Molecular dynamics analysis of supercontraction in spider dragline silk

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Civil and Environmental Engineering, 2013.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student-submitted PDF version of thesis.Includes bibliographical references (p. 67-73).Spider dragline silk is a material that has evolved over millions of years to develop finely tuned mechanical properties. It is a protein-based fiber, used as the main structural component in spider webs and as a lifeline for the spider, and it combines strength and extensibility to give it toughness currently unmatched by synthetic materials. Dragline silk has the unusual tendency of shrinking by up to 50% when exposed to high humidity, a phenomenon called supercontraction. Supercontraction is thought to occur due to the association of water molecules with the amorphous region of silk proteins. The water molecules are believed to break the hydrogen bonds that connect the protein strands, causing a fundamental reorganization of molecular structure, which is manifested at the macro scale by a large retraction in length. However, the details of these mechanisms remain unknown and have not been directly demonstrated in prior research. Here we use full-scale atomic modeling of spider silk using molecular dynamics to investigate the structure and properties of this material at a length scale that is not yet accessible by experimental methods. A model of spider silk protein is used to explore the phenomenon of supercontraction. Two classes of simulations with different models are performed, and in both cases the models show a reorganization of the molecular structure consistent with the theory of supercontraction, yet fail to show the dramatic change in size that is observed on the macro scale.by Laura Batty.M.Eng

Autism diagnosis in the United Kingdom: Perspectives of autistic adults, parents and professionals

Accessing an autism diagnosis is a key milestone, both for an individual and their family. Using a qualitative methodology, the current study examined the views and experiences of ten autistic adults, ten parents of children on the autism spectrum, and ten professionals involved in autism diagnosis, all based in the United Kingdom (UK). Interviewing these 30 respondents about the diagnostic process and subsequent support options, the goal was to identify aspects of the diagnostic process that are working well, and areas in which improvements are needed. Using thematic analysis, three key themes were identified: the process of understanding and accepting autism; multiple barriers to satisfaction with the diagnostic process; and inadequate post-diagnostic support provisio

Genes Are Often Sheltered from the Global Histone Hyperacetylation Induced by HDAC Inhibitors

Histone deacetylase inhibitors (HDACi) are increasingly used as therapeutic agents, but the mechanisms by which they alter cell behaviour remain unclear. Here we use microarray expression analysis to show that only a small proportion of genes (∼9%) have altered transcript levels after treating HL60 cells with different HDACi (valproic acid, Trichostatin A, suberoylanilide hydroxamic acid). Different gene populations respond to each inhibitor, with as many genes down- as up-regulated. Surprisingly, HDACi rarely induced increased histone acetylation at gene promoters, with most genes examined showing minimal change, irrespective of whether genes were up- or down-regulated. Many genes seem to be sheltered from the global histone hyperacetyation induced by HDACi

Social Inequalities in Height: Persisting Differences Today Depend upon Height of the Parents

BACKGROUND: Substantial increases in height have occurred concurrently with economic development in most populations during the last century. In high-income countries, environmental exposures that can limit genetic growth potential appear to have lessened, and variation in height by socioeconomic position may have diminished. The objective of this study is to investigate inequalities in height in a cohort of children born in the early 1990s in England, and to evaluate which factors might explain any identified inequalities. METHODS AND FINDINGS: 12,830 children from The Avon Longitudinal Study of Parents and Children (ALSPAC), a population based cohort from birth to about 11.5 years of age, were used in this analysis. Gender- and age-specific z-scores of height at different ages were used as outcome variables. Multilevel models were used to take into account the repeated measures of height and to analyze gender- and age-specific relative changes in height from birth to 11.5 years. Maternal education was the main exposure variable used to examine socioeconomic inequalities. The roles of parental and family characteristics in explaining any observed differences between maternal education and child height were investigated. Children whose mothers had the highest education compared to those with none or a basic level of education, were 0.39 cm longer at birth (95% CI: 0.30 to 0.48). These differences persisted and at 11.5 years the height difference was 1.4 cm (95% CI: 1.07 to 1.74). Several other factors were related to offspring height, but few changed the relationship with maternal education. The one exception was mid-parental height, which fully accounted for the maternal educational differences in offspring height. CONCLUSIONS: In a cohort of children born in the 1990s, mothers with higher education gave birth to taller boys and girls. Although height differences were small they persisted throughout childhood. Maternal and paternal height fully explained these differences.Bruna Galobardes, Valerie A. McCormack, Peter McCarron, Laura D. Howe, John Lynch, Debbie A. Lawlor and George Davey Smit

SUMOylation of the Forkhead Transcription Factor FOXL2 Promotes Its Stabilization/Activation through Transient Recruitment to PML Bodies

International audienceBACKGROUND: FOXL2 is a transcription factor essential for ovarian development and maintenance. It is mutated in the genetic condition called Blepharophimosis Ptosis Epicantus inversus Syndrome (BPES) and in cases of isolated premature ovarian failure. We and others have previously shown that FOXL2 undergoes several post-translational modifications. METHODS AND PRINCIPAL FINDINGS: Here, using cells in culture, we show that interference with FOXL2 SUMOylation leads to a robust inhibition of its transactivation ability, which correlates with a decreased stability. Interestingly, FOXL2 SUMOylation promotes its transient recruitment to subnuclear structures that we demonstrate to be PML (Promyelocytic Leukemia) Nuclear Bodies. Since PML bodies are known to be sites where post-translational modifications of nuclear factors take place, we used tandem mass spectrometry to identify new post-translational modifications of FOXL2. Specifically, we detected four phosphorylated, one sulfated and three acetylated sites. CONCLUSIONS: By analogy with other transcription factors, we propose that PML Nuclear Bodies might transiently recruit FOXL2 to the vicinity of locally concentrated enzymes that could be involved in the post-translational maturation of FOXL2. FOXL2 acetylation, sulfation, phosphorylation as well as other modifications yet to be discovered might alter the transactivation capacity of FOXL2 and/or its stability, thus modulating its global intracellular activity

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Impaired semantic memory in the formation and maintenance of delusions post-traumatic brain injury: a new cognitive model of delusions

This paper proposes a new cognitive model to explain the aetiology of delusions irrespective of diagnosis and/or phenomenology. The model hypothesises the influence of two processes in the formation and maintenance of delusions; (i) impaired perceptual abilities, particularly affect perception, which fosters the encoding of (ii) idiosyncratic semantic memories, especially those with an affective/self-referential valence. Previous research has established that schizophrenia patients with delusions have impaired semantic memory function. In the current paper we sought to provide evidence for (ii) abnormal semantic processing in persons with delusions with an alternative aetiology. Performance of four cases with a significant delusion post a traumatic brain injury was examined on a broad range of semantic memory tests. Overall semantic processing was impaired in the four cases relative to a normative healthy control sample. Cases performed better on tasks which required categorical identification, relative to the novel production of semantic information, which was poor in all four of the cases. These data offer preliminary evidence for our hypothesis of impaired semantic processing in persons with delusions. Findings will need to be empirically verified in larger sample groups and in those with alternative aetiologies.11 page(s