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Rhodium-catalysed connective synthesis of diverse reactive probes bearing S(VI) electrophilic warheads
Get PDFFunding: We thank Redbrick Molecular, EPSRC (EP/N025652/1; EP/ W002914/1) and the Leverhulme Trust (RPG-2018-030) for funding.The value of small molecules that chemically modify proteins is increasingly being recognised and utilised in both chemical biology and drug discovery. The discovery of such chemical tools may be enabled by screening diverse sets of reactive probes. Most existing sets of reactive probes are armed with cysteine-directed warheads, a limitation that we sought to address. A connective synthesis was developed in which α-diazoamide substrates, armed with a S(VI) warhead, were reacted with diverse co-substrates. A high-throughput approach was used to identify promising substrate/co-substrate/catalyst combinations which were then prioritised for purification by mass-directed HPLC to yield a total of thirty reactive probes. The structural diversity of the probe set was increased by the multiplicity of reaction types between rhodium carbenoids and the many different co-substrate classes, and the catalyst-driven selectivity between these pathways. The probes were screened for activity against Trypanosma brucei, and four probes with promising anti-trypanosomal activity were identified. Remarkably, the synthetic approach was compatible with building blocks bearing three different S(VI) warheads, enabling the direct connective synthesis of diverse reactive probes armed with non-cysteine-directed warheads. Reactive probes that are synthetically accessible using our approach may be of value in the discovery of small molecule modifiers for investigating and engineering proteins.Peer reviewe
The Clinical Frailty Scale is a valid and independent predictor of one-year survival in patients sustaining a hip fracture : scottish Hip Fracture Audit data from 8,092 patients
Get PDFAims: Hip fracture patients have a significant mortality risk. Risk stratification tools are important in guiding management and family discussions. Aims were to assess the associations and validity of the Clinical Frailty Scale (CFS) in predicting mortality and return to original residence within 30 days using national hip fracture registry data. Methods: Routinely collected clinical registry data for all patients presenting with a hip fracture in Scotland aged 50 years and over between February 2022 and December 2023 with a completed CFS score were analyzed. The association of frailty with mortality and return to original residence was assessed using multivariable Cox regression and logistic regression analysis, respectively, adjusting for confounders to present adjusted hazard (aHRs) and odds ratios (aORs). Results: Of 15,546 patients, 8,573 had completed the CFS. Exclusion for missingness gave a final sample of 8,092. Most (71.4%) were female with a median American Society of Anesthesiologists (ASA) grade of 3 (IQR 3 to 3) and CFS of 5 (IQR 4 to 7). Vulnerable and frail patients (CFS ≥ 4) were older, more likely to be admitted from a higher care setting, and had increased mortality risk on the same admission. Higher CFS scores were associated with increased mortality risk: mildly frail (CFS 4 to 5), aHR 1.67 (95% CI 1.53 to 1.87); and frail (CFS 6 to 8), aHR 3.01 (95% CI 2.59 to 3.50). CFS and ASA grade showed similar performance in predicting one-year mortality (CFS area under curve (AUC) 0.72, 95% CI 0.71 to 0.73; ASA AUC 0.66, 95% CI 0.65 to 0.67) and return to residence (CFS AUC 0.63, 95% CI 0.62 to 0.65; ASA AUC 0.61, 95% CI 0.60 to 0.62). Conclusions: The CFS is a pragmatic and validated tool for assessing frailty, which has a strong association with mortality risk in patients with hip fractures. Its predictive accuracy supports its integration into national hip fracture registries. While its utility in predicting return to pre-injury residence is moderate, it remains a valuable component of comprehensive patient assessment.Peer reviewe
Unpacking 'irrational' behaviours : situating the antibiotic selling practices of drug sellers in East Africa
Get PDFFunding: The Holistic Approach to Unravel Antibacterial Resistance in East Africa is a Global Context Consortia Award (MR/S004785/1) funded by the National Institute for Health Research, Medical Research Council, and the Department of Health and Social Care. The award is also part of the EDCTP2 program supported by the European Union. This work is supported in part by the Makerere University-Uganda Virus Research Institute Center of Excellence for Infection and Immunity Research and Training (MUII). MUII is supported through the DELTAS Africa Initiative (grant number 107743). This paper was funded in part by a grant from a Scottish Funding Council GCRF Consolidator Award.Stewardship of antibiotic medicines will likely play a key role in curtailing the rise of antimicrobial resistance (AMR) globally. In East Africa, drug sellers are a critical group for interventions because they often dispense without prescription and violate regulations designed to facilitate antibiotic stewardship. Currently, measures to tackle regulatory avoidance are often rooted in individuated cognitive-behavioural approaches that label sellers’ actions as ‘irrational’. This study, part of a larger interdisciplinary investigation of AMR drivers in East Africa, conducted in-depth interviews [n = 105] with drug sellers in Kenya, Tanzania and Uganda to explore sellers’ accounts of their own behaviours. Its findings seem contradictory; sellers are aware of regulations and express a desire to comply, yet confirm non-compliance is common. The paper’s contribution is to demonstrate that such behaviour is ‘situationally rational’ when contextualised within a broader socio-material assemblage of unenforced regulation, fierce market competition, relational customer interactions and professional commitment to communities in resource-poor healthcare settings. The paper concludes that an understanding of the structural and relational dynamics driving current behaviours is a necessary precondition for the design of new interventions bringing professional and commercial motivations into closer alignment, something which could make antibiotic stewardship situationally rational for sellers and customers alike.Peer reviewe
Associations of estrogen with modifiable and non-modifiable risk factors for dementia : a narrative review
Get PDFFemale sex is associated with higher incidence and risk of dementia. Estrogen may represent one important mechanism contributing to the increase in incidence rates. In this review, we synthesize narratively the evidence for associations between estrogen?across the life course from menarche to menopause, estrogen-containing hormonal contraception and hormone replacement therapies, and pregnancy?with potential modifiable risk factors for dementia. These include education, hearing loss, traumatic brain injury, hypertension, alcohol use, obesity, smoking, depression, physical inactivity, diabetes, low-density lipoprotein (LDL) cholesterol, social isolation, air pollution, and untreated visual loss, as well as apolipoprotein E ε4. In addition, evidence is summarized for associations with sleep, diet, and stress. Evidence suggests that estrogen is associated with some of these modifiable risk factors for dementia, particularly LDL cholesterol, smoking, and depression. Research needs to further define these associations and understand whether interventions targeting estrogen levels at key life stages could offer intervention opportunities to reduce future risk of dementia in women.Peer reviewe
Marked length spectrum rigidity from rigidity on subsets
Get PDFWe introduce a new method for studying length spectrum rigidity problems based on a combination of ideas from dynamical systems and geometric group theory. This allows us to compare the marked length spectrum of metrics and distance-like functions coming from various geometric origins. Using our new perspective, we provide concise proofs of well-known length spectrum rigidity results and are able to extend classical results to a variety of new settings. Our methods rely on studying Manhattan curves and a coarse geometric analogue of Teichmüller space equipped with a symmetrized version of the Thurston metric.Peer reviewe
Chemical evolution history of MaNGA galaxies
Get PDFFunding: The authors are grateful for the support of CONACYT grants CB-285080 and FC-2016-01-1916, and funding from the PAPIIT-DGAPA-IN100519, PAPIIT-DGAPA-IN103820, PAPIIT-DGAPA-IG100622, PAPIIT-DGAPA-IN112620, and PAPIIT-DGAPA-IA100420 (UNAM) projects. A.C.F. acknowledges financial support by the Spanish Ministry of Science and Innovation through the research grant PID2019-107427-GB-31. G.A.B. gratefully acknowledges support by the ANID BASAL project FB210003.We show the results of a study using the spectral synthesis technique study for the full MaNGA sample showing their chemical enrichment history (ChEH) as well as the evolution of the stellar mass–metallicity relation (MZR) over cosmic time. We find that the more massive galaxies became enriched first and the lower-mass galaxies did so later, producing a change in the MZR that becomes shallower in time. Separating the sample into morphology and star-forming status bins, some particularly interesting results appear: The mass dependence of the MZR becomes less relevant for later morphological types, to the extent that it inverts for Sd/Irr galaxies, suggesting that morphology is at least as important a factor as mass in the chemical evolution. The MZR for the full sample shows a flattening at the high-mass end and another in the low-mass range, but the former only appears for retired galaxies, while the latter only appears for star-forming galaxies. We also find that the average metallicity gradient is currently negative for all mass bins, but for low-mass galaxies, it was inverted at some point in the past, before which all galaxies had a positive gradient. We also compare how diverse the ChEHs are in the different bins we considered, as well as what primarily drives the diversity: By how much galaxies become enriched, or how quickly they do so.Peer reviewe
Stepping out of the shadow? The nature and durability of new firm formation in former coalfield communities
Get PDFFunding: The authors wish to acknowledge the funding they received for the project from the ESRC grant number ES/W010259/1.One of the most contentious issues in regional development is the reasons for the persistence of spatial variations in new firm formation. Drawing on a unique dataset from the UK’s single largest entrepreneurship initiative scheme, we add to this extant literature by examining the nature of entrepreneurship in former UK coal mining communities which have been blighted by the process of industrial restructuring during the 1980s and 1990s. Our findings are simultaneously intuitive and counterintuitive: former coal mining locations have lower levels of start-ups, feature higher levels of entrants from the unemployment but are more likely to survive compared with start-ups in other locations. Additionally, we examined other associated factors potentially driving start-up rates. Here, we found that the presence of closely related industries and higher high-tech start-up rates were important in raising start-counts, but in-migration had the opposite effect. Given our reported findings around unemployment and hazard rates in the programme examined, modifications to this policy initiative seem appropriate. We conclude that the socio-economic “shadow” cast by a location’s past appears to be a deeply and temporally enduring legacy of the mining industry which fundamentally shapes future patterns of regional entrepreneurship.Peer reviewe
Good trans kids and bad trans lovers as expressions of trans misogyny in the Seven Sages/Sindbad story matter and the Roman de Silence
Get PDFThis article takes the theoretical framework of trans misogyny to two versions of the Seven Sages/Sindbad story matter – the Hebrew Mishle Sendebar and the Latin Historia septem sapientum– as well as to the French Seven Sages continuation Marques de Rome and to the Roman de Silence. These texts, which were all produced in the North-East of French-speaking lands between c. 1175 and 1350, contain two strikingly consistent character types: the trans lover and the trans kid. In this article, we suggest that violent trans misogynistic force is brought to bear on the figure of the trans lover, whose body is figured as a site of guilt. The trans kids, on the other hand, who are often but not exclusively trans masculine characters, evade lethal forms of punishment, and are typically infantilised in these same texts. These contrasting depictions are not only related to one another but also reinforce wider systems of misogyny.Peer reviewe
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