Azoniaspiro salts: towards bridging the gap between room-temperature ionic liquids and molten salts.

In a continued effort to improve the suitability of ionic liquids in applications operating at raised temperatures, novel spirocyclic 'azoniaspiro' salts (with cations derived from five-, six-, seven-and eight-membered rings) are prepared and characterised. The structural and thermal properties of these salts are compared against those of established analogues. The stable geometries and ion pairing behaviour of these species are investigated via a combined experimental/computational approach, employing X-ray crystallography and Density Functional Theory (DFT) methods. Subsequently, the thermal stabilities of these organic salts are characterised and compared using a broad range of techniques. Hyphenated Thermogravimetry-Mass Spectrometry investigations enable complex mechanisms underlying thermal decomposition to be elucidated. Lastly, transition state structures are optimised, corresponding to plausible decomposition mechanisms of the azoniaspiro salt, 6-azoniaspiro[6.5]dodecanium chloride, and one prototypical monocyclic species 1-butyl-1-methylpiperidinium chloride, using DFT. The observed improved thermal stabilities of the azoniaspiro salts, and their potential higher-temperature stable-liquid ranges, render them promising candidates for future ionic liquid applications

CR1 Knops blood group alleles are not associated with severe malaria in the Gambia

The Knops blood group antigen erythrocyte polymorphisms have been associated with reduced falciparum malaria-based in vitro rosette formation (putative malaria virulence factor). Having previously identified single-nucleotide polymorphisms (SNPs) in the human complement receptor 1 (CR1/CD35) gene underlying the Knops antithetical antigens Sl1/Sl2 and McC(a)/McC(b), we have now performed genotype comparisons to test associations between these two molecular variants and severe malaria in West African children living in the Gambia. While SNPs associated with Sl:2 and McC(b+) were equally distributed among malaria-infected children with severe malaria and control children not infected with malaria parasites, high allele frequencies for Sl 2 (0.800, 1,365/1,706) and McC(b) (0.385, 658/1706) were observed. Further, when compared to the Sl 1/McC(a) allele observed in all populations, the African Sl 2/McC(b) allele appears to have evolved as a result of positive selection (modified Nei-Gojobori test Ka-Ks/s.e.=1.77, P-value <0.05). Given the role of CR1 in host defense, our findings suggest that Sl 2 and McC(b) have arisen to confer a selective advantage against infectious disease that, in view of these case-control study data, was not solely Plasmodium falciparum malaria. Factors underlying the lack of association between Sl 2 and McC(b) with severe malaria may involve variation in CR1 expression levels

Communities of practice for contemporary leadership development and knowledge exchange through work-based learning

This study explores the experiences of leaders who have led organisations and teams through an extended period of crisis management whilst completing a UK work-based master’s programme. This paper examines contemporary approaches to work-based learning and explores the effect of organisational and workforce demands in a volatile era of global economic uncertainty. Theoretical and conceptual foundations relating to experiential learning, digital education and communities of learning are analysed and discussed. Taking an inductive qualitative approach, the study analyses semi-structured questionnaire data from senior leaders. The widespread adoption of technology exposes challenges to facilitation and the academic-employer interface, impacting upon learning communities and knowledge exchange opportunities. The findings also suggest enhanced leaders’ adaptive traits, including confidence and self-reliance. This study illuminates critical issues associated with contemporary workbased learning, specifically relating to prolonged macro uncertainty and the effect upon workplaces as sites of knowledge and learning, and risks to dynamic relationships between the psychosocial work environment, genuine opportunities to learn and learner well-being. This work seeks to inform the design of future programs, specifically in terms developing inter and intra-organisational communities of learning and knowledge exchange to enhance best practice and inculcate crucial leadership skills

A satellite DNA array barcodes chromosome 7 and regulates totipotency via ZFP819.

Mammalian genomes are a battleground for genetic conflict between repetitive elements and KRAB-zinc finger proteins (KZFPs). We asked whether KZFPs can regulate cell fate by using ZFP819, which targets a satellite DNA array, ZP3AR. ZP3AR coats megabase regions of chromosome 7 encompassing genes encoding ZSCAN4, a master transcription factor of totipotency. Depleting ZFP819 in mouse embryonic stem cells (mESCs) causes them to transition to a 2-cell (2C)-like state, whereby the ZP3AR array switches from a poised to an active enhancer state. This is accompanied by a global erosion of heterochromatin roadblocks, which we link to decreased SETDB1 stability. These events result in transcription of active LINE-1 elements and impaired differentiation. In summary, ZFP819 and TRIM28 partner up to close chromatin across Zscan4, to promote exit from totipotency. We propose that satellite DNAs may control developmental fate transitions by barcoding and switching off master transcription factor genes

The HUSH complex is a gatekeeper of type I interferon through epigenetic regulation of LINE-1s

The Human Silencing Hub (HUSH) complex is necessary for epigenetic repression of LINE-1 elements. We show that HUSH-depletion in human cell lines and primary fibroblasts leads to induction of interferon-stimulated genes (ISGs) through JAK/STAT signaling. This effect is mainly attributed to MDA5 and RIG-I sensing of double-stranded RNAs (dsRNAs). This coincides with upregulation of primate-conserved LINE-1s, as well as increased expression of full-length hominid-specific LINE-1s that produce bidirectional RNAs, which may form dsRNA. Notably, LTRs nearby ISGs are derepressed likely rendering these genes more responsive to interferon. LINE-1 shRNAs can abrogate the HUSH-dependent response, while overexpression of an engineered LINE-1 construct activates interferon signaling. Finally, we show that the HUSH component, MPP8 is frequently downregulated in diverse cancers and that its depletion leads to DNA damage. These results suggest that LINE-1s may drive physiological or autoinflammatory responses through dsRNA sensing and gene-regulatory roles and are controlled by the HUSH complex

Predictability of evolutionary trajectories in fitness landscapes

Experimental studies on enzyme evolution show that only a small fraction of all possible mutation trajectories are accessible to evolution. However, these experiments deal with individual enzymes and explore a tiny part of the fitness landscape. We report an exhaustive analysis of fitness landscapes constructed with an off-lattice model of protein folding where fitness is equated with robustness to misfolding. This model mimics the essential features of the interactions between amino acids, is consistent with the key paradigms of protein folding and reproduces the universal distribution of evolutionary rates among orthologous proteins. We introduce mean path divergence as a quantitative measure of the degree to which the starting and ending points determine the path of evolution in fitness landscapes. Global measures of landscape roughness are good predictors of path divergence in all studied landscapes: the mean path divergence is greater in smooth landscapes than in rough ones. The model-derived and experimental landscapes are significantly smoother than random landscapes and resemble additive landscapes perturbed with moderate amounts of noise; thus, these landscapes are substantially robust to mutation. The model landscapes show a deficit of suboptimal peaks even compared with noisy additive landscapes with similar overall roughness. We suggest that smoothness and the substantial deficit of peaks in the fitness landscapes of protein evolution are fundamental consequences of the physics of protein folding.Comment: 14 pages, 7 figure

Duration and urgency of transfer in births planned at home and in freestanding midwifery units in England: secondary analysis of the Birthplace national prospective cohort study

Background: In England, there is a policy of offering healthy women with straightforward pregnancies a choice of birth setting. Options may include home or a freestanding midwifery unit (FMU). Transfer rates from these settings are around 20%, and higher for nulliparous women. The duration of transfer is of interest because of the potential for delay in access to specialist care and is also of concern to women. We aimed to estimate the duration of transfer in births planned at home and in FMUs and explore the effects of distance and urgency on duration. Methods: This was a secondary analysis of data collected in a national prospective cohort study including 27,842 ‘low risk’ women with singleton, term, ‘booked’ pregnancies, planning birth in FMUs or at home in England from April 2008 to April 2010. We described transfer duration using the median and interquartile range, for all transfers and those for reasons defined as potentially urgent or non-urgent, and used cumulative distribution curves to compare transfer duration by urgency. We explored the effect of distance for transfers from FMUs and described outcomes in women giving birth within 60 minutes of transfer. Results: The median overall transfer time, from decision to transfer to first OU assessment, was shorter in transfers from home compared with transfers from FMUs (49 vs 60 minutes; p < 0.001). The median duration of transfers before birth for potentially urgent reasons (home 42 minutes, FMU 50 minutes) was 8–10 minutes shorter compared with transfers for non-urgent reasons. In transfers for potentially urgent reasons, the median overall transfer time from FMUs within 20 km of an OU was 47 minutes, increasing to 55 minutes from FMUs 20-40 km away and 61 minutes in more remote FMUs. In women who gave birth within 60 minutes after transfer, adverse neonatal outcomes occurred in 1-2% of transfers. Conclusions: Transfers from home or FMU commonly take up to 60 minutes from decision to transfer, to first assessment in an OU, even for transfers for potentially urgent reasons. Most transfers are not urgent and emergencies and adverse outcomes are uncommon, but urgent transfer is more likely for nulliparous women

Implications of sperm banking for health-related quality of life up to 1 year after cancer diagnosis.

Sperm banking is recommended for all men diagnosed with cancer where treatment is associated with risk of long-term gonadatoxicity, to offer the opportunity of fatherhood and improved quality of life. However, uptake of sperm banking is lower than expected and little is known about why men refuse. Our aims were to determine: (i) demographic and medical variables associated with decisions about banking and (ii) differences in quality of life between bankers and non-bankers at diagnosis (Time 1 (T1)) and 1 year later (Time 2 (T2))

Association between Knops blood group polymorphisms and susceptibility to malaria in an endemic area of the Brazilian Amazon

Complement receptor 1 (CR1) gene polymorphisms that are associated with Knops blood group antigens may influence the binding of Plasmodium parasites to erythrocytes, thereby affecting susceptibility to malaria. The aim of this study was to evaluate the genotype and allele and haplotype frequencies of single-nucleotide polymorphisms (SNPs) of Knops blood group antigens and examine their association with susceptibility to malaria in an endemic area of Brazil. One hundred and twenty-six individuals from the Brazilian Amazon were studied. The CR1-genomic fragment was amplified by PCR and six SNPs and haplotypes were identified after DNA sequence analysis. Allele and haplotype frequencies revealed that the Knb allele and H8 haplotype were possibly associated with susceptibility to Plasmodium falciparum. The odds ratios were reasonably high, suggesting a potentially important association between two Knops blood antigens (Knb and KAM+) that confer susceptibility to P. falciparum in individuals from the Brazilian Amazon

<i>Plasmodium falciparum </i>var genes expressed in children with severe malaria encode CIDRα1 domains

Most severe Plasmodium falciparum infections are experienced by young children. Severe symptoms are precipitated by vascular sequestration of parasites expressing a particular subset of the polymorphic P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion molecules. Parasites binding human endothelial protein C receptor (EPCR) through the CIDRα1 domain of certain PfEMP1 were recently associated with severe malaria in children. However, it has remained unclear to which extend the EPCR‐binding CIDRα1 domains epitomize PfEMP1 expressed in severe malaria. Here, we characterized the near full‐length transcripts dominating the var transcriptome in children with severe malaria and found that the only common feature of the encoded PfEMP1 was CIDRα1 domains. Such genes were highly and dominantly expressed in both children with severe malarial anaemia and cerebral malaria. These observations support the hypothesis that the CIDRα1‐EPCR interaction is key to the pathogenesis of severe malaria and strengthen the rationale for pursuing a vaccine or adjunctive treatment aiming at inhibiting or reducing the damaging effects of this interaction