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A new iron-based T sub(1) contrast agent consisting of a complex of iron ions coordinated to phosphate and amine ligands (Fe sub((phos)) in short) has been characterized by spectroscopic and magnetic measurements. NMR relaxation studies showed r sub(1) values to be dependent on the phosphate salt concentration, K sub(2)HPO sub(4), present in the medium, r sub(1) reaches a maximum value of 2.5 mM super(-1) s super(-1) for measurements carried out at 7 T and 298 K. super(31)P MRS, Moessbauer spectroscopy and magnetic measurements of Fe sub((phos)) solutions suggest paramagnetic Fe super(3+) ions present in the studied iron-phosphate complex. In vitro and in vivo toxicity experiments with C6 cells and CD1 mice, respectively, demonstrated lack of toxicity for Fe sub((phos)) at the highest dose tested in the MRI experiments (12 mM iron for C6 cells and 0.32 mmol iron/kg for mice). Finally, T sub(1) weighted images of brain tumours in mice have shown positive contrast enhancement of Fe sub((phos)) for tumour afflicted regions in the brain.

Oxazocines are key structural intermediates in the synthesis of natural products and pharmaceutical molecules. However, the synthesis of oxazocines especially in a highly enantioselective manner, is a long‐standing formidable challenge due to unfavorable energetics involved in cyclization. Herein, a series of new PNP‐Ligand P‐chiral stereocenter is first designed and synthesized, called MQ‐Phos, and successfully applied it in the Pd‐catalyzed enantioselective higher‐order formal [4+4]‐cycloaddition of α, β‐unsaturated imines with 2‐(hydroxymethyl)‐1‐arylallyl carbonates. The reaction features mild conditions, excellent regio‐ and enantiocontrol and a broad substrate scope (54 examples). Various medium‐sized rings can be afforded in moderate to excellent yields (up to 92%) and excellent enantioselectivity (up to 99% ee). The newly developed MQ‐Phos is critical for synthesis of the medium‐sized ring in excellent catalytic reactivity and enantioselectivity. A series of new PNP‐Ligands P‐chiral stereocenter, called MQ‐Phos, are designed and successfully applied it in the Pd‐catalyzed enantioselective higher‐order formal [4+4]‐cycloaddition of α, β‐unsaturated imines with 2‐(hydroxymethyl)‐1‐arylallyl carbonates.

Phosphorus in the form of phosphate (Pi) is an essential element for metabolic processes, including lipid metabolism. In yeast, the inositol polyphosphate kinase vip1 mediated synthesis of inositol heptakisphosphate (IP7) regulates the phosphate-responsive (PHO) signaling pathway, which plays an important role in response to Pi stress. The role of vip1 in Pi stress and lipid metabolism of Candida albicans has not yet been studied. We found that when vip1Δ/Δ was grown in glucose medium, if Pi was supplemented in the medium or mitochondrial Pi transporter was overexpressed in the strain, the lipid droplet (LD) content was reduced and membrane damage was alleviated. However, further studies showed that neither the addition of Pi nor the overexpression of the Pi transporter affected the energy balance of vip1Δ/Δ. In addition, the LD content of vip1Δ/Δ grown in Pi limitation medium PNMC was lower than that grown in SC, and the metabolic activity of vip1Δ/Δ grown in PNMC was also lower than that grown in SC medium. This suggests that the increase in Pi demand by a high energy metabolic rate is the cause of LD accumulation in vip1Δ/Δ. In addition, in the vip1Δ/Δ strains, the core transcription factor PHO4 in the PHO pathway was transported to the vacuole and degraded, which reduced the pathway activity. However, this does not mean that knocking out vip1 completely blocks the activation of the PHO pathway, because the LD content of vip1Δ/Δ grown in the medium with β-glycerol phosphate as the Pi source was significantly reduced. In summary, the increased Pi demand and the decreased PHO pathway activity in vip1Δ/Δ ultimately lead to LD accumulation and cell membrane damage.

Vertical integration in health care has recently garnered scrutiny by antitrust authorities and state regulators. We examined trends, geographic variation, and price effects of vertical integration and joint contracting between physicians and hospitals, using physician affiliations and all-payer claims data from Massachusetts from the period 2013-17. Vertical integration and joint contracting with small and medium health systems rose from 19.5 percent in 2013 to 32.8 percent in 2017 for primary care physicians and from 26.1 percent to 37.8 percent for specialists. Vertical integration and joint contracting with large health systems slightly declined, whereas geographic variation in these physician affiliations rose. We found that vertical integration and joint contracting led to price increases from 2013 to 2017, from 2.1 percent to 12.0 percent for primary care physicians and from 0.7 percent to 6.0 percent for specialists, with the greatest increases seen in large health systems. These findings can inform policy makers seeking to limit growth in health care prices.

In Aotearoa New Zealand, being enrolled with a Primary Health Care (PHC) provider furnishes opportunities for lower cost access to PHC, preventative care and secondary health care services, and provides better continuity of care. We examine the characteristics of populations not enrolled, and whether enrolment is associated with amenable mortality. We retrieved records of all deaths registered 2008 to 2017 in Aotearoa New Zealand, which included demographic and primary cause of death information. Deaths were classified as premature (aged under 75 years) or not, and amenable to health care intervention or not. The Primary Health Organisation (PHO) Enrolment Collection dataset provided the PHC enrolment status. Logistic regression was used to estimate the risk of amenable deaths by PHO enrolment status, adjusted for the effects of age, sex, ethnicity and deprivation. A total of 308,628 mortality records were available. Of these, 38.2% were premature deaths, and among them 47.8% were amenable deaths. Cardiovascular diseases made up almost half of the amenable deaths. Males, youths aged 15-24 years, Pacific peoples, Māori and those living in the most socio-economically deprived areas demonstrated a higher risk of amenable mortality compared to their respective reference category. One in twenty (4.3%) people who had died had no active enrolment status in any of the calendar years in the study. The adjusted odds of amenable mortality among those not enrolled in a PHO was 39% higher than those enrolled [Odds Ratio = 1.39, 95% Confidence Interval 1.30-1.47]. Being enrolled in a PHC system is associated with a lower level of amenable mortality. Given demonstrated inequities in enrolment levels across age and ethnic groups, efforts to improve this could have significant benefits on health equity.

The Mitogen-Activated Protein Kinase (MAPK) Slt2 is central to signaling through the yeast Cell Wall Integrity (CWI) pathway. MAPKs are regulated by phosphorylation at both the threonine and tyrosine of the conserved TXY motif within the activation loop (T190/Y192 in Slt2). Since phosphorylation at both sites results in the full activation of MAPKs, signaling through MAPK pathways is monitored with antibodies that detect dually phosphorylated forms. However, most of these antibodies also recognize monophosphorylated species, whose relative abundance and functionality are diverse. By using different phosphospecific antibodies and phosphate-affinity (Phos-tag) analysis on distinct Slt2 mutants, we determined that Y192- and T190-monophosphorylated species coexist with biphosphorylated Slt2, although most of the Slt2 pool remains unphosphorylated following stress. Among the monophosphorylated forms, only T190 exhibited biological activity. Upon stimulation, Slt2 is first phosphorylated at Y192, mainly by the MAPKK Mkk1, and this phosphorylation is important for the subsequent T190 phosphorylation. Similarly, dephosphorylation of Slt2 by the Dual Specificity Phosphatase (DSP) Msg5 is ordered, with dephosphorylation of T190 depending on previous Y192 dephosphorylation. Whereas Y192 phosphorylation enhances the Slt2 catalytic activity, T190 is essential for this activity. The conserved T195 residue is also critical for Slt2 functionality. Mutations that abolish the activity of Slt2 result in a high increase in inactive Y192-monophosphorylated Slt2. The coexistence of different Slt2 phosphoforms with diverse biological significance highlights the importance of the precise detection of the Slt2 phosphorylation status.

Tau is a microtubule-associated protein which regulates the assembly and stability of microtubules in the axons of neurons. Tau is also a major component of neurofibrillary tangles (NFTs), a pathological hallmark in Alzheimer's disease (AD). A characteristic of AD tau is hyperphosphorylation with more than 40 phosphorylation sites. Aggregates of hyperphosphorylated tau are also found in other neurodegenerative diseases which are collectively called tauopathies. Although a large number of studies have been performed on the phosphorylation of AD tau, it is not known if there is disease-specific phosphorylation among tauopathies. This is due to the lack of a proper method for analyzing tau phosphorylation . Most previous phosphorylation studies were conducted using a range of phosphorylation site-specific antibodies. These studies describe relative changes of different phosphorylation sites, however, it is hard to estimate total, absolute and collective changes in phosphorylation. To overcome these problems, we have recently applied the Phos-Tag technique to the analysis of tau phosphorylation and . This method separates tau into many bands during SDS-PAGE depending on its phosphorylation states, creating a bar code appearance. We propose calling this banding pattern of tau the \"phospho-tau bar code.\" In this review article, we describe what is newly discovered regarding tau phosphorylation through the use of the Phos-Tag. We would like to propose its use for the postmortem diagnosis of tauopathy which is presently done by immunostaining diseased brains with anti-phospho-antibodies. While Phos-tag SDS-PAGE, like other biochemical assays, will lose morphological information, it could provide other types of valuable information such as disease-specific phosphorylation.

Background Despite three decades of policy initiatives to improve integration of health care, delivery of health care in New Zealand remains fragmented, and health inequities persist for Māori and other high priority populations. An evidence base is needed to increase the chances of success with implementation of large-system transformation (LST) initiatives in a complex adaptive system. Methods This research aimed to identify key elements that support implementation of LST initiatives, and to investigate contextual factors that influence these initiatives. The realist logic of enquiry, nested within the macro framing of complex adaptive systems, formed the overall methodology for this research and involved five phases: theory gleaning from a local LST initiative, literature review, interviews, workshop, and online survey. NVivo software programme was used for thematic analysis of the interview, workshop, and the survey data. We identified key elements and explained variations in success (outcomes) by identifying mechanisms triggered by various contexts in which LST initiatives are implemented. Results The research found that a set of 10 key elements need to be present in the New Zealand health system to increase chances of success with implementation of LST initiatives. These are: (i) an alliancing way of working; (ii) a commitment to te Tiriti o Waitangi; (iii) an understanding of equity; (iv) clinical leadership and involvement; (v) involved people, whānau, and community; (vi) intelligent commissioning; (vii) continuous improvement; (viii) integrated health information; (ix) analytic capability; and (x) dedicated resources and time. The research identified five contextual factors that influenced implementation of LST initiatives: a history of working together, distributed leadership from funders, the maturity of Alliances, capacity and capability for improvement, and a continuous improvement culture. The research found that the key mechanism of trust is built and nurtured over time through sharing of power by senior health leaders by practising distributed leadership, which then creates a positive history of working together and increases the maturity of Alliances. Discussion Two authors (KMS and PBJ) led the development and implementation of the local LST initiative. This prior knowledge and experience provided a unique perspective to the research but also created a conflict of interest and introduced potential bias, these were managed through a wide range of data collection methods and informed consent from participants. The evidence-base for successful implementation of LST initiatives produced in this research contains knowledge and experience of senior system leaders who are often in charge of leading these initiatives. This evidence base enables decision makers to make sense of complex processes involved in the successful implementation of LST initiatives. Conclusions Use of informal trust-based networks provided a critical platform for successful implementation of LST initiatives in the New Zealand health system. Maturity of these networks relies on building and sustaining high-trust relationships among the network members. The role of local and central agencies and the government is to provide the policy settings and conditions in which trust-based networks can flourish. Other This study was approved by the Victoria University of Wellington Human Ethics Committee (Ethics Approval Number 27,356). The research was supported by the Victoria University of Wellington research grant (222,809) and from the University of Auckland Department of Medicine research fund (H10779).

Biosensors show promising prospects in the assays of various targets due to their advantages of high sensitivity, good selectivity and rapid response. Molecular recognition is a key event of biosensors, which usually involves the interaction of antigen–antibody, aptamer–target, lectin–sugar, boronic acid–diol, metal chelation and DNA hybridization. Metal ions or complexes can specifically recognize phosphate groups in peptides or proteins, obviating the use of biorecognition elements. In this review, we summarized the design and applications of biosensors with metal ion–phosphate chelation interaction for molecular recognition. The sensing techniques include electrochemistry, fluorescence, colorimetry and so on.

Starting from the universal concept of entropy production, a large number of new results are obtained and a wealth of novel thermodynamic, kinetic, and molecular mechanistic insights are provided into the coupling of oxidation and ATP synthesis in the vital process of oxidative phosphorylation (OX PHOS). The total dissipation, Φ , in OX PHOS with succinate as respiratory substrate is quantified from measurements, and the partitioning of Φ into the elementary components of ATP synthesis, leak, slip, and other losses is evaluated for the first time. The thermodynamic efficiency, η , of the coupled process is calculated from the data on Φ and shown to agree well with linear nonequilibrium thermodynamic calculations. Equations for the P/O ratio based on total oxygen consumed and extra oxygen consumed are derived from first principles and the source of basal (state 4) mitochondrial respiration is postulated from molecular mechanistic considerations based on Nath’s two-ion theory of energy coupling within the torsional mechanism of energy transduction and ATP synthesis. The degree of coupling, q , between oxidation and ATP synthesis is determined from the experimental data and the irreversible thermodynamics analysis. The optimality of biological free energy converters is explored in considerable detail based on (i) the standard biothermodynamic approach, and (ii) a new biothermokinetic approach developed in this work, and an effective solution that is shown to arise from consideration of the molecular aspects in Nath’s theory is formulated. New experimental data in state 4 with uncouplers and redox inhibitors of OX PHOS and on respiratory control in the physiological state 3 with ADP and uncouplers are presented. These experimental observations are shown to be incompatible with Mitchell’s chemiosmotic theory. A novel scheme of coupling based on Nath’s two-ion theory of energy coupling within the torsional mechanism is proposed and shown to explain the data and also pass the test of consistency with the thermodynamics, taking us beyond the chemiosmotic theory. It is concluded that, twenty years since its first proposal, Nath’s torsional mechanism of energy transduction and ATP synthesis is now well poised to catalyze the progress of experimental and theoretical research in this interdisciplinary field.