Miniature battery-free epidural cortical stimulators.

Miniaturized neuromodulation systems could improve the safety and reduce the invasiveness of bioelectronic neuromodulation. However, as implantable bioelectronic devices are made smaller, it becomes difficult to store enough power for long-term operation in batteries. Here, we present a battery-free epidural cortical stimulator that is only 9 millimeters in width yet can safely receive enough wireless power using magnetoelectric antennas to deliver 14.5-volt stimulation bursts, which enables it to stimulate cortical activity on-demand through the dura. The device has digitally programmable stimulation output and centimeter-scale alignment tolerances when powered by an external transmitter. We demonstrate that this device has enough power and reliability for real-world operation by showing acute motor cortex activation in human patients and reliable chronic motor cortex activation for 30 days in a porcine model. This platform opens the possibility of simple surgical procedures for precise neuromodulation.

Ligand-Assisted Direct Lithography of Upconverting and Avalanching Nanoparticles for Nonlinear Photonics.

Upconverting nanoparticles (UCNPs) exhibit unique nonlinear optical properties that can be harnessed in microscopy, sensing, and photonics. However, forming high-resolution nano- and micropatterns of UCNPs with large packing fractions is still challenging. Additionally, there is limited understanding of how nanoparticle patterning chemistries are affected by the particle size. Here, we explore direct patterning chemistries for 6-18 nm Tm3+-, Yb3+/Tm3+-, and Yb3+/Er3+-based UCNPs using ligands that form either new ionic linkages or covalent bonds between UCNPs under ultraviolet (UV), electron-beam (e-beam), and near-infrared (NIR) exposure. We study the effect of UCNP size on these patterning approaches and find that 6 nm UCNPs can be patterned with compact ionic-based ligands. In contrast, patterning larger UCNPs requires long-chain, cross-linkable ligands that provide sufficient interparticle spacing to prevent irreversible aggregation upon film casting. Compared to approaches that use a cross-linkable liquid monomer, our patterning method limits the cross-linking reaction to the ligands bound on UCNPs deposited as a thin film. This highly localized photo-/electron-initiated chemistry enables the fabrication of densely packed UCNP patterns with high resolutions (∼1 µm with UV and NIR exposure; <100 nm with e-beam). Our upconversion NIR lithography approach demonstrates the potential to use inexpensive continuous-wave lasers for high-resolution 2D and 3D lithography of colloidal materials. The deposited UCNP patterns retain their upconverting, avalanching, and photoswitching behaviors, which can be exploited in patterned optical devices for next-generation UCNP applications.

Suspected geriatric onset of attention-deficit/hyperactivity disorder in a patient with comorbid bipolar disorder.

BACKGROUND: An increasing number of adults over 60 years old are presenting with requests for treatment of attention-deficit/hyperactivity disorder (ADHD). However, the prevalence of ADHD in older adults in geriatrics is unknown. Further, comorbid bipolar disorder and adult ADHD are likely underrecognized with many patients only receiving treatment for one of these conditions. The occurrence of bipolar disorder with geriatric onset ADHD is unknown. CASE PRESENTATION: A 64-year-old Hispanic woman with a psychiatric history of bipolar I disorder (diagnosed in early adulthood) was diagnosed with ADHD suspected of geriatric onset, and able to be successfully managed on concurrent mood stabilizers and psychostimulant medication. CONCLUSIONS: The findings of this case report emphasize the importance of appropriately recognizing and treating comorbid ADHD and bipolar disorder in any age group, including the geriatric population for which this occurrence appears to be very rare. Additionally, this case report demonstrates the safe utilization of psychostimulant medications in a geriatric patient with bipolar disorder without inducing a manic episode or other significant adverse reactions.

An Industry Perspective on the use of Forced Degradation Studies to Assess Comparability of Biopharmaceuticals.

Forced degradation, also known as stress testing, is used throughout pharmaceutical development for many purposes including assessing the comparability of biopharmaceutical products according to ICH Guideline Q5E. These formal comparability studies, the results of which are submitted to health authorities, investigate potential impacts of manufacturing process changes on the quality, safety, and efficacy of the drug. Despite the wide use of forced degradation in comparability assessments, detailed guidance on the design and interpretation of such studies is scarce. The BioPhorum Development Group is an industry-wide consortium enabling networking and sharing of common practices for the development of biopharmaceuticals. The BioPhorum Development Group Forced Degradation Workstream recently conducted several group discussions and a benchmarking survey to understand current industry approaches for the use of forced degradation studies to assess comparability of protein-based biopharmaceuticals. The results provide insight into the design of forced degradation studies, analytical characterization and testing strategies, data evaluation criteria, as well as some considerations and differences for non-platform modalities (e.g., non-traditional mAbs). This article presents survey responses from several global companies of various sizes and provides an industry perspective and experience regarding the practicalities of using forced degradation to assess comparability.

Re-imagining metastatic breast cancer care delivery: a patient-partnered qualitative study.

PURPOSE: While significant progress in metastatic breast cancer (MBC) treatment has prolonged survival and improved prognosis, there remain substantial gaps in providing patient-centered supportive care. The specific care delivery needs for metastatic cancer differ from that of early-stage cancer due to the incurable nature and lifelong duration of the condition. The objective of this study was to assess how patients living with MBC would re-imagine cancer care delivery. METHODS: This qualitative study was conducted in partnership with patient-led organizations Guiding Researchers and Advocates to Scientific Partnerships (GRASP) and Project Life, a nonprofit, online wellness community founded by patients with MBC for patients living with MBC. Virtual semi-structured interviews (n = 36) were conducted with Project Life members purposively sampled from the groups' overall membership. The interview guide contained items surrounding patients' lived experiences of MBC, greatest unmet needs related to care, and perspectives on virtual wellness community involvement. Interviews were coded using two-stage deductive and inductive analysis. RESULTS: Three major themes for re-imagining cancer care delivery were identified, including holistic care, information needs, and conceptual shifts. Within these several subthemes emerged with patients re-imagining referrals to non-oncological services, caregiver support, acceptance of integrative medicine, streamlined clinical trial enrollment, curated quality patient resources, MBC-specific terminology and approaches, long-term life and goal-of-care planning, and patient-centered voice throughout. CONCLUSION: People living with metastatic cancers have specific supportive care needs. These findings highlight patient-driven areas for re-imagination that are most salient for individuals with MBC.

Macrocyclic 1,2-Hydroxypyridinone-Based Chelators as Potential Ligands for Thorium-227 and Zirconium-89 Radiopharmaceuticals.

Thorium-227 (227Th) is an α-emitting radionuclide that has shown preclinical and clinical promise for use in targeted α-therapy (TAT), a type of molecular radiopharmaceutical treatment that harnesses high energy α particles to eradicate cancerous lesions. Despite these initial successes, there still exists a need for bifunctional chelators that can stably bind thorium in vivo. Toward this goal, we have prepared two macrocyclic chelators bearing 1,2-hydroxypyridinone groups. Both chelators can be synthesized in less than six steps from readily available starting materials, which is an advantage over currently available platforms. The complex formation constants (log ßmlh) of these ligands with Zr4+ and Th4+, measured by spectrophotometric titrations, are greater than 34 for both chelators, indicating the formation of exceedingly stable complexes. Radiolabeling studies were performed to show that these ligands can bind [227Th]Th4+ at concentrations as low as 10-6 M, and serum stability experiments demonstrate the high kinetic stability of the formed complexes under biological conditions. Identical experiments with zirconium-89 (89Zr), a positron-emitting radioisotope used for positron emission tomography (PET) imaging, demonstrate that these chelators can also effectively bind Zr4+ with high thermodynamic and kinetic stability. Collectively, the data reported herein highlight the suitability of these ligands for use in 89Zr/227Th paired radioimmunotheranostics.

Siderocalin fusion proteins enable a new 86Y/90Y theranostic approach.

The mammalian protein siderocalin binds bacterial siderophores and their iron complexes through cation-π and electrostatic interactions, but also displays high affinity for hydroxypyridinone complexes of trivalent lanthanides and actinides. In order to circumvent synthetic challenges, the use of siderocalin-antibody fusion proteins is explored herein as an alternative targeting approach for precision delivery of trivalent radiometals. We demonstrate the viability of this approach in vivo, using the theranostic pair 90Y (ß-, t1/2 = 64 h)/86Y (ß+, t1/2 = 14.7 h) in a SKOV-3 xenograft mouse model. Ligand radiolabeling with octadentate hydroxypyridinonate 3,4,3-LI(1,2-HOPO) and subsequent protein binding were achieved at room temperature. The results reported here suggest that the rapid non-covalent binding interaction between siderocalin fusion proteins and the negatively charged Y(iii)-3,4,3-LI(1,2-HOPO) complexes could enable purification-free, cold-kit labeling strategies for the application of therapeutically relevant radiometals in the clinic.

A Qualitative Study of the Impact of the COVID-19 Pandemic on Metastatic Breast Cancer Care.

The COVID-19 pandemic substantially impacted the delivery of oncology care, particularly for individuals with metastatic cancers. The objective of this study was to qualitatively evaluate the impacts of COVID-19 on metastatic breast cancer (MBC) care among patients. This study consisted of 36 semi-structured qualitative interviews conducted virtually with people living with MBC, who were members of a patient support organization called Project Life. Project Life is an MBC patient-led, web-based wellness community. Responses were analyzed using Phronetic Iterative Analysis. Interviews were conducted from March 14, 2022, to May 31, 2022. Analysis from 36 individual in-depth qualitative interviews revealed the following themes during COVID-19: (1) variable preferences for telehealth (2) disruptions to care, (3) virtualization of social care. Wide variations existed in preferences surrounding telehealth, centered around ideas of convenience. Disruptions to care included delays to diagnostic care, isolation from caregivers, and interruptions associated with COVID-19 infection. These results call for adaptability in oncology care given wide-ranging preferences on telehealth and the shifting of available support services.

Distributed Impact Wave Detection in Steel I-Beam with a Weak Fiber Bragg Gratings Array.

In this paper, acoustic, dynamic and static strain variations along a steel I-beam generated by an impact load are reconstructed simultaneously within a single measurement. Based on the chirped pulse φ-OTDR system with the single-shot measurement technique, both a higher strain-sensing resolution and a higher measurable vibration frequency are achieved. In addition, a weak fiber Bragg gratings array (WFBGA) with enhanced Rayleigh reflection is employed as a sensor, providing high signal-to-noise ratio Rayleigh traces, resulting in lower measurement uncertainty. In the experiments, the damping constant and fundamental frequency of the damped harmonic oscillator could then be measured based on the recovered strain variation profile for further structural health analysis. Compared with commercial strain gauges, linear potentiometers, and OFDR systems, the proposed sensing system ensures a distributed, quantitative, and high-frequency sensing ability, with an extensive range of potential applications.

Dinuclear nitrido-bridged osmium complexes inhibit the mitochondrial calcium uniporter and protect cortical neurons against lethal oxygen-glucose deprivation.

Dysregulation of mitochondrial calcium uptake mediated by the mitochondrial calcium uniporter (MCU) is implicated in several pathophysiological conditions. Dinuclear ruthenium complexes are effective inhibitors of the MCU and have been leveraged as both tools to study mitochondrial calcium dynamics and potential therapeutic agents. In this study, we report the synthesis and characterization of Os245 ([Os2(µ-N)(NH3)8Cl2]3+) which is the osmium-containing analogue of our previously reported ruthenium-based inhibitor Ru265. This complex and its aqua-capped analogue Os245' ([Os2(µ-N)(NH3)8(OH2)2]5+) are both effective inhibitors of the MCU in permeabilized and intact cells. In comparison to the ruthenium-based inhibitor Ru265 (k obs = 4.92 × 10-3 s-1), the axial ligand exchange kinetics of Os245 are two orders of magnitude slower (k obs = 1.63 × 10-5 s-1) at 37 °C. The MCU-inhibitory properties of Os245 and Os245' are different (Os245 IC50 for MCU inhibition = 103 nM; Os245' IC50 for MCU inhibition = 2.3 nM), indicating that the axial ligands play an important role in their interactions with this channel. We further show that inhibition of the MCU by these complexes protects primary cortical neurons against lethal oxygen-glucose deprivation. When administered in vivo to mice (10 mg kg-1), Os245 and Os245' induce seizure-like behaviors in a manner similar to the ruthenium-based inhibitors. However, the onset of these seizures is delayed, a possible consequence of the slower ligand substitution kinetics for these osmium complexes. These findings support previous studies that demonstrate inhibition of the MCU is a promising therapeutic strategy for the treatment of ischemic stroke, but also highlight the need for improved drug delivery strategies to mitigate the pro-convulsant effects of this class of complexes before they can be implemented as therapeutic agents. Furthermore, the slower ligand substitution kinetics of the osmium analogues may afford new strategies for the development and modification of this class of MCU inhibitors.

Measurement of Restrained and Unrestrained Shrinkage of Reinforced Concrete Using Distributed Fibre Optic Sensors.

Shrinkage is an important component of the behaviour of reinforced concrete (RC) structures, however, the number of variables that affect shrinkage make it a complex time-dependent phenomenon. Additionally, as new concrete materials with lower embodied carbon gain popularity, there is a need for an in-depth understanding into their shrinkage behaviour before they can be widely adopted by industry. Currently, the shrinkage behaviour of concrete is studied using discrete measurements on small-scale unrestrained prisms. Distributed fibre optic sensing (DFOS) potentially provides a method of measuring both restrained (with reinforcement) and unrestrained (without reinforcement) shrinkage in both small-scale specimens and structural elements. In the current study, methods of measuring distributed unrestrained shrinkage strains were developed and evaluated, and the restrained shrinkage strains in different types of structural members were studied. Unrestrained shrinkage strains were measured using fibres optic cables embedded in small concrete prisms, while restrained shrinkage strains were measured with fibres bonded to the longitudinal reinforcement. Unrestrained shrinkage strains were found to be highly variable (as large as 3800 microstrain range) depending on location, but further research needs to be undertaken to account for end effects, early-stage shrinkage, and bond between the fibre optic cable and the concrete. Restrained shrinkage strains from structural members revealed non-uniform shrinkage strain distributions along member length due to functional grading as well as high supplementary cementitious material concretes, suggesting that shrinkage models will need to account for this variability.

Carboxylate-Capped Analogues of Ru265 Are MCU Inhibitor Prodrugs.

The mitochondrial calcium uniporter (MCU) is a transmembrane protein that resides on the inner membrane of the mitochondria and mediates calcium uptake into this organelle. Given the critical role of mitochondrial calcium trafficking in cellular function, inhibitors of this channel have arisen as tools for studying the biological relevance of this process and as potential therapeutic agents. In this study, four new analogues of the previously reported Ru-based MCU inhibitor [ClRu(NH3)4(µ-N)Ru(NH3)4Cl]Cl3 (Ru265) are reported. These compounds, which bear axial carboxylate ligands, are of the general formula [(RCO2)Ru(NH3)4(µ-N)Ru(NH3)4(O2CR)]X3, where X = NO3- or CF3SO3- and R = H (1), CH3 (2), CH2CH3 (3), and (CH2)2CH3 (4). These complexes were fully characterized by IR spectroscopy, NMR spectroscopy, and elemental analysis. X-ray crystal structures of 1 and 3 were obtained, revealing the expected presence of both the linear Ru(µ-N)Ru core and axial formate and propionate ligands. The axial carboxylate ligands of complexes 1-4 are displaced by water in buffered aqueous solution to give the aquated compound Ru265'. The kinetics of these processes were measured by 1H NMR spectroscopy, revealing half-lives that span 5.9-9.9 h at 37 °C. Complex 1 with axial formate ligands underwent aquation approximately twice as fast as the other compounds. In vitro cytotoxicity and mitochondrial membrane potential measurements carried out in HeLa and HEK293T cells demonstrated that none of these four complexes negatively affects cell viability or mitochondrial function. The abilities of 1-4 to inhibit mitochondrial calcium uptake in permeabilized HEK293T cells were assessed and compared to that of Ru265. Fresh solutions of 1-4 are approximately 2-fold less potent than Ru265 with IC50 values in the range of 14.7-19.1 nM. Preincubating 1-4 in aqueous buffers for longer time periods to allow for the aquation reactions to proceed increases their potency of mitochondrial uptake inhibition to match that of Ru265. This result indicates that 1-4 are aquation-activated prodrugs of Ru265'. Finally, 1-4 were shown to inhibit mitochondrial calcium uptake in intact, nonpermeabilized cells, revealing their value as tools and potential therapeutic agents for mitochondrial calcium-related disorders.

Stable Chelation of the Uranyl Ion by Acyclic Hexadentate Ligands: Potential Applications for 230U Targeted α-Therapy.

Uranium-230 is an α-emitting radionuclide with favorable properties for use in targeted α-therapy (TAT), a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To successfully implement this radionuclide for TAT, a bifunctional chelator that can stably bind uranium in vivo is required. To address this need, we investigated the acyclic ligands H2dedpa, H2CHXdedpa, H2hox, and H2CHXhox as uranium chelators. The stability constants of these ligands with UO22+ were measured via spectrophotometric titrations, revealing log ßML values that are greater than 18 and 26 for the "pa" and "hox" chelators, respectively, signifying that the resulting complexes are exceedingly stable. In addition, the UO22+ complexes were structurally characterized by NMR spectroscopy and X-ray crystallography. Crystallographic studies reveal that all six donor atoms of the four ligands span the equatorial plane of the UO22+ ion, giving rise to coordinatively saturated complexes that exclude solvent molecules. To further understand the enhanced thermodynamic stabilities of the "hox" chelators over the "pa" chelators, density functional theory (DFT) calculations were employed. The use of the quantum theory of atoms in molecules revealed that the extent of covalency between all four ligands and UO22+ was similar. Analysis of the DFT-computed ligand strain energy suggested that this factor was the major driving force for the higher thermodynamic stability of the "hox" ligands. To assess the suitability of these ligands for use with 230U TAT in vivo, their kinetic stabilities were probed by challenging the UO22+ complexes with the bone model hydroxyapatite (HAP) and human plasma. All four complexes were >95% stable in human plasma for 14 days, whereas in the presence of HAP, only the complexes of H2CHXdedpa and H2hox remained >80% intact over the same period. As a final validation of the suitability of these ligands for radiotherapy applications, the in vivo biodistribution of their UO22+ complexes was determined in mice in comparison to unchelated [UO2(NO3)2]. In contrast to [UO2(NO3)2], which displays significant bone uptake, all four ligand complexes do not accumulate in the skeletal system, indicating that they remain stable in vivo. Collectively, these studies suggest that the equatorial-spanning ligands H2dedpa, H2CHXdedpa, H2hox, and H2CHXhox are highly promising candidates for use in 230U TAT.

Photochemistry and in vitro anticancer activity of Pt(IV)Re(I) conjugates.

The photophysical and photochemical properties of two Pt(IV)Re(I) conjugates were studied via both experimental and computational methods. Both conjugates exhibit modest photocytotoxicity against ovarian cancer cells. X-ray fluorescence microscopy showed that Pt and Re colocalize in cells whether they had been irradiated or not. This work demonstrates the potential of photoactivated multilimetallic agents for combating cancer.

Accessing lanthanide-based, in situ illuminated optical turn-on probes by modulation of the antenna triplet state energy.

Luminescent lanthanides possess ideal properties for biological imaging, including long luminescent lifetimes and emission within the optical window. Here, we report a novel approach to responsive luminescent Tb(iii) probes that involves direct modulation of the antenna excited triplet state energy. If the triplet energy lies too close to the 5D4 Tb(iii) excited state (20 500 cm-1), energy transfer to 5D4 competes with back energy transfer processes and limits lanthanide-based emission. To validate this approach, a series of pyridyl-functionalized, macrocyclic lanthanide complexes were designed, and the corresponding lowest energy triplet states were calculated using density functional theory (DFT). Subsequently, three novel constructs L3 (nitro-pyridyl), L4 (amino-pyridyl) and L5 (fluoro-pyridyl) were synthesized. Photophysical characterization of the corresponding Gd(iii) complexes revealed antenna triplet energies between 25 800 and 30 400 cm-1 and a 500-fold increase in quantum yield upon conversion of Tb(L3) to Tb(L4) using the biologically relevant analyte H2S. The corresponding turn-on reaction can be monitored using conventional, small-animal optical imaging equipment in presence of a Cherenkov radiation emitting isotope as an in situ excitation source, demonstrating that antenna triplet state energy modulation represents a viable approach to biocompatible, Tb-based optical turn-on probes.

Towards the stable chelation of radium for biomedical applications with an 18-membered macrocyclic ligand.

Targeted alpha therapy is an emerging strategy for the treatment of disseminated cancer. [223Ra]RaCl2 is the only clinically approved alpha particle-emitting drug, and it is used to treat castrate-resistant prostate cancer bone metastases, to which [223Ra]Ra2+ localizes. To specifically direct [223Ra]Ra2+ to non-osseous disease sites, chelation and conjugation to a cancer-targeting moiety is necessary. Although previous efforts to stably chelate [223Ra]Ra2+ for this purpose have had limited success, here we report a biologically stable radiocomplex with the 18-membered macrocyclic chelator macropa. Quantitative labeling of macropa with [223Ra]Ra2+ was accomplished within 5 min at room temperature with a radiolabeling efficiency of >95%, representing a significant advancement over conventional chelators such as DOTA and EDTA, which were unable to completely complex [223Ra]Ra2+ under these conditions. [223Ra][Ra(macropa)] was highly stable in human serum and exhibited dramatically reduced bone and spleen uptake in mice in comparison to bone-targeted [223Ra]RaCl2, signifying that [223Ra][Ra(macropa)] remains intact in vivo. Upon conjugation of macropa to a single amino acid ß-alanine as well as to the prostate-specific membrane antigen-targeting peptide DUPA, both constructs retained high affinity for 223Ra, complexing >95% of Ra2+ in solution. Furthermore, [223Ra][Ra(macropa-ß-alanine)] was rapidly cleared from mice and showed low 223Ra bone absorption, indicating that this conjugate is stable under biological conditions. Unexpectedly, this stability was lost upon conjugation of macropa to DUPA, which suggests a role of targeting vectors in complex stability in vivo for this system. Nonetheless, our successful demonstration of efficient radiolabeling of the ß-alanine conjugate with 223Ra and its subsequent stability in vivo establishes for the first time the possibility of delivering [223Ra]Ra2+ to metastases outside of the bone using functionalized chelators, marking a significant expansion of the therapeutic utility of this radiometal in the clinic.

Biocompatible metal-organic frameworks for the storage and therapeutic delivery of hydrogen sulfide.

Hydrogen sulfide (H2S) is an endogenous gasotransmitter with potential therapeutic value for treating a range of disorders, such as ischemia-reperfusion injury resulting from a myocardial infarction or stroke. However, the medicinal delivery of H2S is hindered by its corrosive and toxic nature. In addition, small molecule H2S donors often generate other reactive and sulfur-containing species upon H2S release, leading to unwanted side effects. Here, we demonstrate that H2S release from biocompatible porous solids, namely metal-organic frameworks (MOFs), is a promising alternative strategy for H2S delivery under physiologically relevant conditions. In particular, through gas adsorption measurements and density functional theory calculations we establish that H2S binds strongly and reversibly within the tetrahedral pockets of the fumaric acid-derived framework MOF-801 and the mesaconic acid-derived framework Zr-mes, as well as the new itaconic acid-derived framework CORN-MOF-2. These features make all three frameworks among the best materials identified to date for the capture, storage, and delivery of H2S. In addition, these frameworks are non-toxic to HeLa cells and capable of releasing H2S under aqueous conditions, as confirmed by fluorescence assays. Last, a cellular ischemia-reperfusion injury model using H9c2 rat cardiomyoblast cells corroborates that H2S-loaded MOF-801 is capable of mitigating hypoxia-reoxygenation injury, likely due to the release of H2S. Overall, our findings suggest that H2S-loaded MOFs represent a new family of easily-handled solid sources of H2S that merit further investigation as therapeutic agents. In addition, our findings add Zr-mes and CORN-MOF-2 to the growing lexicon of biocompatible MOFs suitable for drug delivery.

Tuning the Kinetic Inertness of Bi3+ Complexes: The Impact of Donor Atoms on Diaza-18-Crown-6 Ligands as Chelators for 213Bi Targeted Alpha Therapy.

The radionuclide 213Bi can be applied for targeted α therapy (TAT): a type of nuclear medicine that harnesses α particles to eradicate cancer cells. To use this radionuclide for this application, a bifunctional chelator (BFC) is needed to attach it to a biological targeting vector that can deliver it selectively to cancer cells. Here, we investigated six macrocyclic ligands as potential BFCs, fully characterizing the Bi3+ complexes by NMR spectroscopy, mass spectrometry, and elemental analysis. Solid-state structures of three complexes revealed distorted coordination geometries about the Bi3+ center arising from the stereochemically active 6s2 lone pair. The kinetic properties of the Bi3+ complexes were assessed by challenging them with a 1000-fold excess of the chelating agent diethylenetriaminepentaacetic acid (DTPA). The most kinetically inert complexes contained the most basic pendent donors. Density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations were employed to investigate this trend, suggesting that the kinetic inertness is not correlated with the extent of the 6s2 lone pair stereochemical activity, but with the extent of covalency between pendent donors. Lastly, radiolabeling studies of 213Bi (30-210 kBq) with three of the most promising ligands showed rapid formation of the radiolabeled complexes at room temperature within 8 min for ligand concentrations as low as 10-7 M, corresponding to radiochemical yields of >80%, thereby demonstrating the promise of this ligand class for use in 213Bi TAT.

Sharpened and Mechanically Durable Carbon Fiber Electrode Arrays for Neural Recording.

Bioelectric medicine treatments target disorders of the nervous system unresponsive to pharmacological methods. While current stimulation paradigms effectively treat many disorders, the underlying mechanisms are relatively unknown, and current neuroscience recording electrodes are often limited in their specificity to gross averages across many neurons or axons. Here, we develop a novel, durable carbon fiber electrode array adaptable to many neural structures for precise neural recording. Carbon fibers ( [Formula: see text] diameter) were sharpened using a reproducible blowtorchmethod that uses the reflection of fibers against the surface of a water bath. The arrays were developed by partially embedding carbon fibers in medical-grade silicone to improve durability. We recorded acute spontaneous electrophysiology from the rat cervical vagus nerve (CVN), feline dorsal root ganglia (DRG), and rat brain. Blowtorching resulted in fibers of 72.3 ± 33.5-degree tip angle with [Formula: see text] exposed carbon. Observable neural clusters were recorded using sharpened carbon fiber electrodes fromrat CVN ( [Formula: see text]), feline DRG ( [Formula: see text]), and rat brain ( [Formula: see text]). Recordings from the feline DRG included physiologically relevant signals from increased bladder pressure and cutaneous brushing. These results suggest that this carbon fiber array is a uniquely durable and adaptable neural recordingdevice. In the future, this device may be useful as a bioelectric medicine tool for diagnosis and closed-loop neural control of therapeutic treatments and monitoring systems.