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 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

Two Longterm Studies of Seasonal Variation in Depressive Symptoms among Community Participants

Background: There is evidence that seasonal variation in depressive symptoms is common in the population. However, research is limited by a reliance on longterm retrospective methods. Methods: Seasonal patterns were tested in two samples of community participants recruited in separate prospective studies in the Midwestern (n = 556 males/females) and Pacific Northwestern (n = 206 males) United States. Participants completed self-report measures of depressive symptoms 10-19 times from ages 14-36 years (n = 8,316 person observations). These data were compared with local meteorological conditions (e.g., solar radiation) recorded across the 2 weeks prior to each self-report. Results: In within-subjects analyses, participants’ depressive symptoms and the probability of clinically significant symptoms varied with the time of year, as hypothesized (highest in the weeks of early Winter; lowest in early Fall). However, effects sizes were modest and were not explained by recent sunlight or other meteorological conditions. Limitations: Samples were not nationally representative. Participants did not complete retrospective reports of seasonal depression or measures of current vegetative symptoms. Conclusions: Neither time of the year or recent seasonally linked meteorological conditions were powerful influences on depressive symptoms experienced by community populations in relevant geographic regions. Prior studies may have overestimated the prevalence and significance of seasonal variation in depressive symptoms for the general population.This is an author's peer-reviewed manuscript, as accepted by the publisher. The published article is copyrighted by Elsevier and can be found at: http://www.journals.elsevier.com/journal-of-affective-disorders/.Keywords: Seasonal depression, Adolescence, Community, Longitudina

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

Parental Monitoring During Early Adolescence Deters Adolescent Sexual Initiation: Discrete-Time Survival Mixture Analysis

We used discrete-time survival mixture modeling to examine 5,305 adolescents from the 1997 National Longitudinal Survey of Youth regarding the impact of parental monitoring during early adolescence (ages 14–16) on initiation of sexual intercourse and problem behavior engagement (ages 14–23). Four distinctive parental-monitoring groups were identified and labeled as “High,” “Increasing,” “Decreasing,” and “Low”. About 68% of adolescents received a high level of parental monitoring from ages 14 to 16 (High), 6 and 9% respectively exhibited an accelerated (Increasing) and a decelerated trajectory (Decreasing), and 17% had consistently low parental monitoring (Low). Relative to participants in the Low group, adolescents in the High group delayed sexual initiation by 1.5 years. Males, relative to females, were more likely to have had a low trajectory of parental monitoring, and were more likely to initiate sexual intercourse before age 14. In contrast to White Adolescents, Hispanics and Blacks were less likely to receive High parental monitoring, and had a higher rate of early sexual initiation before age 14. The study demonstrates the temporal relationship of parental monitoring with adolescent sexual initiation from a longitudinal perspective. An increase of parental monitoring across ages is accompanied with a decrease of sexual risk. The continual high level of parental monitoring from ages 14 to 16 also mitigated the risk of engagement in substance use and delinquent behaviors from ages 14 to 23

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