Unveiling the Structure-Modulator Relationships in Thorium-Based Metal-Organic Framework Crystallization.

Acid modulator has been the most widely employed ingredient for highly crystalline metal-organic framework (MOF) synthesis. However, the mechanistic understanding of thorium (Th)-based MOF crystallization remains a great challenge due to the intrinsic properties of fast olation and oxolation reactions of Th species in solution. Here, we constructed a series of Th-based MOFs by adding different modulators (formic acid, acetic acid, trifluoroacetic acid, and benzoic acid) to a synthetic solution along with tetratopic 1,3,5,7-adamantane tetracarboxylic acid (H4ATC), a three-dimensional (3D) ligand with a rigid aliphatic backbone. This work presents an in-depth study of the structure-modulator relationship between the H4ATC ligand and coordinating modulators in the Th-based MOF crystallization process. Crystal structures of these Th-based MOFs reveal that formic acid and acetic acid modulators can compete with the H4ATC ligand to form NU-52 and NU-54; these MOFs possess Th nodes linked by the corresponding modulator. Alternatively, usage of trifluoroacetic acid and benzoic acid modulators results in NU-53 and NU-55; these MOFs possess Th nodes coordinated by only the H4ATC ligand, regardless of the modulator amount. This work highlights that both the identity and amount of modulator play a crucial role in determining the resulting Th-based MOF structures when H4ATC is selected as the coordinated ligand.

Leveraging Nitrogen Linkages in the Formation of a Porous Thorium-Organic Nanotube Suitable for Iodine Capture.

We report the synthesis, characterization, and iodine capture application of a novel thorium-organic nanotube, TSN-626, [Th6O4(OH)4(C6H4NO2)7(CHO2)5(H2O)3]·3H2O. The classification as a metal-organic nanotube (MONT) distinguishes it as a rare and reduced dimensionality subset of metal-organic frameworks (MOFs); the structure is additionally hallmarked by low node connectivity. TSN-626 is composed of hexameric thorium secondary building units and mixed O/N-donor isonicotinate ligands that demonstrate selective ditopicity, yielding both terminating and bridging moieties. Because hard Lewis acid tetravalent metals have a propensity to bind with electron donors of rival hardness (e.g., carboxylate groups), such Th-N coordination in a MOF is uncommon. However, the formation of key structural Th-N bonds in TSN-626 cap some of the square antiprismatic metal centers, a position usually occupied by terminal water ligands. TSN-626 was characterized by using complementary analytical and computational techniques: X-ray diffraction, vibrational spectroscopy, N2 physisorption isotherms, and density functional theory. TSN-626 satisfies design aspects for the chemisorption of iodine. The synergy between accessibility through pores, vacancies at the metal-oxo nodes, and pendent N-donor sites allowed a saturated iodine loading of 955 mg g-1 by vapor methods. The crystallization of TSN-626 diversifies actinide-MOF linker selection to include soft electron donors, and these Th-N linkages can be leveraged for the investigation of metal-to-ligand bonding and unconventional topological expressions.

Unusual Metal-Organic Framework Topology and Radiation Resistance through Neptunyl Coordination Chemistry.

A Np(V) neptunyl metal-organic framework (MOF) with rod-shaped secondary building units was synthesized, characterized, and irradiated with γ rays. Single-crystal X-ray diffraction data revealed an anionic framework containing infinite helical chains of actinyl-actinyl interaction (AAI)-connected neptunyl ions linked together through tetratopic tetrahedral organic ligands (NSM). NSM exhibits an unprecedented net, demonstrating that AAIs may be exploited to give new MOFs and new topologies. To probe its radiation stability, we undertook the first irradiation study of a transuranic MOF and its organic linker building block using high doses of γ rays. Diffraction and spectroscopic data demonstrated that the radiation resistance of NSM is greater than that of its linker building block alone. Approximately 6 MGy of irradiation begins to induce notable changes in the long- and short-range order of the framework, whereas 3 MGy of irradiation induces total X-ray amorphization and changes in the local vibrational bands of the linker building block.

A historical overview of the activation and porosity of metal-organic frameworks.

Since the first reports of metal-organic frameworks (MOFs), this unique class of crystalline, porous materials has garnered increasing attention in a wide variety of applications such as gas storage and separation, catalysis, enzyme immobilization, drug delivery, water capture, and sensing. A fundamental feature of MOFs is their porosity which provides space on the micro- and meso-scale for confining and exposing their functionalities. Therefore, designing MOFs with high porosity and developing suitable activation methods for preserving and accessing their pore space have been a common theme in MOF research. Reticular chemistry allows for the facile design of MOFs from highly tunable metal nodes and organic linkers in order to realize different pore structures, topologies, and functionalities. With the hope of shedding light on future research endeavors in MOF porosity, it is worthwhile to examine the development of MOFs, with an emphasis on their porosity and how to properly access their pore space. In this review, we will provide an overview of the historic evolution of porosity and activation of MOFs, followed by a synopsis of the strategies to design and preserve permanent porosity in MOFs.

Unprecedented Radiation Resistant Thorium-Binaphthol Metal-Organic Framework.

A thorium-organic framework (TOF-16) containing hexameric secondary building units connected by functionalized binaphthol linkers was synthesized, characterized, and irradiated to probe its radiation resistance. Radiation stability was examined using γ-rays and 5 MeV He2+ ions to simulate α particles. γ-irradiation of TOF-16 to an unprecedented 4 MGy dose resulted in no apparent bulk structural damage visible by X-ray diffraction. To further probe radiation stability, we conducted the first He2+ ion irradiation study of a metal-organic framework (MOF). Diffraction data indicate onset of crystallinity loss upon approximately 15 MGy of irradiation and total loss of crystallinity upon exposure to approximately 25 MGy of He2+ ion irradiation. The high radiation resistance observed suggests MOFs can withstand radiation exposure at doses found in nuclear waste streams and highlights the need for a systematic approach to understand and eventually design frameworks with exceptional radiation resistance.

Stabilization of an Unprecedented Hexanuclear Secondary Building Unit in a Thorium-Based Metal-Organic Framework.

The crystal structures of thorium clusters are important for understanding the formation and transformation mechanisms of actinide species in solution, which can in turns benefit nuclear waste processing and management. However, stabilizing thorium clusters in aqueous solution is quite challenging because of their fast olation and oxolation reactions. Here, we report a thorium-based metal-organic framework, NU-905, with the formula [Th6(µ3-O)2(HCOO)4(H2O)6(TCPP)4] [TCPP = tetrakis(4-carboxyphenyl)porphyrin], synthesized by a solvothermal reaction in N, N-dimethylformamide and water at 120 °C. NU-905 contains a hexanuclear secondary building unit (SBU), [Th6(µ3-O)2(HCOO)4(H2O)6], which has never been reported previously. The SBUs are capped and bridged by the tetratopic linker TCPP to form a three-dimensional network with scu topology. The activated NU-905 exhibits permanent porosity and shows high catalytic activity for the selective photooxidation of a mustard gas simulant.

Energy-structure-property relationships in uranium metal-organic frameworks.

Located at the foot of the periodic table, uranium is a relatively underexplored element possessing rich chemistry. In addition to its high relevance to nuclear power, uranium shows promise for small molecule activation and photocatalysis, among many other powerful functions. Researchers have used metal-organic frameworks (MOFs) to harness uranium's properties, and in their quest to do so, have discovered remarkable structures and unique properties unobserved in traditional transition metal MOFs. More recently, (e.g. the last 8-10 years), theoretical calculations of framework energetics have supplemented structure-property studies in uranium MOFs (U-MOFs). In this Perspective, we summarize how these budding energy-structure-property relationships in U-MOFs enable a deeper understanding of chemical phenomena, enlarge chemical space, and elevate the field to targeted, rather than exploratory, discovery. Importantly, this Perspective encourages interdisciplinary connections between experimentalists and theorists by demonstrating how these collaborations have elevated the entire U-MOF field.

Back to the Basics: Developing Advanced Metal-Organic Frameworks Using Fundamental Chemistry Concepts.

Over the past 25 years, metal-organic frameworks (MOFs) have developed into an increasingly intricate class of crystalline porous materials in which the choice of building blocks offers significant control over the physical properties of the resulting material. Despite this complexity, fundamental coordination chemistry design principles provided a strategic basis to design highly stable MOF structures. In this Perspective, we provide an overview of these design strategies and discuss how researchers leverage fundamental chemistry concepts to tune reaction parameters and synthesize highly crystalline MOFs. We then discuss these design principles in the context of several literature examples, highlighting both relevant fundamental chemistry principles and additional design principles required to access stable MOF structures. Finally, we envision how these fundamental concepts may offer access to even more advanced structures with tailored properties as the MOF field looks toward the future.

Influence of Linker Identity on the Photochemistry of Uranyl-Organic Frameworks.

While uranyl-based metal-organic frameworks (MOFs) boast impressive photocatalytic abilities, significant questions remain regarding their excitation pathways and methods to fine-tune their performance due to the lack of information regarding heterogeneous uranyl catalysis. Herein, we investigated how linker identity and photoexcitation impact uranyl photocatalysis when the uranyl coordination environment remains constant. Toward this end, we prepared three uranyl-based MOFs (NU-1301, NU-1307, and ZnTCPP-U2) and then examined the structural and photochemical properties of each through X-ray diffraction, X-ray absorption, and photoluminescence. We then correlated our observations to the photocatalytic performance for fluorination of cyclooctane. The excitation profile from NU-1301 and NU-1307 exhibited spin-forbidden linker transitions and uranyl vibronic progressions, with uranyl excitation and emission being most dominant in NU-1301. Consequently, NU-1301 was a more active photocatalyst than NU-1307. In contrast, the excitation profile from ZnTCPP-U2 contained transitions associated with the porphyrin linker exclusively. Photocatalytic activity from ZnTCPP-U2 significantly underperformed in comparison to that of the other two MOFs. These data suggest that linkers' photophysical properties can be used to predict the photocatalytic behavior of uranyl-containing MOFs.

Gynecological intrauterine brachytherapy training for radiation therapists: The development and implementation of a training program.

PURPOSE: Gynecological brachytherapy (GynBT) is an important part of gynecological cancer management. At Olivia Newton-John Cancer Wellness & Research Centre (ONJCWRC), Melbourne, Australia, radiation therapists (RTs) are integral to the MRI adaptive GynBT program workflow. However, there is limited GynBT training available for RTs in Australia. A GynBT training program has been developed at ONJCWRC to meet this need and support RTs in becoming competent, proficient and confident in the various roles in GynBT. This is a preliminary report on the development and implementation of a credentialing program, providing a structured approach to GynBT training of RTs. METHODS AND MATERIALS: A credentialing program was designed with modules and competency assessments to ensure efficiency and proficiency of RTs in the GynBT workflow. The program includes theoretical modules in anatomy, international GynBT guidelines, radiation safety and local protocols; and practical modules in equipment, ultrasound for GynBT, operating theatre procedures, MRI, contouring, applicator reconstruction, planning, quality assurance and treatment delivery. Learning strategies include self-directed learning, tutorials, practical sessions, and third-party courses. The program concludes with an exit examination assessing major competencies. RESULTS: The program was implemented in April 2018 with three RTs completing the program and passing the exit examination on first attempt. On post-program survey, the RTs felt the program was comprehensive, helping to build their confidence, and proficiency in GynBT. CONCLUSIONS: A GynBT RT credentialing program was successfully developed and implemented to improve the quality of training at ONJCWRC. This program is mandatory for RTs joining the GynBT team. This program can provide a framework for implementation of GynBT training in other centers.

Identification of a metastable uranium metal-organic framework isomer through non-equilibrium synthesis.

Since the structure of supramolecular isomers determines their performance, rational synthesis of a specific isomer hinges on understanding the energetic relationships between isomeric possibilities. To this end, we have systematically interrogated a pair of uranium-based metal-organic framework topological isomers both synthetically and through density functional theory (DFT) energetic calculations. Although synthetic and energetic data initially appeared to mismatch, we assigned this phenomenon to the appearance of a metastable isomer, driven by levers defined by Le Châtelier's principle. Identifying the relationship between structure and energetics in this study reveals how non-equilibrium synthetic conditions can be used as a strategy to target metastable MOFs. Additionally, this study demonstrates how defined MOF design rules may enable access to products within the energetic phase space which are more complex than conventional binary (e.g., kinetic vs. thermodynamic) products.

Squeezing the box: isoreticular contraction of pyrene-based linker in a Zr-based metal-organic framework for Xe/Kr separation.

Isoreticular synthesis is a powerful tool to enhance specific attributes of a metal-organic framework (MOF). While the isoreticular expansion of MOF structure are prevalent in the literature, the compression of a topology holds great promise for separations due to the contracted pore apertures and/or cavities. Herein, we report the synthesis, characterization and Xe/Kr separation capability of a new Zr-based MOF, NU-1106, connected by the tetratopic linker 1,3,6,8-pyrene tetracarboxylate, which exhibits a compressed ftw topology compared to the extended ones reported previously. NU-1106 showed selective uptake of Xenon over Krypton, providing the potential for use for separations.

Benign Integration of a Zn-Azolate Metal-Organic Framework onto Textile Fiber for Ammonia Capture.

Ammonia (NH3) exposure has a serious impact on human health because of its toxic and corrosive nature. Therefore, efficient personal protective equipment (PPE) such as masks is necessary to eliminate and mitigate NH3 exposure risks. Because economically and environmentally viable conditions are of interest for large-scale manufacture of PPE, we herein report a benign procedure to synthesize a Zn-azolate metal-organic framework (MOF), MFU-4, for NH3 capture. The surface area and morphology of MFU-4 obtained in alcohol solvents at room temperature is consistent with that of traditionally synthesized MFU-4 in N,N-dimethylformamide at 140 °C. In addition to its large NH3 uptake capacity at 1 bar (17.7 mmol/g), MFU-4 shows outstanding performance in capturing NH3 at low concentration (10.8 mmol/g at 0.05 bar). Furthermore, the mild synthetic conditions implemented make it facile to immobilize MFU-4 onto cotton textile fiber. Enhanced NH3 capture ability of the MFU-4/fiber composite was also attributed to the well-exposed MOF particles. The benign synthetic MFU-4 procedure, high NH3 uptake, and easy integration onto fiber pave the way toward implementation of similar materials in PPE.

Synergistic effects of polymyxin and ionic liquids on lipid vesicle membrane stability and aggregation.

Ionic liquids (ILs) have been investigated for potential antibacterial and antibiotic applications due to their ability to destabilize and permeabilize the lipid bilayers in cell membranes. Bacterial assays have shown that combining ILs with antibiotics can provide a synergistic enhancement of their antibacterial activities. We have characterized the mechanism by which the conventional ILs 1-butyl-3-methylimidazolium chloride (BMICl) and 1-butyl-3-methylimidazolium tetrafluoroborate (BMIBF4) enhance the lipid membrane permeabilization of the well-known antibiotic polymyxin B (PMB). We studied the sizes and membrane permeabilities of multilamellar and unilamellar lipid bilayer vesicles in the presence of ILs alone in aqueous solution, PMB alone, and ILs combined together with PMB. Light scattering-based experiments show that vesicle sizes dramatically increase when ILs are combined with PMB, which suggests that the materials combine to synergistically enhance lipid membrane disruption leading to vesicle aggregation. Lipid bilayer leakage experiments using tris (2,2'-bipyridyl) ruthenium (II) (Ru(bpy)32+) trapped in lipid vesicles, in which the trapped Ru(bpy)32+ fluorescence lifetime increases when it leaks out of the vesicle, show that combining BMIBF4 and PMB together permeabilize the membrane significantly more than with PMB or the IL alone. This demonstrates that ILs can assist in antibiotic permeabilization of lipid bilayers which could explain the increased antibiotic activities in the presence of ILs in solution.

Kinetics and mass spectrometric measurements of myoglobin unfolding in aqueous ionic liquid solutions.

Recent studies have characterized the effects of aqueous ionic liquids on myoglobin unfolding for the broader purposes of understanding their effects on protein structures, stabilities, and ultimately biocompatibilities for future applications. Here, we investigated the effects of four different ionic liquids (ILs) on the thermal stability, unfolding kinetics, and tertiary shape of myoglobin. We compared results for four different ILs: 1-butyl-3-methyl imidazolium tetrafluoroborate (BMIBF4); 1-butyl-3-methyl pyrrolidinium tetrafluoroborate (PyrrBF4); 1-ethyl-3-methyl imidazolium acetate (EMIAc); and tetramethylguanidinium acetate (TMGAc). Results showed that ILs accelerate myoglobin unfolding kinetics both through aqueous solution ionic strength effects and ionic liquid-specific effects. Arrhenius plots of observed rate constants reveal that some ILs lower the energy barrier to unfolding, possibly by destabilizing the native protein state. The magnitude of these ionic liquid effects correlates with their effects on protein thermodynamic stabilities. Hydrogen-deuterium exchange (HDX) experiments using ESI-MS showed that myoglobin exhibits a more open, and presumably less stable, tertiary shape in aqueous IL solutions. Overall, BMIBF4 and TMGAc exhibit the strongest effect on the myoglobin stability, unfolding rate, and tertiary structure while PyrrBF4 and EMIAc have weaker effects under our experimental conditions.

Clinically relevant outcomes based on analysis of pooled data from 2 trials of duloxetine in patients with knee osteoarthritis.

OBJECTIVE: To determine response with duloxetine versus placebo in patients with osteoarthritis (OA) of the knee using the Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responder index and other clinically relevant outcomes including minimal clinically important improvement (MCII) and patient acceptable symptom state (PASS) for pain and function. METHODS: Data were pooled from two 13-week, randomized, double-blind, placebo-controlled trials comparing duloxetine 60 to 120 mg/day with placebo in patients with symptomatic OA of the knee. Treatment response was determined according to the OMERACT-OARSI responder index, ≥ 30% pain reduction, ≥ 50% pain reduction, and MCII and PASS for pain and function. (ClinicalTrials.gov identifiers NCT00433290 and NCT00408421) RESULTS: Duloxetine-treated patients were 33% more likely to experience an OMERACT-OARSI response than placebo-treated patients [p < 0.001, number needed to treat (NNT) = 6]. A significantly greater percentage of duloxetine-treated patients, compared with placebo-treated patients, reported ≥ 30% improvement in pain from baseline to endpoint (p < 0.001, NNT = 5) and ≥ 50% improvement in pain relative to baseline (p < 0.001, NNT = 7). The duloxetine-treated patients were also more likely to fulfill MCII criteria for pain (p < 0.001, NNT = 6) and function (p < 0.001, NNT = 7), and to achieve PASS for pain (p < 0.001, NNT = 6) and function (p = 0.009, NNT = 9). More duloxetine-treated patients compared with placebo-treated patients experienced ≥ 1 treatment-emergent adverse event (p = 0.003, number needed to harm = 8). CONCLUSION: Significantly more patients receiving duloxetine than placebo achieved an OMERACT-OARSI response, improvements in pain and function exceeding the level accepted as MCII, and reached PASS. Results support the clinical relevance of outcomes of prior duloxetine studies in symptomatic OA of the knee.

Pain mechanisms in osteoarthritis: understanding the role of central pain and current approaches to its treatment.

In this literature review, the mechanisms underlying pain associated with osteoarthritis (OA) are discussed, along with evidence for the efficacy of medications thought to act centrally to relieve OA pain. We survey the cascade of events from inflammation to activation of nociceptive and neuropathic pathways, to the development and maintenance of central and peripheral sensitization. Preclinical and clinical evidence for the sensitization hypothesis is discussed, along with recently identified genetic variations that may increase sensitivity to pain in patients with OA. Evidence is presented for the efficacy of centrally acting analgesics for OA pain (opioids, antiepileptics, tricyclic antidepressants, and serotonin/norepinephrine receptor inhibitors).

Comparative effectiveness of a prenatal medical food to prenatal vitamins on hemoglobin levels and adverse outcomes: a retrospective analysis.

BACKGROUND: The role of folate in pregnancy is well established, with most prenatal vitamins (PNVs) on the market containing at least 800 µg of folic acid. Folic acid must be converted in the body to L-methylfolate, the natural and biologically active form of folate. The role of vitamin B(12) in pregnancy is less characterized, and most PNV formulations contain only 0 to 12 µg. The present study was undertaken to evaluate whether taking a prenatal medical food containing L-methylfolate and much higher doses of vitamin B(12) results in higher hemoglobin levels and thus, a lower incidence of anemia during pregnancy. OBJECTIVE: The objective of this exploratory study was to evaluate the effects of the prenatal medical food versus standard PNVs on hemoglobin levels and adverse outcomes throughout pregnancy. METHODS: For this retrospective analysis, we reviewed the charts of female patients taking either a prenatal medical food or standard PNV during pregnancy. Hemoglobin levels measured at initiation of prenatal care, end of second trimester, and delivery were recorded. Patients who had received additional iron supplementation, beyond that contained in the prenatal medical food or PNV they were taking and before anemia screening at the end of the second trimester, were excluded from the study. Fisher exact test, χ(2) test, student t test, and ANOVA were used to evaluate differences between the treatment groups. RESULTS: Data were analyzed from 112 charts: 58 patients (51.8%) were taking the prenatal medical food; 54 patients (48.2%) were taking standard PNVs. Mean (SD) age at first prenatal visit was 27 (4.6) years in the medical food group and 28.8 (3.5) years in the PNV group (P = 0.024). Mean (SD) body mass indices were 29.1 (6.5) and 31.7 (8.9) in the medical food and PNV groups, respectively (P = NS). In the medical food group, 35 women (60.3%) were white/Caucasian, 17 (29.3%) were African American, and 6 (10.4%) were of other races. In the PNV group, 24 women (44.4%) were white/Caucasian, 25 (46.3%) were African American, and 5 (9.3%) were of other races. However, race was not significantly different between the two groups. At end of second trimester and at delivery, mean (SD) hemoglobin levels were higher in the prenatal medical food group (11.8 [1.1] g/dL and 11.8 [1.3] g/dL, respectively) than in the PNV group (11.3 [1.2] g/dL and 10.7 [1.2] g/dL, respectively) (P = 0.011 and P = 0.001, respectively). Significantly fewer cases of anemia were reported at end of second trimester in the prenatal medical food group than in the PNV group (39.7% vs 74.1%; P = 0.001). CONCLUSIONS: In the present study, supplementation with a prenatal medical food containing L-methylfolate and high-dose vitamin B(12) may maintain hemoglobin levels and decrease rates of anemia in pregnancy more effectively than standard prenatal vitamins; however, prospective, controlled studies are warranted. ClinicalTrials.gov identifier: NCT01193192.