The 18‐membered macrocycle H2macropa was investigated for 225Ac chelation in targeted alpha therapy (TAT). Radiolabeling studies showed that macropa, at submicromolar concentration, complexed all ...225Ac (26 kBq) in 5 min at RT. 225Ac(macropa)+ remained intact over 7 to 8 days when challenged with either excess La3+ ions or human serum, and did not accumulate in any organ after 5 h in healthy mice. A bifunctional analogue, macropa‐NCS, was conjugated to trastuzumab as well as to the prostate‐specific membrane antigen‐targeting compound RPS‐070. Both constructs rapidly radiolabeled 225Ac in just minutes at RT, and macropa‐Tmab retained >99 % of its 225Ac in human serum after 7 days. In LNCaP xenograft mice, 225Ac‐macropa‐RPS‐070 was selectively targeted to tumors and did not release free 225Ac over 96 h. These findings establish macropa to be a highly promising ligand for 225Ac chelation that will facilitate the clinical development of 225Ac TAT for the treatment of soft‐tissue metastases.
Actinium in action! A macrocyclic ligand exhibits unprecedented radiolabeling efficiency for the large α‐emitting radionuclide 225Ac3+. This ligand is extremely promising for the implementation of 225Ac in targeted alpha therapy for cancer. RCY=radiochemical yield.
Conspectus Over hundreds of new organic semiconductor molecules have been synthesized as hole transport materials (HTMs) for perovskite solar cells. However, to date, the well-known N 2,N 2,N 2′,N ...2′,N 7,N 7,N 7′, octakis-(4-methoxyphenyl)-9,9-spirobi-9,9′-spirobi9H-fluorene-2,2′,7,7′-tetramine (spiro-OMeTAD) is still the best choice for the best perovskite device performance. Nevertheless, there is a consensus that spiro-OMeTAD by itself is not stable enough for long-term stable devices, and its market price makes its use in large-scale production costly. Novel synthetic routes for new HTMs have to be sought that can be carried out in fewer synthetic steps and can be easily scaled up for commercial purposes. On the one hand, synthetic chemists have taken, as a first approach, the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energy levels of the spiro-OMeTAD molecule as a reference to synthesize molecules with similar energy levels, although these HOMO and LUMO energy levels often have been measured indirectly in solution using cyclic voltammetry. On the other hand, the “spiro” chemical core has also been studied as a structural motif for novel HTMs. However, only a few molecules incorporated as HTMs in complete functional perovskite solar cells have been capable of matching the performance of the best-performing perovskite solar cells made using spiro-OMeTAD. In this Account, we describe the advances in the synthesis of HTMs that have been tested in perovskite solar cells. The comparison of solar cell efficiencies is of course very challenging because the solar cell preparation conditions may differ from laboratory to laboratory. To extract valuable information about the HTM molecular structure–device function relationship, we describe those examples that always have used spiro-OMeTAD as a control device and have always used identical experimental conditions (e.g., the use of the same chemical dopant for the HTM or the lack of it). The pioneering work was focused on well-understood organic semiconductor moieties such as arylamine, carbazole, and thiophene. Those chemical structures have been largely employed and studied as HTMs, for instance, in organic light-emitting devices. Interestingly, most research groups have reported the hole mobility values for their novel HTMs. However, only a few examples have been found that have measured the HOMO and LUMO energy levels using advanced spectroscopic techniques to determine these reference energy values directly. Moreover, it has been shown that those molecules, upon interacting with the perovskite layer, often have different HOMO and LUMO energies than the values estimated indirectly using solution-based electrochemical methods. Last but not least, porphyrins and phthalocyanines have also been synthesized as potential HTMs for perovskite solar cells. Their optical and physical properties, such as high absorption and good energy transfer capabilities, open new possibilities for HTMs in perovskite solar cells.
In November 2014, President Obama announced his intention to dramatically reshape immigration law through administrative channels. Together with relief policies announced in 2012, his initiatives ...would shield nearly half the population of unauthorized immigrants from removal and enable them to work in the United States. These events have drawn renewed attention to the President's power to shape immigration law. They also have reignited a longstanding controversy about whether constitutional limits exist on a central source of executive authority: the power to enforce the law. In using the Obama relief policies to explore these dynamics, we make two central claims. First, it is futile to try to constrain the enforcement power by tying it to a search for congressional enforcement priorities. Congress has no discernible priorities when it comes to a very wide swath of enforcement activity—a reality especially true for immigration law today. The immigration code has evolved over time into a highly reticulated statute through the work of numerous Congresses and political coalitions. The modern structure of immigration law also effectively delegates vast screening authority to the President. Interlocking historical, political, and legislative developments have opened a tremendous gap between the law on the books and the law on the ground. Under these conditions, there can be no meaningful search for congressionally preferred screening criteria. Far from reflecting a faithful-agent framework, then, immigration enforcement more closely resembles a two-principals model of policymaking—one in which the Executive can and should help construct the domain of regulation through its independent judgments about how and when to enforce the law. Second, when exploring limits on the enforcement power, we should focus not on who benefits from enforcement discretion but on how the Executive institutionalizes its discretion. The Obama relief initiatives are innovative: they bind the exercise of prosecutorial discretion to a more rule-like decision-making process, constrain the judgments of line-level officials by subjecting them to centralized supervision, and render the exercise of enforcement discretion far more transparent to the public than is customary. These efforts to better organize the enforcement bureaucracy ultimately advance core rule-of-law values without undermining deterrence or legal compliance, as some critics have worried. Moreover, while our focus on discretion's institutionalization requires contextualized judgments that may rarely translate into clear doctrinal rules to govern the enforcement power, we believe it is generally unnecessary and unwise to use constitutional law to limit the President's authority over how to organize the enforcement bureaucracy.
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Dostopno za:
BFBNIB, DOBA, IZUM, KILJ, NMLJ, NUK, PILJ, PNG, PRFLJ, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The controlled self‐assembly of peptide‐ and protein‐based pharmaceuticals is of central importance for their mode of action and tuning of their properties. Peptide YY3–36 (PYY3–36) is a 36‐residue ...peptide hormone that reduces food intake when peripherally administered. Herein, we describe the synthesis of a PYY3–36 analogue functionalized with a metal‐ion‐binding 2,2’‐bipyridine ligand that enables self‐assembly through metal complexation. Upon addition of CuII, the bipyridine‐modified PYY3–36 peptide binds stoichiometric quantities of metal ions in solution and contributes to the organization of higher‐order assemblies. In this study, we aimed to explore the size effect of the self‐assembly in vivo by using non‐invasive quantitative single‐photon emission computed tomography/computed tomography (SPECT/CT) imaging. For this purpose, bipyridine‐modified PYY3–36 was radiolabeled with a chelator holding 111InIII, followed by the addition of CuII to the bipyridine ligand. SPECT/CT imaging and biodistribution studies showed fast renal clearance and accumulation in the kidney cortex. The radiolabeled bipyridyl‐PYY3–36 conjugates with and without CuII presented a slightly slower excretion 1 h post injection compared to the unmodified‐PYY3–36, thus demonstrating that higher self‐assemblies of the peptide might have an effect on the pharmacokinetics.
Peptide self‐assembly: Radiolabeling of a re‐engineered peptide YY3–36 (PYY3–36) with a 2,2’‐bipyridine ligand enabled higher‐order self‐assemblies through coordination with CuII. We studied the effect of the self‐assembly in vivo by using non‐invasive quantitative bioimaging. Abiotic ligands might influence the controlled release of biopharmaceuticals from subcutaneous depots.
Three hole transport materials (HTMs) based on a substituted triphenylamine moiety have been synthesized and successfully employed in triple‐cation mixed‐halide PSCs, reaching efficiencies of 19.4 %. ...The efficiencies, comparable to those obtained using spiro‐OMeTAD, point them out as promising candidates for easily attainable and cost‐effective alternatives for PSCs, given their facile synthesis from commercially available materials. Interestingly, although all these HTMs show similar chemical and physical properties, they provide different carrier recombination kinetics. Our results demonstrate that is feasible through the molecular design of the HTM to minimize carrier losses and, thus, increase the solar cell efficiencies.
Three hole transport materials (HTMs) based on a substituted triphenylamine moiety have been synthesized and employed in perowskite solar cells, reaching efficiencies of 19.4 %. Although all these HTMs show very similar chemical and physical properties, they provide different carrier recombination kinetics.
Prolonged pair bonds have the potential to improve reproductive performance of socially monogamous animals by increasing pair familiarity and enhancing coordination and cooperation between pair ...members. However, this has proved very difficult to test robustly because of important confounds such as age and reproductive experience. Here, we address limitations of previous studies and provide a rigorous test of the mate familiarity effect in the socially monogamous blue-footed booby, Sula nebouxii, a long-lived marine bird with a high divorce rate. Taking advantage of a natural disassociation between age and pair bond duration in this species, and applying a novel analytical approach to a 24 year database, we found that those pairs which have been together for longer establish their clutches five weeks earlier in the season, hatch more of their eggs and produce 35% more fledglings, regardless of age and reproductive experience. Our results demonstrate that pair bond duration increases individual fitness and further suggest that synergistic effects between a male and female's behaviour are likely to be involved in generating a mate familiarity effect. These findings help to explain the age- and experience-independent benefits of remating and their role in life-history evolution.
3D inverse opal (3D‐IO) oxides are very appealing nanostructures to be integrated into the photoelectrodes of dye‐sensitized solar cells (DSSCs). Due to their periodic interconnected pore network ...with a high pore volume fraction, they facilitate electrolyte infiltration and enhance light scattering. Nonetheless, preparing 3D‐IO structures directly on nonflat DSSC electrodes is challenging. Herein, 3D‐IO TiO2 structures are prepared by templating with self‐assembled polymethyl methacrylate spheres on glass substrates, impregnation with a mixed TiO2:SiO2 precursor and calcination. The specific surface increases from 20.9 to 30.7 m2 g−1 after SiO2 removal via etching, which leads to the formation of mesopores. The obtained nanostructures are scraped from the substrate, processed as a paste, and deposited on photoelectrodes containing a mesoporous TiO2 layer. This procedure maintains locally the 3D‐IO order. When sensitized with the novel benzothiadiazole dye YKP‐88, DSSCs containing the modified photoelectrodes exhibit an efficiency of 10.35% versus 9.26% for the same devices with conventional photoelectrodes. Similarly, using the ruthenium dye N719 as sensitizer an efficiency increase from 5.31% to 6.23% is obtained. These improvements originate mainly from an increase in the photocurrent density, which is attributed to an enhanced dye loading obtained with the mesoporous 3D‐IO structures due to SiO2 removal.
A significant improvement of the photocurrent density and hence the power conversion efficiency of dye‐sensitized solar cells (DSSCs) is achieved by integrating mesoporous 3D inverse opal TiO2 nanostructures into the photoelectrode. Using an organic dye for sensitization leads to efficiencies up to 10.35%, which is the highest value reported using inverse opal structures as photoactive component in the photoelectrode.
The transcription factor NFAT5, also known as TonEBP, belongs to the family of Rel homology domain-containing factors, which comprises the NF-κB proteins and the calcineurin-dependent NFAT1 to NFAT4. ...NFAT5 shares several structural and functional features with other Rel-family factors, for instance it recognizes DNA elements with the same core sequence as those bound by NFAT1 to 4, and like NF-κB it responds to Toll-like receptors (TLR) and activates macrophage responses to microbial products. On the other hand, NFAT5 is quite unique among Rel-family factors as it can be activated by hyperosmotic stress caused by elevated concentrations of extracellular sodium ions. NFAT5 regulates specific genes but also others that are inducible by NF-κB and NFAT1 to 4. The ability of NFAT5 to do so in response to hypertonicity, microbial products, and inflammatory stimuli may extend the capabilities of immune cells to mount effective anti-pathogen responses in diverse microenvironment and signaling conditions. Recent studies identifying osmostress-dependent and -independent functions of NFAT5 have broadened our understanding of how NFAT5 may modulate immune function. In this review we focus on the role of NFAT5 in macrophages and T cells in different contexts, discussing findings from
mouse models of NFAT5 deficiency and reviewing current knowledge on its mechanisms of regulation. Finally, we propose several questions for future research.
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