The metal borides, Hf
MOs
B
(M = Mn, Fe, Co), which are the first Os-rich quaternary variants of the prolific Ti
Co
B
structure type, were investigated computationally and experimentally. In their ...crystal structures, osmium builds a network of prisms, in which the other elements are located. The magnetic M elements are found in face-connected Os
square prisms leading to M-chains with intra- and interchain distances of about 3.0 and 6.5 Å, respectively. Density functional theory (DFT) showed that magnetic ordering is hugely favored for M = Mn and Fe but only slightly favored for M = Co. Experimental investigations then confirmed and extended the DFT predictions as a metamagnetic behavior was found for the M = Mn and Fe phases, whereby the antiferromagnetic interactions (
= 19 and 90 K) found at low magnetic fields change to ferromagnetic at higher fields. A very broad transition (
= 45 K) is found for M = Co, suggesting spin-glass behavior for this phase. For M = Fe, a hard-magnet hysteresis at 5 K is found with a 40 kA/m coercivity, and even at room temperature, a significant hysteresis is found. This study paves the way for the discovery of Os-based magnets in this structure type and other intermetallics.
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IJS, KILJ, NUK, PNG, UL, UM
Heat shock protein 27 (Hsp27) is a molecular chaperone highly expressed in aggressive cancers, where it is involved in numerous pro-tumorigenic signaling pathways. Using functional genomics we ...identified for the first time that Hsp27 regulates the gene signature of transcriptional co-activators YAP and TAZ, which are negatively regulated by the Hippo Tumor Suppressor pathway. The Hippo pathway inactivates YAP by phosphorylating and increasing its cytoplasmic retention with the 14.3.3 proteins. Gain and loss of function experiments in prostate, breast and lung cancer cells showed that Hsp27 knockdown induced YAP phosphorylation and cytoplasmic localization while overexpression of Hsp27 displayed opposite results. Mechanistically, Hsp27 regulates the Hippo pathway by accelerating the proteasomal degradation of ubiquitinated MST1, the core Hippo kinase, resulting in reduced phosphorylation/activity of LATS1 and MOB1, its downstream effectors. Importantly, our in vitro results were supported by data from human tumors; clinically, high expression of Hsp27 in prostate tumors is correlated with increased expression of YAP gene signature and reduced phosphorylation of YAP in lung and invasive breast cancer clinical samples. This study reveals for the first time a link between Hsp27 and the Hippo cascade, providing a novel mechanism of deregulation of this tumor suppressor pathway across multiple cancers.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
Cluster headache is the most severe primary headache disorder. A genetic basis has long been suggested by family and twin studies; however, little is understood about the genetic variants ...that contribute to cluster headache susceptibility.
Methods
We conducted a literature search of the MEDLINE database using the PubMed search engine to identify all human genetic studies for cluster headache. In this article we provide a review of those genetic studies, along with an overview of the pathophysiology of cluster headache and a brief review of migraine genetics, which have both been significant drivers of cluster headache candidate gene selection.
Results
The investigation of cluster headache genetic etiology has been dominated by candidate gene studies. Candidate selection has largely been driven by the pathophysiology, such as the striking rhythmic nature of the attacks, which spurred close examination of the circadian rhythm genes CLOCK and HCRTR2. More recently, unbiased genetic approaches such as genome-wide association studies (GWAS) have yielded new genetic avenues of interest including ADCYAP1R1 and MME.
Conclusions
The majority of candidate genes studied for cluster headache suffer from poor reproducibility. Broader genetic interrogation through larger unbiased GWAS, exome, and whole genome studies may provide more robust candidates, and in turn provide a clearer understanding of the causes of cluster headache.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Developmental maturity (e.g. body condition, body mass) at major life‐history transitions is known to affect fitness across a wide range of taxa.
Fledging (leaving the nest), a major ...life‐history transition in birds, is associated with high post‐fledging mortality and is widely assumed to be related to poor initial flight ability of fledglings, which, in turn, might be related to developmental maturity at fledging.
We investigated individual variation in developmental maturity of both somatic and physiological traits at this critical life‐history transition in different ecological contexts (year, first or second broods) to determine the importance of physiological traits related to oxygen‐carrying capacity (haematocrit, haemoglobin) for individual variation in initial flight ability at fledging.
Haemoglobin concentration and haematocrit at fledging had much higher variance than somatic traits and were more variable across ecological contexts. Furthermore, fledgling haemoglobin concentration was the least developmentally mature of all traits (on average, only 78% of adult concentration).
Fledglings from second broods, which are known to have lower post‐fledging survival, were less developmentally mature than fledglings from first broods for all traits (except tarsus), with haematocrit and haemoglobin concentration being the most developmentally immature traits (in first vs. second broods, haematocrit: 47·1% vs. 40·9%; haemoglobin: 13·3 vs. 11·6 g dL−1).
Models predicting individual variation in two aspects of initial flight ability (total energy gain, take‐off angle) were significantly improved when physiological traits (in particular haemoglobin) were incorporated into models based on somatic traits.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK
The metal borides, Hf2MOs5B2 (M = Mn, Fe, Co), which are the first Os-rich quaternary variants of the prolific Ti3Co5B2 structure type, were investigated computationally and experimentally. In their ...crystal structures, osmium builds a network of prisms, in which the other elements are located. The magnetic M elements are found in face-connected Os8 square prisms leading to M-chains with intra- and interchain distances of about 3.0 and 6.5 Å, respectively. Density functional theory (DFT) showed that magnetic ordering is hugely favored for M = Mn and Fe but only slightly favored for M = Co. Experimental investigations then confirmed and extended the DFT predictions as a metamagnetic behavior was found for the M = Mn and Fe phases, whereby the antiferromagnetic interactions (T N = 19 and 90 K) found at low magnetic fields change to ferromagnetic at higher fields. A very broad transition (T N = 45 K) is found for M = Co, suggesting spin-glass behavior for this phase. For M = Fe, a hard-magnet hysteresis at 5 K is found with a 40 kA/m coercivity, and even at room temperature, a significant hysteresis is found. This study paves the way for the discovery of Os-based magnets in this structure type and other intermetallics.
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IJS, KILJ, NUK, PNG, UL, UM
DNA methylation and Polycomb are key factors in the establishment of vertebrate cellular identity and fate. Here we report de novo missense mutations in DNMT3A, which encodes the DNA ...methyltransferase DNMT3A. These mutations cause microcephalic dwarfism, a hypocellular disorder of extreme global growth failure. Substitutions in the PWWP domain abrogate binding to the histone modifications H3K36me2 and H3K36me3, and alter DNA methylation in patient cells. Polycomb-associated DNA methylation valleys, hypomethylated domains encompassing developmental genes, become methylated with concomitant depletion of H3K27me3 and H3K4me3 bivalent marks. Such de novo DNA methylation occurs during differentiation of Dnmt3a
pluripotent cells in vitro, and is also evident in Dnmt3a
dwarf mice. We therefore propose that the interaction of the DNMT3A PWWP domain with H3K36me2 and H3K36me3 normally limits DNA methylation of Polycomb-marked regions. Our findings implicate the interplay between DNA methylation and Polycomb at key developmental regulators as a determinant of organism size in mammals.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
COVID-19 public health restrictions, such as social distancing and self-isolation, have been particularly challenging for vulnerable people with health conditions and/or complex social needs. Link ...worker social prescribing is widespread in the UK and elsewhere and is regarded as having the potential to provide support to vulnerable people during the pandemic. This qualitative study explores accounts of how an existing social prescribing service adapted to meet clients' needs in the first wave of the pandemic, and of how clients experienced these changes.
Data were collected in a deprived urban area of North East England via remote interviews with clients (n = 44), link workers (n = 5) and service provider managerial staff (n = 8) from May-September 2020. Thematic data analysis was conducted.
The research found that service providers quickly adapted to remote intervention delivery aiming to serve existing clients and other vulnerable groups. Service providers experienced improved access to some existing clients via telephone in the first months of remote delivery and in some cases were able to engage clients who had previously not attended appointments at GP surgeries. However, link workers also experienced challenges in building rapport with clients, engaging clients with the aims of the intervention and providing a service to digitally excluded people. Limited link worker capacity meant clients experienced variable contact with link workers with only some experiencing consistent support that was highly valued for helping to manage their conditions and mental wellbeing. Limited access to linked services also adversely affected clients. Clients living in less affluent circumstances and/or with worse health were more likely to experience negative impacts on their long-term condition. Some found their health and progress with social prescribing was 'on hold' or 'going backwards', which sometimes negatively affected their health.
Social prescribing offered valued support to some during the pandemic, but remote support sometimes had limited impact for clients and findings highlight the vulnerability of social prescribing's success when linked services are disrupted. Findings also show the need for more to be done in the upscaling of social prescribing to provide support to digitally excluded populations.
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CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Most people want to remain at home as they age. Ageing in place - remaining at home and connected to the community - is a national and international policy priority; however, to better ...understand how policy might be implemented, a more nuanced understanding is required about older adults' lived experiences of ageing in place, especially the experiences of those aged 80 and above. Objective To describe and explore the social processes which enable ageing in place from the perspective of community-dwelling older people (80+). Methods Forty-six respondents (80-100+ years) participated in the first wave of a longitudinal qualitative study set in North East England. Semi-structured interviews were conducted in participants' homes between June 2022 and January 2023. Interviews were analysed using reflexive thematic analysis. Results Participants positioned their homes as a place of freedom and as the antithesis of a 'care home'. Remaining in place was important for all participants; a key priority for them was to remain physically active to enable this. However, many participants faced significant hurdles to remaining in place. These were primarily related to health and mobility issues. Some participants were able to overcome such barriers by drawing on financial resources and available social networks. Conclusion The home is central to understanding older peoples' (80+) experiences of ageing. In a socio-political context which promotes ageing in place, the social factors shaping experiences of ageing in place must be considered. This involves attending to the challenges of later life, particularly health and especially mobility and physical function. Currently, those with resources (social and economic) are better equipped to respond to such challenges, thus potentially exacerbating widening inequalities in ageing. By foregrounding the perspectives of those ageing in place alongside social factors shaping their experiences, our study has important implications for policy and health and social care. We show that a more equitable allocation of resources is vital to fulfil the ageing in place policy agenda. Furthermore, we highlight a need to recognise commitments to ageing in place displayed by people aged 80 and above, especially when remaining in place becomes difficult to achieve. Keywords: Ageing in place, Very old, Oldest old, 80+, Home, Economic resources, Social connections, Qualitative research
Globally, autosomal recessive IFNAR1 deficiency is a rare inborn error of immunity underlying susceptibility to live attenuated vaccine and wild-type viruses. We report seven children from five ...unrelated kindreds of western Polynesian ancestry who suffered from severe viral diseases. All the patients are homozygous for the same nonsense IFNAR1 variant (p.Glu386*). This allele encodes a truncated protein that is absent from the cell surface and is loss-of-function. The fibroblasts of the patients do not respond to type I IFNs (IFN-α2, IFN-ω, or IFN-β). Remarkably, this IFNAR1 variant has a minor allele frequency >1% in Samoa and is also observed in the Cook, Society, Marquesas, and Austral islands, as well as Fiji, whereas it is extremely rare or absent in the other populations tested, including those of the Pacific region. Inherited IFNAR1 deficiency should be considered in individuals of Polynesian ancestry with severe viral illnesses.
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