activates mTORC1 pathway via NOX2-drived ROS overgeneration leading to DRG neuronal apoptosis. Bortezomib (Bort), a chemotherapeutic agent, is widely used for the clinical treatment of cancers. However, Bort-induced peripheral neurotoxicity (BIPN) significantly restricts its clinical application, which is difficult to deal with since the underlying mechanisms of BIPN are unclear. Here, we showed that Bort activates mTORC1 pathway leading to dorsal root ganglion (DRG) neuronal apoptosis. Inhibition of mTORC1 with rapamycin or knockdown of raptor, regulatory-associated protein of mTORC1, with shRNA dramatically rescued the cells from Bort-caused apoptosis. In addition, we found that Bort-activated mTORC1 pathway was attributed to Bort elevation of reactive oxygen species (ROS). This is supported by the evidence that using ROS scavenger N-acetyl cysteine (NAC) significantly alleviated Bort-activated mTORC1 pathway. Furthermore, we revealed that upregulation of NOX2 contributed to Bort-elicited ROS overproduction, leading to mTORC1 pathway-dependent apoptosis in DRG neurons. Inhibition of NOX2 with apocynin remarkably diminished Bort-induced overgeneration of ROS, activation of mTORC1 pathway and apoptosis in the cells. Taken together, these results indicate that Bort activation of mTORC1 pathway mediated by NOX2-drived ROS leads to apoptotic death in DRG neurons. Our findings highlight that manipulation of intracellular ROS level or NOX2 or mTORC1 activity may be exploited for prevention of BIPN.

60 APPLIED LIFE SCIENCES↗

Dichloroacetate enhances the anti-tumor effect of sorafenib via modulating the ROS-JNK-Mcl-1 pathway in liver cancer cells

Liver cancer is one of the most common and high recurrence malignancies. Besides radiotherapy and surgery, chemotherapy also plays an essential role in the treatment of liver cancer. Sorafenib and sorafenib-based combination therapies have been proven efficacy against tumors. However, previous clinical studies have indicated that some patients with liver cancer are resistant to sorafenib treatment and the existing strategies are not satisfactory in the clinic. Therefore, it is urgent to investigate strategies to improve the effectiveness of sorafenib for liver cancer and to explore effective drug combinations. In the present study, we found that dichloroacetate (DCA) could significantly enhance the anti-tumor effect of sorafenib on liver cancer cells, including reduced viability and dramatically promoted apoptosis in liver cancer cells. Moreover, compared to sorafenib alone, the combination of DCA and sorafenib markedly increased the degradation of anti-apoptotic protein Mcl-1 by enhancing its phosphorylation. Overexpression of Mcl-1 could significantly attenuate the synergetic effect of DCA and sorafenib on apoptosis induction in liver cancer cells. Furthermore, we found that the ROS-JNK pathway was obviously activated in the DCA combined sorafenib group. The levels of ROS and p-JNK were dramatically up-regulated in the two drug combination groups. Antioxidant NAC could alleviate the synergetic effects of DCA and sorafenib on ROS generation, JNK activation, Mcl-1 degradation, and cell apoptosis. Moreover, DCA and sorafenib's effects on Mcl-1 degradation and apoptosis could also be inhibited by JNK inhibitor ‘SP’600125. Finally, the synergetic effects of DCA and sorafenib on tumor growth suppression, Mcl-1 degradation and induction of apoptosis were also validated in liver cancer xenograft in vivo. These findings indicate that DCA enhances the anti-tumor effect of sorafenib via the ROS-JNK-Mcl-1 pathway in liver cancer cells. This study may provide new insights to improve the chemotherapeutic effect of sorafenib, which may be benecial for further clinical application of sorafenib in liver cancer treatment.

60 APPLIED LIFE SCIENCES↗

Synaptic Zn2+ potentiates the effects of cocaine on striatal dopamine neurotransmission and behavior

Abstract Cocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc (Zn 2+ ) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that Zn 2+ concentrations in postmortem brain (caudate) tissue from humans who died of cocaine overdose were significantly lower than in control subjects. Moreover, the level of striatal Zn 2+ content in these subjects negatively correlated with plasma levels of benzoylecgonine, a cocaine metabolite indicative of recent use. In mice, repeated cocaine exposure increased synaptic Zn 2+ concentrations in the caudate putamen (CPu) and nucleus accumbens (NAc). Cocaine-induced increases in Zn 2+ were dependent on the Zn 2+ transporter 3 (ZnT3), a neuronal Zn 2+ transporter localized to synaptic vesicle membranes, as ZnT3 knockout (KO) mice were insensitive to cocaine-induced increases in striatal Zn 2+ . ZnT3 KO mice showed significantly lower electrically evoked DA release and greater DA clearance when exposed to cocaine compared to controls. ZnT3 KO mice also displayed significant reductions in cocaine locomotor sensitization, conditioned place preference (CPP), self-administration, and reinstatement compared to control mice and were insensitive to cocaine-induced increases in striatal DAT binding. Finally, dietary Zn 2+ deficiency in mice resulted in decreased striatal Zn 2+ content, cocaine locomotor sensitization, CPP, and striatal DAT binding. These results indicate that cocaine increases synaptic Zn 2+ release and turnover/metabolism in the striatum, and that synaptically released Zn 2+ potentiates the effects of cocaine on striatal DA neurotransmission and behavior and is required for cocaine-primed reinstatement. In sum, these findings reveal new insights into cocaine’s pharmacological mechanism of action and suggest that Zn 2+ may serve as an environmentally derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders.

60 APPLIED LIFE SCIENCES↗