Enantiopure planar chiral and chiral-at-metal iridacycles derived from bulky cobalt sandwich complexes

Reaction of (η5-(S)-2-(4-methylethyl)oxazolinylcyclopentadienyl)(η4-tetraphenylcyclobutadiene)cobalt with [IrCp*Cl2]2 in acetonitrile with KPF6 and KOt-Bu resulted in S,Sp,SIr and S,Rp,RIr configured acetonitrile and Cp* coordinated cationic iridacycles (d.r. up to 4.8 : 1 – kinetic control), the planar chiral configuration dictating the configuration of the pseudo-tetrahedral iridium-based stereogenic centre. Addition of water to the cycloiridation reaction resulted in an increase in yield (up to 78%) at the cost of diastereoselectivity. Use of the corresponding substrate containing a t-Bu rather than an i-Pr substituted oxazoline gave exclusively the S,Sp,SIr diastereoisomer, and under the same conditions (S)-2-ferrocenyl- 4-(1,1-dimethylethyl)oxazoline cycloiridated to give only the S,Sp,SIr diastereoisomer. Substitution reactions of the title complexes at iridium proceeded with retention of configuration, a computational study revealing the proposed coordinatively unsaturated intermediate of a dissociative mechanism to display a relatively weak Co-Ir interaction, and a pronounced steric effect as the basis of stereocontrol

Where do you stand?: An exploration of perspectives toward feet, foot health, and footwear using innovative digital methods

Background: The cost of losing foot health is significant to the person, healthcare systems, and economy, with diabetes related foot health issues alone costing over £1 billion annually in the UK. Yet many foot health problems are preventable through alternative health behaviour. It is therefore important to understand how feet, foot health and footwear are conceptualised to gain understanding about how these might influence foot health behaviour and inform health messages that seek to protect or improve foot health through altered health behaviour. This research seeks to explore attitudes and beliefs and identify phenomena that may act as barriers or motivators to the proactive self-management of foot health, Methods Public conversations involving 2,699 expressions related to feet, footwear or foot health on Facebook, Twitter, and Instagram were extracted. Conversations on Facebook and Twitter were scraped with NVivo’s NCapture plugin whereby data is extracted and downloaded to NVivo. Extracted files were uploaded to the Big Content Machine (software developed at the University of Salford) which facilitated the search for keywords ‘foot’, ‘feet’, ‘footwear’, ‘shoe’, and ‘shoes’. Instagram was scraped by hand. Data was analysed using a Thematic Analysis approach. Results Three themes were identified; 1) connections and disconnections derived from social and cultural constructs, 2) phenomena beyond attitudes and beliefs that relate to symbolic representations and the impact when foot health is lost, and 3) phenomena relating to SoMe as a conduit for the exploration of attitudes and beliefs. Conclusions This novel research exemplifies complex and sometimes incongruous perspectives about feet including their value for what they facilitate, contrasted with negative feelings about the negative impact that can have aesthetically when feet work hard. Sometimes feet were devalued, with expressions of disgust, disconnection, and ridicule. The importance of contextual, social, and cultural phenomena with implications for optimising foot health messages. Knowledge gaps including factors related to children’s foot health and development, and how to treat foot health problems. The power of communities with shared experience to influence decisions, theories, and behaviour about foot health was also revealed. While people do talk about feet in some social contexts, it is not always in a way that promotes overt, positive foot health behaviour. Finally, this research demonstrates the benefit of exploring perspectives in uncontrived settings and illuminates the potential utility of SoMe as a vehicle to promote foot health self-management behaviour that is responsive to the social and demographic variances of engagers who inhabit those spaces

Proteomic Analysis of GLUT4 Storage Vesicles Reveals Tumor Suppressor Candidate 5 (TUSC5) as a Novel Regulator of Insulin Action in Adipocytes.

Insulin signaling augments glucose transport by regulating glucose transporter 4 (GLUT4) trafficking from specialized intracellular compartments, termed GLUT4 storage vesicles (GSVs), to the plasma membrane. Proteomic analysis of GSVs by mass spectrometry revealed enrichment of 59 proteins in these vesicles. We measured reduced abundance of 23 of these proteins following insulin stimulation and assigned these as high confidence GSV proteins. These included established GSV proteins such as GLUT4 and insulin-responsive aminopeptidase, as well as six proteins not previously reported to be localized to GSVs. Tumor suppressor candidate 5 (TUSC5) was shown to be a novel GSV protein that underwent a 3.7-fold increase in abundance at the plasma membrane in response to insulin. siRNA-mediated knockdown of TUSC5 decreased insulin-stimulated glucose uptake, although overexpression of TUSC5 had the opposite effect, implicating TUSC5 as a positive regulator of insulin-stimulated glucose transport in adipocytes. Incubation of adipocytes with TNFα caused insulin resistance and a concomitant reduction in TUSC5. Consistent with previous studies, peroxisome proliferator-activated receptor (PPAR) γ agonism reversed TNFα-induced insulin resistance. TUSC5 expression was necessary but insufficient for PPARγ-mediated reversal of insulin resistance. These findings functionally link TUSC5 to GLUT4 trafficking, insulin action, insulin resistance, and PPARγ action in the adipocyte. Further studies are required to establish the exact role of TUSC5 in adipocytes

Nitrosylation of Nitric-Oxide-Sensing Regulatory Proteins Containing [4Fe-4S] Clusters Gives Rise to Multiple Iron-Nitrosyl Complexes

The reaction of protein-bound iron–sulfur (Fe-S) clusters with nitric oxide (NO) plays key roles in NO-mediated toxicity and signaling. Elucidation of the mechanism of the reaction of NO with DNA regulatory proteins that contain Fe-S clusters has been hampered by a lack of information about the nature of the iron-nitrosyl products formed. Herein, we report nuclear resonance vibrational spectroscopy (NRVS) and density functional theory (DFT) calculations that identify NO reaction products in WhiD and NsrR, regulatory proteins that use a [4Fe-4S] cluster to sense NO. This work reveals that nitrosylation yields multiple products structurally related to Roussin's Red Ester (RRE, [Fe2(NO)4(Cys)2]) and Roussin's Black Salt (RBS, [Fe4(NO)7S3]. In the latter case, the absence of 32S/34S shifts in the Fe−S region of the NRVS spectra suggest that a new species, Roussin's Black Ester (RBE), may be formed, in which one or more of the sulfide ligands is replaced by Cys thiolates

Integrating ecosystem markets to co-ordinate landscape-scale public benefits from nature

Ecosystem markets are proliferating around the world in response to increasing demand for climate change mitigation and provision of other public goods. However, this may lead to perverse outcomes, for example where public funding crowds out private investment or different schemes create trade-offs between the ecosystem services they each target. The integration of ecosystem markets could address some of these issues but to date there have been few attempts to do this, and there is limited understanding of either the opportunities or barriers to such integration. This paper reports on a comparative analysis of eleven ecosystem markets in operation or close to market in Europe, based on qualitative analysis of 25 interviews, scheme documentation and two focus groups. Our results indicate three distinct types of markets operating from the regional to national scale, with different modes of operation, funding and outcomes: regional ecosystem markets, national carbon markets and green finance. The typology provides new insights into the operation of ecosystem markets in practice, which may challenge traditionally held notions of Payment for Ecosystem Services. Regional ecosystem markets, in particular, represent a departure from traditional models, by using a risk-based funding model and aggregating both supply and demand to overcome issues of free-riding, ecosystem service trade-offs and land manager engagement. Central to all types of market were trusted intermediaries, brokers and platforms to aggregate supply and demand, build trust and lower transaction costs. The paper outlines six options for blending public and private funding for the provision of ecosystem services and proposes a framework for integrating national carbon markets and green finance with regional ecosystem markets. Such integration may significantly increase funding for regenerative agriculture and conservation across multiple habitats and services, whilst addressing issues of additionality and ecosystem service trade-offs between multiple schemes

A Risk Assessment Tool for Predicting Fragility Fractures and Mortality in the Elderly

Existing fracture risk assessment tools are not designed to predict fracture-associated consequences, possibly contributing to the current undermanagement of fragility fractures worldwide. We aimed to develop a risk assessment tool for predicting the conceptual risk of fragility fractures and its consequences. The study involved 8965 people aged >= 60 years from the Dubbo Osteoporosis Epidemiology Study and the Canadian Multicentre Osteoporosis Study. Incident fracture was identified from X-ray reports and questionnaires, and death was ascertained though contact with a family member or obituary review. We used a multistate model to quantify the effects of the predictors on the transition risks to an initial and subsequent incident fracture and mortality, accounting for their complex interrelationships, confounding effects, and death as a competing risk. There were 2364 initial fractures, 755 subsequent fractures, and 3300 deaths during a median follow-up of 13 years (interquartile range [IQR] 7-15). The prediction model included sex, age, bone mineral density, history of falls within 12 previous months, prior fracture after the age of 50 years, cardiovascular diseases, diabetes mellitus, chronic pulmonary diseases, hypertension, and cancer. The model accurately predicted fragility fractures up to 11 years of follow-up and post-fracture mortality up to 9 years, ranging from 7 years after hip fractures to 15 years after non-hip fractures. For example, a 70-year-old woman with aT-score of -1.5 and without other risk factors would have 10% chance of sustaining a fracture and an 8% risk of dying in 5 years. However, after an initial fracture, her risk of sustaining another fracture or dying doubles to 33%, ranging from 26% after a distal to 42% post hip fracture. A robust statistical technique was used to develop a prediction model for individualization of progression to fracture and its consequences, facilitating informed decision making about risk and thus treatment for individuals with different risk profiles. (c) 2020 American Society for Bone and Mineral Research

Reduced bone loss is associated with reduced mortality risk in subjects exposed to nitrogen bisphosphonates: A mediation analysis

Bisphosphonates, potent anti-resorptive agents, have been found to be associated with mortality reduction. Accelerated bone loss is, in itself, an independent predictor of mortality risk, but the relationship between bisphosphonates, bone loss, and mortality is unknown. This study aimed to determine whether the association between bisphosphonates and mortality is mediated by a reduction in the rate of bone loss. Participants from the population‐based Canadian Multicentre Osteoporosis Study were followed prospectively between1996 and 2011. Comorbidities and lifestyle factors were collected at baseline and bone mineral density (BMD) at baseline and at years 3 (for those aged 40 to 60 years), 5, and 10. Rate of bone loss was calculated using linear regression. Information on medication use was obtained yearly. Bisphosphonate users grouped into nitrogen bisphosphonates (nBP; alendronate or risedronate) and etidronate and non‐users (NoRx) were matched by propensity score, including all baseline factors as well as time of treatment. Cox’s proportional hazards models, unadjusted and adjusted for annual rate of bone loss, were used to determine the association between nBP and etidronate versus NoRx. For the treatment groups with significant mortality risk reduction, the percent of mortality reduction mediated by a reduction in the rate of bone loss was estimated using a causal mediation analysis. There were 271 pairs of nBP and matched NoRx and 327 pairs of etidronate and matched NoRx. nBP but not etidronate use was associated with significant mortality risk reduction (hazard ratios [HR]=0.61 [95% confidenceinterval0.39–0.96]and1.35[95%CI0.86–2.11] for nBP and etidronate, respectively). Rapid bone loss was associated with more than2‐fold increased mortality risk compared with no loss. Mediation analysis indicated that39% (95%CI7%–84%) of the nBP association with mortality was related to a reduction in the rate of bone loss. This finding provides an insight into the mechanism of the relationship between nBP and survival benefit in osteoporotic patients

Cobalt-based molecular electrocatalysis of nitrile reduction: evolving sustainability beyond hydrogen

Two new cobalt bis-iminopyridines, [Co(DDP)(H2O)2](NO3)2 (1, DDP = cis-[1,3-bis(2-pyridinylenamine)] cyclohexane) and [Co(cis-DDOP)(NO3)](NO3) (2, cis-DDOP = cis-3,5-bis[(2- Pyridinyleneamin]-trans-hydroxycyclohexane) electrocatalyse the 4-proton, 4-electron reduction of acetonitrile to ethylamine. For 1, this reduction occurs in preference to reduction of protons to H2. A coordinating hydroxyl proton relay in 2 reduces the yield of ethylamine and biases the catalytic system back towards H2

Universality of clone dynamics during tissue development.

The emergence of complex organs is driven by the coordinated proliferation, migration and differentiation of precursor cells. The fate behaviour of these cells is reflected in the time evolution their progeny, termed clones, which serve as a key experimental observable. In adult tissues, where cell dynamics is constrained by the condition of homeostasis, clonal tracing studies based on transgenic animal models have advanced our understanding of cell fate behaviour and its dysregulation in disease (1, 2). But what can be learned from clonal dynamics in development, where the spatial cohesiveness of clones is impaired by tissue deformations during tissue growth? Drawing on the results of clonal tracing studies, we show that, despite the complexity of organ development, clonal dynamics may converge to a critical state characterized by universal scaling behaviour of clone sizes. By mapping clonal dynamics onto a generalization of the classical theory of aerosols, we elucidate the origin and range of scaling behaviours and show how the identification of universal scaling dependences may allow lineage-specific information to be distilled from experiments. Our study shows the emergence of core concepts of statistical physics in an unexpected context, identifying cellular systems as a laboratory to study non-equilibrium statistical physics.Wellcome Trus

UK vaccines network:Mapping priority pathogens of epidemic potential and vaccine pipeline developments

During the 2013–2016 Ebola outbreak in West Africa an expert panel was established on the instructions of the UK Prime Minister to identify priority pathogens for outbreak diseases that had the potential to cause future epidemics. A total of 13 priority pathogens were identified, which led to the prioritisation of spending in emerging diseases vaccine research and development from the UK. This meeting report summarises the process used to develop the UK pathogen priority list, compares it to lists generated by other organisations (World Health Organisation, National Institutes of Allergy and Infectious Diseases) and summarises clinical progress towards the development of vaccines against priority diseases. There is clear technical progress towards the development of vaccines. However, the availability of these vaccines will be dependent on sustained funding for clinical trials and the preparation of clinically acceptable manufactured material during inter-epidemic periods