Barbarossapokalypse

Barbarossapokalypse is a short animated film that explores the mindset behind “sleeping king” legends. Frederick Barbarossa was a Holy Roman Emperor who was particularly popular with his public. After his death, people longed for a return to the “good old days” of his reign. He became a cultural icon for the German people; a symbol of hope, of a better future. While in general, the future often looks grim, hope is not something humanity can afford to lose. What matters is where that hope is drawn from. Symbols like Barbarossa are dangerous, as they can lead to people always looking back, wishing their lives away, and not thinking about the present or the future. Many people see the world as black or white, when in reality things are never that binary and are often much less clear. Barbarossapokalypse is a reminder that good still exists in the world and always will. Successful advancements of all natures throughout history have happened through teamwork and perseverance, and not through the actions of one idolized person. This piece is a call to action to encourage individuals to improve their lives and world, of their own volition, rather than waiting for a hero to do it for them

CHARACTERIZATION OF THE STRUCTURE AND REACTIVITY OF A NICKEL(II)-TRIPEPTIDE MIMIC OF NICKEL SUPEROXIDE DISMUTASE

The tripeptide asparagine-cysteine-cysteine (NCC) was found by the J. Laurence lab to bind nickel very tightly. In fact, NCC was serendipitously discovered as a metal-abstraction peptide tag (MAP-tag) because it was stripping nickel from a standard immobilized metal affinity chromatography (IMAC) resin while the Laurence lab was making a protein previously unknown to bind metals. Given the ability of NCC to bind nickel, the MAP tag has the potential to be a useful biotechnological metal-delivery agent. However, prior to this work, the structure and chemical reactivity of the nickel-peptide complex were undefined. The work presented herein involves structural and reactivity investigations of the MAP-tag bound with NiII in the dianionic complex [Ni-NCC]2-. A series of spectroscopic tools, including electronic absorption, circular dichroism (CD), magnetic CD (MCD), variable-temperature variable field (VTVH) MCD, and X-ray absorption (XAS), as well as density functional theory (DFT) and time-dependent (TD) DFT methods were used to provide insight into the structure of the complex. A summary of the significant findings in this work is provided below. Spectroscopic and computational data collected of Ni-NCC conclude that NiII ion is bound in a 2N:2S square plane with coordination by the N-terminal amine nitrogen, the deprotonated backbone amide nitrogen of Cys2, and two cysteinate sulfur atoms from Cys2 and Cys3. This ligand environment is very similar to that of the nickel ion bound in the protein nickel superoxide dismutase (Ni-SOD), and comparison of the electronic absorption and CD spectra confirms that Ni-NCC and Ni-SOD have the same nickel primary coordination sphere. In addition, Ni-NCC is able to consume superoxide. Therefore, Ni-NCC is both a structural and functional mimic of Ni-SOD and detailed analysis of the electronic and geometric structures of Ni-NCC can provide insight into the minimal unit necessary to afford activity in the enzyme. Over time, the complex LLL-NiII-NCC undergoes site-specific chiral inversion to convert to DLD-NiII-NCC, as determined by spectroscopic analysis of authentic D-containing Ni-NCC peptide complexes and supported by DFT single point energy computations on geometry optimized models of the complex. This structural rearrangement enhances the superoxide scavenging ability of Ni-NCC. Intriguingly, this chiral inversion is not observed in either Ni-SOD or any small molecule mimics of the enzyme, and is therefore unique in this mimic. Upon evaluating the DFT-computed models, this rearrangement of LLL-NiII-NCC to DLD-NiII-NCC exposes one face of the nickel ion in the complex. This may allow for better interaction with exogenous molecules, like CN- and O2.-. Thus, rearrangement within the complex increases superoxide consumption. Although other metal-peptide complexes are known to undergo metal-facilitated, base-catalyzed chiral inversion or racemization, the chiral inversion reaction of Ni-NCC does not demonstrate first-order dependence on hydroxide ion concentration. Therefore, the pathway to chiral inversion in Ni-NCC is distinct from other metal-peptide complexes. Although the chiral inversion reaction of LLL-NiII-NCC to DLD-NiII-NCC is minimally affected by solution pH, the reaction is absolutely dependent on the presence of O2. We propose that O2 is required to oxidize the metal center to generate NiIII-NCC, which is then able to undergo the inversion reaction. Generation of superoxide, as well as NiIII, during the aging of LLL-NiII-NCC supports this hypothesis. Thiolate coordination in NiII-NCC reduces the effective nuclear charge of the nickel ion, necessitating oxidation to LLL-NiIII-NCC before the chiral inversion reaction can be initiated. Additionally, DLD-NiII-NCC also undergoes a small extent of O2-dependent reactivity. However, spectroscopic characterization confirms that DLD-NiII-NCC reaches the same final state as LLL-NiII-NCC. In order to characterize the structure of authentic, O2-free, LLL-NiII-NCC and DLD-NiII-NCC, as well as the O2-exposed forms of the peptides, Ni K-edge XAS was employed. This characterization of authentic, O2-free LLL-NiII-NCC and DLD-NiII-NCC confirmed the proposed 2N:2S square planar coordination in NiII-NCC. Similarities of the pre-edge feature(s), edge energy, and radial distances determined for NiII-NCC with NiII-SOD and other NiII-SOD peptide mimics further supports that Ni-NCC is a structural mimic of the enzyme. In addition, XAS characterization of O2-exposed LLL-NiII-NCC and DLD-NiII-NCC shows that, even during the chiral inversion reaction of Ni-NCC, the immediate structure about the nickel center does not significantly change

Pharmacists' roles in assisted reproductive technology

Background: The global issue of infertility has prompted an increased reliance on Assisted Reproductive Technology (ART) for conception. In Australia, patients have previously accessed ART medications through specialist clinics, however recently due to modifications in ART medication subsidisation, community pharmacists now dispense and counsel patients on ART medications. Patients residing in rural and remote locations face challenges in accessing fertility clinics, which are primarily located in metropolitan and large regional cities. Objective: To investigate the perceived role, experience, confidence, and training requirements that pharmacists have in relation to providing ART medications and counselling to patients. Methods: Purposive sampling related to location of practice, pharmacist experience with ART and self-classification as an ART specialist was used to recruit 19 Australian pharmacists from rural, remote, large regional, and metropolitan areas, who participated in semi-structured interviews based on the Consolidated Framework for Implementation Research (CFIR). Interview transcriptions were transcribed, imported into NVivo, analysed using thematic analysis and mapped to CFIR domains and constructs. Results: Of the nineteen pharmacists interviewed, six were from rural and remote areas and thirteen were from metropolitan or large regional areas. Eight participants perceived themselves as specialist pharmacists in ART, all of which were in metropolitan or large regional locations. Three CFIR domains were identified as relevant for this study, which were further developed, with data mapped to eleven constructs under those domains. Emergent themes were identified that contributed to the pharmacist role including patient needs, external policies, fertility clinics, pharmacist experience and training, procuring ART, and the personal attributes of participants. Some constructs and themes differed between participants dependent on self-reported specialisation status and geographical location (e.g., self-efficacy), whereas others were consistent (e.g., knowledge and belief about the intervention). Pharmacists considered their role not to be limited to the supply and counselling of medication, but to also involve a support role for patients undergoing an emotionally difficult and sensitive journey, without guaranteed success. Conclusion: This study reveals the diverse role of Australian pharmacists in ART, influenced by location, experience, and confidence. Pharmacists have an important role to play in reducing barriers to ART access by offering fertility education, addressing concerns, providing medications and counselling, and monitoring patient well-being, improving outcomes for this cohort of patients particularly in rural and remote areas

MAPping the Chiral Inversion and Structural Transformation of a Metal-Tripeptide Complex having Ni-SOD Activity

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Inorganic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ic102295s.The metal abstraction peptide (MAP) tag is a tripeptide sequence capable of abstracting a metal ion from a chelator and binding it with extremely high affinity at neutral pH. Initial studies on the nickel-bound form of the complex demonstrate that the tripeptide asparagine-cysteine-cysteine (NCC) binds metal with 2N:2S, square planar geometry and behaves as both a structural and functional mimic of Ni superoxide dismutase (Ni-SOD). Electronic absorption, circular dichroism (CD), and magnetic CD (MCD) data collected for Ni-NCC are consistent with a diamagnetic NiII center. It is apparent from the CD signal of Ni-NCC that the optical activity of the complex changes over time. Mass spectrometry data show that the mass of the complex is unchanged. Combined with the CD data, this suggests that chiral rearrangement of the complex occurs. Following incubation of the nickel-containing peptide in D2O and back-exchange into H2O, incorporation of deuterium into non-exchangeable positions is observed, indicating chiral inversion occurs at two of the alpha carbon atoms in the peptide. Control peptides were used to further characterize the chirality of the final nickel-peptide complex, and DFT calculations were performed to validate the hypothesized position of the chiral inversions. In total, these data indicate Ni-SOD activity is increased proportionally to the degree of structural change in the complex over time, as cross-correlation between the change in CD signal and change in SOD activity reveals a linear relationship

Controlling the Chiral Inversion Reaction of the Metallopeptide Ni-Asparagine-Cysteine-Cysteine with Dioxygen

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Inorganic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ic301717q.Synthetically generated metallopeptides have the potential to serve a variety of roles in biotechnology applications, but the use of such systems is often hampered by the inability to control secondary reactions. We have previously reported that the NiII complex of the tripeptide LLL-asparagine-cysteine-cysteine, LLL-NiII-NCC, undergoes metal-facilitated chiral inversion to DLD-NiII-NCC, which increases the observed superoxide scavenging activity. However, the mechanism for this process remained unexplored. Electronic absorption and circular dichroism studies of the chiral inversion reaction of NiII-NCC reveal a unique dependence on dioxygen. Specifically, in the absence of dioxygen, the chiral inversion is not observed, even at elevated pH, whereas the addition of O2 initiates this reactivity and concomitantly generates superoxide. Scavenging experiments using acetaldehyde are indicative of the formation of carbanion intermediates, demonstrating that inversion takes place by deprotonation of the alpha carbons of Asn1 and Cys3. Together, these data are consistent with the chiral inversion being dependent on the formation of a NiIII-NCC intermediate from NiII-NCC and O2. The data further suggest that the anionic thiolate and amide ligands in NiII-NCC inhibit Cα–H deprotonation for the NiII oxidation state, leading to a stable complex in the absence of O2. Together, these results offer insights into the factors controlling reactivity in synthetic metallopeptides

A novel tripeptide model of nickel superoxide dismutase

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Inorganic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ic901828m.Nickel superoxide dismutase (Ni-SOD) catalyzes the disproportionation of superoxide to molecular oxygen and hydrogen peroxide, but the overall reaction mechanism has yet to be determined. Peptide-based models of the 2N:2S nickel coordination sphere of Ni-SOD have provided some insight into the mechanism of this enzyme. Here we show that the coordination sphere of Ni-SOD can be mimicked using the tripeptide asparagine-cysteine-cysteine (NCC). NCC binds nickel with extremely high affinity at physiological pH with 2N:2S geometry, as demonstrated by electronic absorption and circular dichroism (CD) data. Like Ni-SOD, Ni-NCC has mixed amine/amide ligation that favors metal-based oxidation over ligand-based oxidation. Electronic absorption, CD, and magnetic CD data (MCD) collected for Ni-NCC are consistent with a diamagnetic Ni(II) center bound in square planar geometry. Ni-NCC is quasi-reversibly oxidized with a midpoint potential of 0.72(2) V (versus Ag/AgCl) and breaks down superoxide in an enzyme-based assay, supporting its potential use as a model for Ni-SOD chemistry

Embedding the Ni-SOD mimetic Ni-NCC within a polypeptide sequence alters specificity of the reaction pathway

This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Inorganic Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/ic301175f.The unique metal abstracting peptide (MAP) asparagine-cysteine-cysteine (NCC) binds nickel in a square planar 2N:2S geometry and acts as a mimic of the enzyme nickel superoxide dismutase (Ni-SOD). The Ni-NCC tripeptide complex undergoes rapid, site-specific chiral inversion to DLD-NCC in the presence of oxygen. Superoxide scavenging activity increases proportionally with the degree of chiral inversion. Characterization of the NCC sequence within longer peptides with absorption, circular dichroism (CD), and magnetic CD (MCD) spectroscopies and mass spectrometry (MS) shows that the geometry of metal coordination is maintained, though the electronic properties of the complex are varied to a small extent due to bis-amide, rather than amine/amide, coordination. In addition, both the Ni-tripeptides and Ni-pentapeptides have a −2 charge. The study here demonstrates that the chiral inversion chemistry does not occur when NCC is embedded in a longer polypeptide sequence. Nonetheless, the superoxide scavenging reactivity of the embedded Ni-NCC module is similar to that of the chirally inverted tripeptide complex, which is consistent with a minor change in reduction potential for the Ni-pentapeptide. Together, this suggests that the charge of the complex could affect the SOD activity as much as a change in primary coordination sphere. In Ni-NCC and other Ni-SOD mimics, changes in chirality, superoxide scavenging activity, and oxidation of the peptide itself all depend on the presence of dioxygen or its reduced derivatives (e.g., superoxide), and the extent to which each of these distinct reactions occurs is ruled by electronic and steric effects that emenate from the organization of ligands around the metal center

Social participation reduces depressive symptoms among older adults: An 18-year longitudinal analysis in Taiwan

<p>Abstract</p> <p>Background</p> <p>Relatively little empirical attention has focused on the association between social participation and depressive symptoms amongst older adults in Asian nations, where persons over the age of 65 represent a rapidly growing segment of the population. This study explores the dynamic relationship between participation in social activities and trajectories of depressive symptomatology among older Taiwanese adults surveyed over 18 years.</p> <p>Methods</p> <p>Data are from a nationally representative sample of 1,388 adults aged 60-64 first surveyed in 1989 and followed over an 18-year time period for a total of six waves. Individual involvement in social activities was categorized into continuous participation, ceased participation before age 70, initiating participation in older adulthood, never participated, and dropped out before age 70. Two domains of depressive symptoms--negative affect and lack of positive affect--were measured using a 10-item version of the Center for Epidemiologic Studies-Depression Scale.</p> <p>Results</p> <p>Analyses using growth curve modeling showed that continuously participating or initiating participation in social activities later life is significantly associated with fewer depressive symptoms among older Taiwanese adults, even after controlling for the confounding effects of aging, individual demographic differences, and health status.</p> <p>Conclusions</p> <p>These findings suggest that maintaining or initiating social participation in later life benefits the mental health of older adults. Facilitating social activities among older adults is a promising direction for programs intended to promote mental health and successful aging among older adults in Taiwan.</p

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy