Role of Secondary Motifs in Fast Folding Polymers: A Dynamical Variational Principle

A fascinating and open question challenging biochemistry, physics and even geometry is the presence of highly regular motifs such as alpha-helices in the folded state of biopolymers and proteins. Stimulating explanations ranging from chemical propensity to simple geometrical reasoning have been invoked to rationalize the existence of such secondary structures. We formulate a dynamical variational principle for selection in conformation space based on the requirement that the backbone of the native state of biologically viable polymers be rapidly accessible from the denatured state. The variational principle is shown to result in the emergence of helical order in compact structures.Comment: 4 pages, RevTex, 4 eps figure

A self-organized model for cell-differentiation based on variations of molecular decay rates

Systemic properties of living cells are the result of molecular dynamics governed by so-called genetic regulatory networks (GRN). These networks capture all possible features of cells and are responsible for the immense levels of adaptation characteristic to living systems. At any point in time only small subsets of these networks are active. Any active subset of the GRN leads to the expression of particular sets of molecules (expression modes). The subsets of active networks change over time, leading to the observed complex dynamics of expression patterns. Understanding of this dynamics becomes increasingly important in systems biology and medicine. While the importance of transcription rates and catalytic interactions has been widely recognized in modeling genetic regulatory systems, the understanding of the role of degradation of biochemical agents (mRNA, protein) in regulatory dynamics remains limited. Recent experimental data suggests that there exists a functional relation between mRNA and protein decay rates and expression modes. In this paper we propose a model for the dynamics of successions of sequences of active subnetworks of the GRN. The model is able to reproduce key characteristics of molecular dynamics, including homeostasis, multi-stability, periodic dynamics, alternating activity, differentiability, and self-organized critical dynamics. Moreover the model allows to naturally understand the mechanism behind the relation between decay rates and expression modes. The model explains recent experimental observations that decay-rates (or turnovers) vary between differentiated tissue-classes at a general systemic level and highlights the role of intracellular decay rate control mechanisms in cell differentiation.Comment: 16 pages, 5 figure

A stagewise response to mitochondrial dysfunction in mitochondrial DNA maintenance disorders

\ua9 2024 The AuthorsMitochondrial DNA (mtDNA) deletions which clonally expand in skeletal muscle of patients with mtDNA maintenance disorders, impair mitochondrial oxidative phosphorylation dysfunction. Previously we have shown that these mtDNA deletions arise and accumulate in perinuclear mitochondria causing localised mitochondrial dysfunction before spreading through the muscle fibre. We believe that mito-nuclear signalling is a key contributor in the accumulation and spread of mtDNA deletions, and that knowledge of how muscle fibres respond to mitochondrial dysfunction is key to our understanding of disease mechanisms. To understand the contribution of mito-nuclear signalling to the spread of mitochondrial dysfunction, we use imaging mass cytometry. We characterise the levels of mitochondrial Oxidative Phosphorylation proteins alongside a mitochondrial mass marker, in a cohort of patients with mtDNA maintenance disorders. Our expanded panel included protein markers of key signalling pathways, allowing us to investigate cellular responses to different combinations of oxidative phosphorylation dysfunction and ragged red fibres. We find combined Complex I and IV deficiency to be most common. Interestingly, in fibres deficient for one or more complexes, the remaining complexes are often upregulated beyond the increase of mitochondrial mass typically observed in ragged red fibres. We further find that oxidative phosphorylation deficient fibres exhibit an increase in the abundance of proteins involved in proteostasis, e.g. HSP60 and LONP1, and regulation of mitochondrial metabolism (including oxidative phosphorylation and proteolysis, e.g. PHB1). Our analysis suggests that the cellular response to mitochondrial dysfunction changes depending on the combination of deficient oxidative phosphorylation complexes in each fibre

30 days wild: development and evaluation of a large-scale nature engagement campaign to improve well-being

There is a need to increase people’s engagement with and connection to nature, both for human well-being and the conservation of nature itself. In order to suggest ways for people to engage with nature and create a wider social context to normalise nature engagement, The Wildlife Trusts developed a mass engagement campaign, 30 Days Wild. The campaign asked people to engage with nature every day for a month. 12,400 people signed up for 30 Days Wild via an online sign-up with an estimated 18,500 taking part overall, resulting in an estimated 300,000 engagements with nature by participants. Samples of those taking part were found to have sustained increases in happiness, health, connection to nature and pro-nature behaviours. With the improvement in health being predicted by the improvement in happiness, this relationship was mediated by the change in connection to nature

Olfactory swab sampling optimization for α-synuclein aggregate detection in patients with Parkinson’s disease

Background: In patients with Parkinson’s disease (PD), real-time quaking-induced conversion (RT-QuIC) detection of pathological α-synuclein (α-syn) in olfactory mucosa (OM) is not as accurate as in other α-synucleinopathies. It is unknown whether these variable results might be related to a different distribution of pathological α-syn in OM. Thus, we investigated whether nasal swab (NS) performed in areas with a different coverage by olfactory neuroepithelium, such as agger nasi (AN) and middle turbinate (MT), might affect the detection of pathological α-syn. Methods: NS was performed in 66 patients with PD and 29 non-PD between September 2018 and April 2021. In 43 patients, cerebrospinal fluid (CSF) was also obtained and all samples were analyzed by RT-QuIC for α-syn. Results: In the first round, 72 OM samples were collected by NS, from AN (NSAN) or from MT (NSMT), and 35 resulted positive for α-syn RT-QuIC, including 27/32 (84%) from AN, 5/11 (45%) from MT, and 3/29 (10%) belonging to the non-PD patients. Furthermore, 23 additional PD patients underwent NS at both AN and MT, and RT-QuIC revealed α-syn positive in 18/23 (78%) NSAN samples and in 10/23 (44%) NSMT samples. Immunocytochemistry of NS preparations showed a higher representation of olfactory neural cells in NSAN compared to NSMT. We also observed α-syn and phospho-α-syn deposits in NS from PD patients but not in controls. Finally, RT-QuIC was positive in 22/24 CSF samples from PD patients (92%) and in 1/19 non-PD. Conclusion: In PD patients, RT-QuIC sensitivity is significantly increased (from 45% to 84%) when NS is performed at AN, indicating that α-syn aggregates are preferentially detected in olfactory areas with higher concentration of olfactory neurons. Although RT-QuIC analysis of CSF showed a higher diagnostic accuracy compared to NS, due to the non-invasiveness, NS might be considered as an ancillary procedure for PD diagnosis

Mechanical Properties of Glassy Polyethylene Nanofibers via Molecular Dynamics Simulations

The extent to which the intrinsic mechanical properties of polymer fibers depend on physical size has been a matter of dispute that is relevant to most nanofiber applications. Here, we report the elastic and plastic properties determined from molecular dynamics simulations of amorphous, glassy polymer nanofibers with diameter ranging from 3.7 to 17.7 nm. We find that, for a given temperature, the Young’s elastic modulus E decreases with fiber radius and can be as much as 52% lower than that of the corresponding bulk material. Poisson’s ratio ν of the polymer comprising these nanofibers was found to decrease from a value of 0.3 to 0.1 with decreasing fiber radius. Our findings also indicate that a small but finite stress exists on the simulated nanofibers prior to elongation, attributable to surface tension. When strained uniaxially up to a tensile strain of ε = 0.2 over the range of strain rates and temperatures considered, the nanofibers exhibit a yield stress σy between 40 and 72 MPa, which is not strongly dependent on fiber radius; this yield stress is approximately half that of the same polyethylene simulated in the amorphous bulk.DuPont MIT AllianceDuPont (Firm) (Young Professor Award

Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol.

Adding abiraterone acetate with prednisolone (AAP) or docetaxel with prednisolone (DocP) to standard-of-care (SOC) each improved survival in STAMPEDE: a multi-arm multi-stage platform randomised controlled protocol recruiting patients with high-risk locally advanced or metastatic PCa starting long-term androgen deprivation therapy (ADT). The protocol provides the only direct, randomised comparative data of SOC+AAP vs SOC+DocP

What factors are associated with recent intimate partner violence? findings from the WHO multi-country study on women's health and domestic violence

<p>Abstract</p> <p>Background</p> <p>Intimate partner violence (IPV) against women is a global public health and human rights concern. Despite a growing body of research into risk factors for IPV, methodological differences limit the extent to which comparisons can be made between studies. We used data from ten countries included in the WHO Multi-country Study on Women's Health and Domestic Violence to identify factors that are consistently associated with abuse across sites, in order to inform the design of IPV prevention programs.</p> <p>Methods</p> <p>Standardised population-based household surveys were done between 2000 and 2003. One woman aged 15-49 years was randomly selected from each sampled household. Those who had ever had a male partner were asked about their experiences of physically and sexually violent acts. We performed multivariate logistic regression to identify predictors of physical and/or sexual partner violence within the past 12 months.</p> <p>Results</p> <p>Despite wide variations in the prevalence of IPV, many factors affected IPV risk similarly across sites. Secondary education, high SES, and formal marriage offered protection, while alcohol abuse, cohabitation, young age, attitudes supportive of wife beating, having outside sexual partners, experiencing childhood abuse, growing up with domestic violence, and experiencing or perpetrating other forms of violence in adulthood, increased the risk of IPV. The strength of the association was greatest when both the woman and her partner had the risk factor.</p> <p>Conclusions</p> <p>IPV prevention programs should increase focus on transforming gender norms and attitudes, addressing childhood abuse, and reducing harmful drinking. Development initiatives to improve access to education for girls and boys may also have an important role in violence prevention.</p