Frustration in fuzzy protein complexes leads to interaction versatility

Disordered proteins frequently serve as interaction hubs involving a constrained variety of partners. Complexes with different partners frequently exhibit distinct binding modes, involving regions that remain disordered in the bound state. While the conformational properties of disordered proteins are well-characterized in their free states, less is known about the molecular mechanisms by which specificity can be achieved not with one but with multiple partners. Using the energy landscape theory concept of protein frustration, we demonstrate that complexes of disordered proteins exhibit a high degree of local frustration, especically at the binding interface. These suboptimal interactions lead to the possibility of multiple bound substates, each displaying distinct frustration patterns, which are differently populated in complexes with different partners. These results explain how specificity of disordered proteins can be achieved without a single common bound conformation and how the confliict between different interactions can be used to control the binding to multiple partners

Student abstracts of selected articles

Vowel Nasality in Sudanese by Ron Trail, abstracted from Robins, R. H. 1957. Vowel Nasality in Sudanese, A Phonological and Grammatical Study. Studies in Linguistic Analysis, J.R. Firth ed. London: The Philological Society, 87-103. Style in Huichol by Nancy Freiberger, abstracted from Grimes, Joseph E. 1955. Style in Huichol Structure, Language 31.31-35. Trique Tone by Richard Bergman, abstracted from Longacre, Robert E. 1952. Five Phonemic Pitch Levels in Trique, Acta Linguistica 7.62-82. Tonme Representation in Mazatec Orthography by Ron Trail, abstracted from Gudschinsky, Sarah. 1959. Toneme Representation in Mazatec Orthography, Word, 15.446-52. Totonac Verb Inflection by Kenneth D. Smith, abstracted from Aschmann, Herman, and Wonderly, William L. 1952. Affixes and Implicit Categories in Totonac Verb Inflections, IJAL 18.130-45. Have as a Function Word by Jean Haggar, abstracted from Fries, Charles C. 1948. Have as a Function Word, Language Learning, 1.3,4-8. Bella Coola Phonology by Margie Griffin, abstracted from Newman, Stanley, 1947. Bella Coola I: Phonology, IJAL 13.129-34. Old High German Umlaut by Elwood Jacobson, abstracted from Twaddell, W. Freeman. 1938. A Note on Old High German Umlaut, Monatshefte für deutschen Unterricht, 30:177-81. Reprinted in Readings in Linguistics, edited by Martin Joos, 1958. Washington: American Council of Learned Societies, 85-87. The Phonemic Principle by Nancy Freiberger, abstracted from Swadesh, Morris, 1934. The Phonemic Principle, Language 10.117-29. Reprinted in Readings in Linguistics, edited by Martin Joos. 1958. Washington: American Council of Learned Societies, 1957, 32-37. Meaning and Dictionary Making by Nancy Freiberger, abstracted from Nida, Eugene A. 1958. Analysis of Meaning and Dictionary Making, IJAL 24.279-92. Mazateco Whistle Speech by Nancy Freiberger, abstracted from Cowan, George M. 1948. Mazateco Whistle Speech, Language 24.280-86. Voiceless Vowels in Comanche by Bob Beadle, abstracted from Canonge, Elliot D. 1957. Voiceless Vowels in Comanche, IJAL, 23.63-67. Noun Possession in Villa Alta Zapotec by Gwen Young, abstracted from Mary Leal and Otis Leal, 1954. Noun Possession in Villa Alta Zapotec, IJAL 20.215-216. Sound Patterns by Richard Bergman, abstracted from Sapir, Edward. 1925. Sound Patterns in Language. Language, 1.37-51

Chasing up and locking down the virus: Optimal pandemic interventions within a network

During the COVID-19 pandemic countries invested significant amounts of resources into its containment. In early stages of the pandemic most of the (nonpharmaceutical) interventions can be classified into two groups: (i) testing and identification of infected individuals, (ii) social distancing measures to reduce the transmission probabilities. Furthermore, both groups of measures may, in principle, be targeted at certain subgroups of a networked population. To study such a problem, we propose an extension of the SIR model with additional compartments for quarantine and different courses of the disease across several network nodes. We develop the structure of the optimal allocation and study a numerical example of three symmetric regions that are subject to an asymmetric progression of the disease (starting from an initial hotspot). Key findings include that (i) for our calibrations policies are chosen in a “flattening-the-curve,” avoiding hospital congestion; (ii) policies shift from containing spillovers from the hotspot initially to establishing a symmetric pattern of the disease; and (iii) testing that can be effectively targeted allows to reduce substantially the duration of the disease, hospital congestion and the total cost, both in terms of lives lost and economic costs

Photonic reservoir computing using a small network of micro-ring resonators

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Self-homodyne tomography of a twin-beam state

A self-homodyne detection scheme is proposed to perform two-mode tomography on a twin-beam state at the output of a nondegenerate optical parametric amplifier. This scheme has been devised to improve the matching between the local oscillator and the signal modes, which is the main limitation to the overall quantum efficiency in conventional homodyning. The feasibility of the measurement is analyzed on the basis of Monte-Carlo simulations, studying the effect of non-unit quantum efficiency on detection of the correlation and the total photon-number oscillations of the twin-beam state.Comment: 13 pages (two-column ReVTeX) including 21 postscript figures; to appear on Phys. Rev.

An interdisciplinary intervention to prevent falls in community-dwelling elderly persons: protocol of a cluster-randomized trial [PreFalls]

<p>Abstract</p> <p>Background</p> <p>Prevention of falls in the elderly is a public health target in many countries around the world. While a large number of trials have investigated the effectiveness of fall prevention programs, few focussed on interventions embedded in the general practice setting and its related network. In the Prevent Falls (PreFalls) trial we aim to investigate the effectiveness of a pre-tested multi-modal intervention compared to usual care in this setting.</p> <p>Methods/Design</p> <p>PreFalls is a controlled multicenter prospective study with cluster-randomized allocation of about 40 general practices to an experimental or a control group. We aim to include 382 community dwelling persons aged 65 and older with an increased risk of falling. All participating general practitioners are trained to systematically assess the risk of falls using a set of validated tests. Patients from intervention practices are invited to participate in a 16-weeks exercise program with focus on fall prevention delivered by specifically trained local physiotherapists. Patients from practices allocated to the control group receive usual care. Main outcome measure is the number of falls per individual in the first 12 months (analysis by negative binomial regression). Secondary outcomes include falls in the second year, the proportion of participants falling in the first and the second year, falls associated with injury, risk of falls, fear of falling, physical activity and quality of life.</p> <p>Discussion</p> <p>Reducing falls in the elderly remains a major challenge. We believe that with its strong focus on a both systematic and realistic fall prevention strategy adapted to primary care setting PreFalls will be a valuable addition to the scientific literature in the field.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01032252">NCT01032252</a></p

Pharmacological Inhibition of polysialyltransferase ST8SiaII Modulates Tumour Cell Migration

YesPolysialic acid (polySia), an α-2,8-glycosidically linked polymer of sialic acid, is a developmentally regulated posttranslational modification predominantly found on NCAM (neuronal cell adhesion molecule). Whilst high levels are expressed during development, peripheral adult organs do not express polySia-NCAM. However, tumours of neural crest-origin re-express polySia-NCAM: its occurrence correlates with aggressive and invasive disease and poor clinical prognosis in different cancer types, notably including small cell lung cancer (SCLC), pancreatic cancer and neuroblastoma. In neuronal development, polySia-NCAM biosynthesis is catalysed by two polysialyltransferases, ST8SiaII and ST8SiaIV, but it is ST8SiaII that is the prominent enzyme in tumours. The aim of this study was to determine the effect of ST8SiaII inhibition by a small molecule on tumour cell migration, utilising cytidine monophosphate (CMP) as a tool compound. Using immunoblotting we showed that CMP reduced ST8iaII-mediated polysialylation of NCAM. Utilizing a novel HPLC-based assay to quantify polysialylation of a fluorescent acceptor (DMB-DP3), we demonstrated that CMP is a competitive inhibitor of ST8SiaII (Ki = 10 μM). Importantly, we have shown that CMP causes a concentration-dependent reduction in tumour cell-surface polySia expression, with an absence of toxicity. When ST8SiaII-expressing tumour cells (SH-SY5Y and C6-STX) were evaluated in 2D cell migration assays, ST8SiaII inhibition led to significant reductions in migration, while CMP had no effect on cells not expressing ST8SiaII (DLD-1 and C6-WT). The study demonstrates for the first time that a polysialyltransferase inhibitor can modulate migration in ST8SiaII-expressing tumour cells. We conclude that ST8SiaII can be considered a druggable target with the potential for interfering with a critical mechanism in tumour cell dissemination in metastatic cancers.Yorkshire Cancer Research; EPSRC; Association for International Cancer Research; Jordanian Government PhD scholarshi

Systematic literature review of determinants of sedentary behaviour in older adults:a DEDIPAC study

BACKGROUND: Older adults are the most sedentary segment of society and high sedentary time is associated with poor health and wellbeing outcomes in this population. Identifying determinants of sedentary behaviour is a necessary step to develop interventions to reduce sedentary time. METHODS: A systematic literature review was conducted to identify factors associated with sedentary behaviour in older adults. Pubmed, Embase, CINAHL, PsycINFO and Web of Science were searched for articles published between 2000 and May 2014. The search strategy was based on four key elements: (a) sedentary behaviour and its synonyms; (b) determinants and its synonyms (e.g. correlates, factors); (c) types of sedentary behaviour (e.g. TV viewing, sitting, gaming) and (d) types of determinants (e.g. environmental, behavioural). Articles were included in the review if specific information about sedentary behaviour in older adults was reported. Studies on samples identified by disease were excluded. Study quality was rated by means of QUALSYST. The full review protocol is available from PROSPERO (PROSPERO 2014: CRD42014009823). The analysis was guided by the socio-ecological model framework. RESULTS: Twenty-two original studies were identified out of 4472 returned by the systematic search. These included 19 cross-sectional, 2 longitudinal and 1 qualitative studies, all published after 2011. Half of the studies were European. The study quality was generally high with a median of 82 % (IQR 69-96 %) using Qualsyst tool. Personal factors were the most frequently investigated with consistent positive association for age, negative for retirement, obesity and health status. Only four studies considered environmental determinants suggesting possible association with mode of transport, type of housing, cultural opportunities and neighbourhood safety and availability of places to rest. Only two studies investigated mediating factors. Very limited information was available on contexts and sub-domains of sedentary behaviours. CONCLUSION: Few studies have investigated determinants of sedentary behaviour in older adults and these have to date mostly focussed on personal factors, and qualitative studies were mostly lacking. More longitudinal studies are needed as well as inclusion of a broader range of personal and contextual potential determinants towards a systems-based approach, and future studies should be more informed by qualitative work

2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia:New treatments and clinical guidance

This 2023 statement updates clinical guidance for homozygous familial hypercholesterolaemia (HoFH), explains the genetic complexity, and provides pragmatic recommendations to address inequities in HoFH care worldwide. Key strengths include updated criteria for the clinical diagnosis of HoFH and the recommendation to prioritize phenotypic features over genotype. Thus, a low-density lipoprotein cholesterol (LDL-C) &gt;10 mmol/L (&gt;400 mg/dL) is suggestive of HoFH and warrants further evaluation. The statement also provides state-of-the art discussion and guidance to clinicians for interpreting the results of genetic testing and for family planning and pregnancy. Therapeutic decisions are based on the LDL-C level. Combination LDL-C-lowering therapy - both pharmacologic intervention and lipoprotein apheresis (LA) - is foundational. Addition of novel, efficacious therapies (i.e. inhibitors of proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential to attain LDL-C goal or reduce the need for LA. To improve HoFH care around the world, the statement recommends the creation of national screening programmes, education to improve awareness, and management guidelines that account for the local realities of care, including access to specialist centres, treatments, and cost. This updated statement provides guidance that is crucial to early diagnosis, better care, and improved cardiovascular health for patients with HoFH worldwide.</p

Associations of β-Amyloid and Vascular Burden With Rates of Neurodegeneration in Cognitively Normal Members of the 1946 British Birth Cohort

OBJECTIVE: To quantify the independent and interactive associations of amyloid-β (Aβ) and white matter hyperintensity volume (WMHV) - a marker of presumed cerebrovascular disease (CVD) - with rates of neurodegeneration, and to examine the contributions of APOE ε4 and vascular risk measured at different stages of adulthood in cognitively normal members of the 1946 British birth cohort. METHODS: Participants underwent brain MRI and florbetapir-Aβ positron emission tomography as part of Insight 46, an observational population-based study. Changes in whole brain, ventricular and hippocampal volume were directly measured from baseline and repeat volumetric T1 MRI using the Boundary Shift Integral. Linear regression was used to test associations with: baseline Aβ deposition; baseline WMHV; APOE ε4; and office-based Framingham heart study-cardiovascular risk scores (FHS-CVS) and systolic blood pressure (BP) at ages 36, 53 and 69 years. RESULTS: 346 cognitively normal participants (mean [SD] age at baseline scan 70.5 [0.6] years; 48% female) had high-quality T1 MRI data from both time-points (mean [SD] scan interval 2.4 [0.2] years). Being Aβ positive at baseline was associated with 0.87 ml/year faster whole brain atrophy (95% CI 0.03, 1.72), 0.39 ml/year greater ventricular expansion (95% CI 0.16, 0.64) and 0.016 ml/year faster hippocampal atrophy (95% CI 0.004, 0.027), while each 10 ml additional WMHV at baseline was associated with 1.07 ml/year faster whole brain atrophy (95% CI 0.47, 1.67), 0.31 ml/year greater ventricular expansion (95% CI 0.13, 0.60) and 0.014 ml/year faster hippocampal atrophy (95% CI 0.006, 0.022). These contributions were independent and there was no evidence that Aβ and WMHV interacted in their effects. There were no independent associations of APOE ε4 with rates of neurodegeneration after adjusting for Aβ status and WMHV, and no clear relationships between FHS-CVS or systolic BP and rates of neurodegeneration when assessed across the whole sample, nor any evidence that they acted synergistically with Aβ. CONCLUSIONS: Aβ and presumed CVD have distinct and additive effects on rates of neurodegeneration in cognitively normal elderly. These findings have implications for the use of MRI measures as biomarkers of neurodegeneration and emphasize the importance of risk management and early intervention targeting both pathways