Using Redox-Active Ligands to Generate Actinide Ligand Radical Species.

Using a redox-active dioxophenoxazine ligand, DOPO (DOPO = 2,4,6,8-tetra-tert-butyl-1-oxo-1H-phenoxazine-9-olate), a family of actinide (U, Th, Np, and Pu) and Hf tris(ligand) coordination compounds was synthesized. The full characterization of these species using 1H NMR spectroscopy, electronic absorption spectroscopy, SQUID magnetometry, and X-ray crystallography showed that these compounds are analogous and exist in the form M(DOPOq)2(DOPOsq), where two ligands are of the oxidized quinone form (DOPOq) and the third is of the reduced semiquinone (DOPOsq) form. The electronic structures of these complexes were further investigated using CASSCF calculations, which revealed electronic structures consistent with metals in the +4 formal oxidation state and one unpaired electron localized on one ligand in each complex. Furthermore, f orbitals of the early actinides show a sizable bonding overlap with the ligand 2p orbitals. Notably, this is the first example of a plutonium-ligand radical species and a rare example of magnetic data being recorded for a homogeneous plutonium coordination complex.

Conversion of Trivalent Uranium Anilido to Tetravalent Uranium Imido Species via Oxidative Deprotonation.

Two uranium(III) anilido complexes were synthesized, Tp*2U(NH-C6H4-p-terpyridine) (2-terpy) and Tp*2U(NH-C6H4-p-CH3) (2-ptol), where Tp* = hydrotris(3,5-dimethylpyrazolyl)borate, by protonation of Tp*2UBn (1-Bn; Bn = benzyl) with 4-[2,6-di(pyridin-2-yl)pyridin-4-yl]benzenamine or p-toluidine, respectively. Conversion to the respective uranium(IV) imido species was possible by oxidation and deprotonation, forming Tp*2U(N-C6H4-p-terpyridine) (3-terpy) and Tp*2U(N-C6H4-p-CH3) (3-ptol). These compounds were characterized by multinuclear NMR spectroscopy, IR spectroscopy, electronic absorption spectroscopy, and X-ray crystallography.

Origin of Bond Elongation in a Uranium(IV) cis-Bis(imido) Complex.

The activation of U-N multiple bonds in an imido analogue of the uranyl ion is accomplished by using a system that is very electron-rich with sterically encumbering ligands. Treating the uranium(VI) trans-bis(imido) UI2(NDIPP)2(THF)3 (DIPP = 2,6-diisopropylphenyl and THF = tetrahydrofuran) with tert-butyl(dimethylsilyl)amide (NTSA) results in a reduction and rearrangement to form the uranium(IV) cis-bis(imido) [U(NDIPP)2(NTSA)2]K2 (1). Compound 1 features long U-N bonds, pointing toward substantial activation of the N═U═N unit, as determined by X-ray crystallography and 1H NMR, IR, and electronic absorption spectroscopies. Computational analyses show that uranium(IV)-imido bonds in 1 are significantly weakened multiple bonds due to polarization toward antibonding and nonbonding orbitals. Such geometric control has important effects on the electronic structures of these species, which could be useful in the recycling of spent nuclear fuels.

Expanding the Library of Uranyl Amide Derivatives: New Complexes Featuring the tert-Butyldimethylsilylamide Ligand.

New uranyl derivatives featuring the amide ligand, -N(SiHMe2) tBu, were synthesized and characterized by X-ray crystallography, multinuclear NMR spectroscopy, and absorption spectroscopies. Steric properties of these complexes were also quantified using the computational program Solid-G. The increased basicity of the free ligand -N(SiHMe2) tBu was demonstrated by direct comparison to -N(SiMe3)2, a popular supporting ligand for uranyl. Substitutional lability on a uranyl center was also demonstrated by exchange with the -N(SiMe3)2 ligand. The increased basicity of this ligand and diverse characterization handles discussed here will make these compounds useful synthons for future reactivity.

The ability of massive osteochondral allografts from the medial tibial plateau to reproduce normal joint contact pressures after glenoid resurfacing: the effect of computed tomography matching.

BACKGROUND: Current techniques for resurfacing of the glenoid in the treatment of arthritis are unpredictable. Computed tomography (CT) studies have demonstrated that the medial tibial plateau has close similarity to the glenoid. The purpose of this study was to assess contact pressures of transplanted massive tibial osteochondral allografts to resurface the glenoid without and with CT matching. METHODS: Ten unmatched cadaveric tibiae were used to resurface 10 cadaveric glenoids with osteochondral allografts. Five cadaveric tibiae and glenoids were CT matched and studied. An internal control group of 4 matched pairs of glenoids, with the contralateral glenoid transplanted to the opposite glenoid, was also included as a best-case scenario to measure the effects of the surgical technique. All glenoids were tested before and after grafting at different abduction and rotation angles, with recording of peak contact pressures. RESULTS: Peak contact pressures were not different from the intact state in the autografted group but were increased in both allografted groups. CT-matched tibial grafts had lower peak pressures than unmatched grafts. Peak pressures were on average 24.8% (range [18.3%, 29.6%]) greater than in the native glenoids for unmatched allografts, 21.8% ([17.0%, 25.5%]) greater for the matched allografts, and 4.9% ([3.8%, 5.5%]) greater for matched autografts. CONCLUSION: Osteochondral grafting from the medial tibial plateau to the glenoid is feasible but results in increased peak contact pressures. The technique is reproducible as defined by the autografted group. Contact pressures between native and allografted glenoids were significantly different. The clinical significance remains unknown. Peak pressures experienced by the glenoid seem highly sensitive to deviations from the native glenoid shape.

Dissecting the dimerization motif of Enterococcus hirae's Zn(II)CopY.

The regulation of the copper homeostasis pathway in Enterococcus hirae is conducted through activity of the zinc metalloprotein Zn(II)CopY, which is a Cu(I)-responsive dimeric repressor (Cobine et al., Biochemistry 41:5822-5829, 2002). Its dimerization domain contains a C-terminal cysteine-rich metal-binding motif used for Cu(I) sensing adjacent to an aliphatic-rich repeating sequence, but it is unclear as to which regions contribute most to the interaction. To accomplish this, a synthetically produced CopY construct (CDG) was fused with solubility enhancement tags so the key components of the elements of the aliphatic repeat and metal-binding site could be probed for their dimerization activity. The resultant fusion constructs were tested using two independent methods. Isothermal titration calorimetry, an in vitro technique, was employed to determine dimer affinity thermodynamically. Protein fragment complementation, an in vivo technique, made it possible to rapidly screen homodimeric and heterodimeric complexes within live cells. The combination of in vivo and in vitro studies enabled the identification of CDG sequences that dimerize and sequences that do not, in addition to deciphering relative dimer affinity between all constructs screened. The in vivo technique allowed the formation of heterodimers to be tested for their ability to form specific complexes between dissimilar CDG analogs.

Thrombotic complications after radiofrequency and cyanoacrylate endovenous ablation: Outcomes of a multicenter real-world experience.

OBJECTIVE: Chronic venous insufficiency (CVI) affects >40% of the U.S. population; thus, intervention for symptomatic venous disease comprises a large portion of many vascular practices. The treatment of superficial CVI has evolved from open surgical treatment to minimally invasive endovenous closure, including both thermal and nonthermal techniques. Thrombotic complications of thermal ablation have been well reported, with an overall complication rate of <2%. However, a paucity of high-powered, real-world data is available on the thrombotic outcomes of nonthermal techniques. In the present study, we compared the incidence of endovenous heat-induced thrombosis (EHIT) and endovenous glue-induced thrombosis (EGIT) in a large cohort of patients with CVI. METHODS: A retrospective review was conducted at two tertiary-level institutions of patients who had undergone superficial endovenous ablation from 2018 to 2021. The patient demographics, comorbidities, and periprocedural outcomes were collected through medical record review. A Caprini risk assessment model score was assigned using the information available from the electronic medical records. The patients were categorized by procedure type (ClosureFast [Medtronic Inc, Minneapolis, MN] radiofrequency ablation [RFA] vs VenaSeal [Medtronic Inc] cyanoacrylate glue closure [CAG]). The primary end point was the incidence of EHIT or EGIT. The secondary end point was the incidence of deep vein thrombosis and/or pulmonary embolism. RESULTS: A total of 803 patients had undergone 1096 procedures during the study period. Their mean age was 62 ± 15 years, and 67% were women. Of the 1096 procedures, 700 were RFA and 396 were CAG procedures, with a combined closure rate of 98% by postprocedure duplex ultrasound at 7 days. The average Caprini score was 5.2 ± 1.8 (RFA, 5.0; vs CAG, 5.4; P < .001). The incidence of EHIT and EGIT was 1.9% and 1.3%, respectively (P = .57). The deep vein thrombosis rate was 0.1% in the RFA cohort and 0.3% in the CAG cohort (P = .81). A comparative analysis of thermal vs nonthermal techniques was performed. A univariate analysis of the risk factors for EHIT and EGIT revealed no significant factors predisposing to thrombotic events. CONCLUSIONS: The results from the present study have demonstrated the safety of RFA and CAG closure techniques for CVI, with lower thrombotic rates than previously reported. Further work might help to identify how these results can be achieved across all venous ablative techniques for CVI, even for patient populations with advanced venous disease and possibly a greater than average risk of thrombotic events.

Looking the same, but remembering differently: Preserved eye-movement synchrony with age during movie watching.

Naturalistic stimuli (e.g., movies) provide the opportunity to study lifelike experiences in the lab. While young adults respond to these stimuli in a highly synchronized manner [as indexed by intersubject correlations (ISC) in their neural activity], older adults respond more idiosyncratically. Here, we examine whether eye-movement synchrony (eye-ISC) also declines with age during movie-watching and whether it relates to memory for the movie. Our results show no age-related decline in eye-ISC, suggesting that age differences in neural ISC are not caused by differences in viewing patterns. Both age groups recalled the same number of episodic details from the movie, but older adults recalled proportionally fewer episodic details due to their greater output of semantic and false information. In both age groups, higher eye-ISC related to a higher proportion of internal details and a lower proportion of false information being recalled. Finally, both older and younger adults showed better cued recall for cues taken from within the same event than those spanning an event boundary, further confirming that events are stored in long-term memory as discrete units with stronger associations within than across event boundaries. Taken together, these findings suggest that naturalistic stimuli drive perception in a similar way in younger and older adults, but age differences in neural synchrony further up the information processing stream may contribute to subtle differences in event memory. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A centrality based multi-objective approach to disease gene association.

Disease Gene Association finds genes that are involved in the presentation of a given genetic disease. We present a hybrid approach which implements a multi-objective genetic algorithm, where input consists of centrality measures based on various relational biological evidence types merged into a complex network. Multiple objective settings and parameters are studied including the development of a new exchange methodology, safe dealer-based crossover. Successful results with respect to breast cancer and Parkinson's disease compared to previous techniques and popular known databases are shown. In addition, the newly developed methodology is also successfully applied to Alzheimer's disease, further demonstrating its flexibility. Across all three case studies the strongest results were produced by the shortest path-based measures stress and betweenness, either in a single objective parameter setting or when used in conjunction in a multi-objective environment. The new crossover technique achieved the best results when applied to Alzheimer's disease.

To lead or to herd: optimal strategies for 3D collective migration of cell clusters.

Cells migrating in clusters play a significant role in a number of biological processes such as embryogenesis, wound healing, and tumor metastasis during cancer progression. A variety of environmental and biochemical factors can influence the collective migration of cells with differing degrees of cell autonomy and inter-cellular coupling strength. For example, weakly coupled cells can move collectively under the influence of contact guidance from neighboring cells or the environment. Alternatively strongly coupled cells might follow one or more leader cells to move as a single cohesive unit. Additionally, chemical and mechanical signaling between these cells may alter the degree of coupling and determine effective cluster sizes. Being able to understand this collective cell migration process is critical in the prediction and manipulation of outcomes of key biological processes. Here we focus on understanding how various environmental and cellular factors influence small clusters of cells migrating collectively within a 3D fibrous matrix. We combine existing knowledge of single-cell migration in 2D and 3D environments, prior experimental observations of cell-cell interactions and collective migration, and a newly developed stochastic model of cell migration in 3D matrices, to simulate the migration of cell clusters in different physiologically relevant environments. Our results show that based on the extracellular environment and the strength of cell-cell mechanical coupling, two distinct optimal approaches to driving collective cell migration emerge. The ability to effectively employ these two distinct migration strategies might be critical for cells to collectively migrate through the heterogeneous tissue environments within the body.

Stalking metal-linked dimers.

Protein dimerization is essential for cellular processes including regulation and biosignalling. While protein-protein interactions can occur through many modes, this review will focus on those interactions mediated through the binding of metal ions to the proteins. Selected techniques used to study protein-protein interactions, including size exclusion chromatography, mass spectrometry, affinity chromatography, and frontal zone chromatography, are described as applied to the characterization of the Enterococcus hirae protein CopY. CopY forms a homodimer to control the expression of proteins involved in the homeostasis of cellular copper levels. At the center of the CopY dimerization interaction lies a metal binding motif, -CxCxxxxCxC-, capable of binding Zn(II) or Cu(I). The binding of metal to this cysteine hook motif, one within each monomer, is critical to the dimerization interaction. The CopY dimer is also stabilized by hydrophobic interactions between the two monomers. The cysteine hook metal binding motif has been identified in numerous other uncharacterized proteins across the biological spectrum. The prevalence of the motif gives evidence to the biological relevance of this motif, both as a metal binding domain and as a dimerization motif.

Chronic restraint stress during withdrawal increases vulnerability to drug priming-induced cocaine seeking via a dopamine D1-like receptor-mediated mechanism.

BACKGROUND: A major obstacle in the treatment of individuals with cocaine addiction is their high propensity for relapse. Although the clinical scenario of acute stress-induced relapse has been well studied in animal models, few pre-clinical studies have investigated the role of chronic stress in relapse or the interaction between chronic stress and other relapse triggers. METHODS: We tested the effect of chronic restraint stress on cocaine seeking in rats using both extinction- and abstinence-based animal relapse models. Rats were trained to press a lever for I.V. cocaine infusions (0.50 mg/kg/infusion) paired with a discrete tone + light cue in daily 3-h sessions. Following self-administration, rats were exposed to a chronic restraint stress procedure (3 h/day) or control procedure (unstressed) during the first seven days of a 13-day extinction period during which lever presses had no programmed consequences. This was followed by cue- and cocaine priming-induced drug seeking tests. In a separate group of rats, cocaine seeking was assessed during forced abstinence both before and after the same chronic stress procedure. RESULTS: A history of chronic restraint stress was associated with increased cocaine priming-induced drug seeking, an effect attenuated by co-administration of SCH-23390 (10.0 µg/kg; i.p.), a dopamine D1-like receptor antagonist, with daily restraint. Repeated SCH-23390 administration but not stress during extinction increased cue-induced reinstatement. CONCLUSIONS: Exposure to chronic stress during early withdrawal may confer lasting vulnerability to some types of relapse, and dopamine D1-like receptors appear to mediate both chronic stress effects on cocaine seeking and extinction of cocaine seeking.