We report the first measurements of self‐healing polymers with embedded shape‐memory alloy (SMA) wires. The addition of SMA wires shows improvements of healed peak fracture loads by up to a factor of ...1.6, approaching the performance of the virgin material. Moreover, the repairs can be achieved with reduced amounts of healing agent. The improvements in performance are due to two main effects: (i) crack closure, which reduces the total crack volume and increases the crack fill factor for a given amount of healing agent and (ii) heating of the healing agent during polymerization, which increases the degree of cure of the polymerized healing agent.
The performance of self‐healing polymers is improved by embedding shape‐memory alloy wires and activating them during healing. Increased healing efficiency is achieved by crack closure and heating of the healing agent during polymerization.
The current understanding of Arctic ecosystems is deeply rooted in the classical view of a bottom-up controlled system with strong physical forcing and seasonality in primary-production regimes. ...Consequently, the Arctic polar night is commonly disregarded as a time of year when biological activities are reduced to a minimum due to a reduced food supply. Here, based upon a multidisciplinary ecosystem-scale study from the polar night at 79°N, we present an entirely different view. Instead of an ecosystem that has entered a resting state, we document a system with high activity levels and biological interactions across most trophic levels. In some habitats, biological diversity and presence of juvenile stages were elevated in winter months compared to the more productive and sunlit periods. Ultimately, our results suggest a different perspective regarding ecosystem function that will be of importance for future environmental management and decision making, especially at a time when Arctic regions are experiencing accelerated environmental change 1.
•The polar night is not a time of biological quiescence•Biological rhythms and activity levels are retained during the polar night•Seabirds are overwintering and actively foraging throughout the polar night•Ecological processes across most phyla and trophic levels remain high
Berge et al. provide evidence that challenges the classical paradigm of biological quiescence during the Arctic polar night. Instead of an ecosystem that has entered a resting state, they document a system in which diversity, activity levels, and biological interactions across most trophic levels and phyla remain high during the winter.
Ion channels mediate voltage fluxes or action potentials that are central to the functioning of excitable cells such as neurons. The KCNB family of voltage-gated potassium channels (Kv) consists of ...two members (KCNB1 and KCNB2) encoded by KCNB1 and KCNB2, respectively. These channels are major contributors to delayed rectifier potassium currents arising from the neuronal soma which modulate overall excitability of neurons. In this study, we identified several mono-allelic pathogenic missense variants in KCNB2, in individuals with a neurodevelopmental syndrome with epilepsy and autism in some individuals. Recurrent dysmorphisms included a broad forehead, synophrys, and digital anomalies. Additionally, we selected three variants where genetic transmission has not been assessed, from two epilepsy studies, for inclusion in our experiments. We characterized channel properties of these variants by expressing them in oocytes of Xenopus laevis and conducting cut-open oocyte voltage clamp electrophysiology. Our datasets indicate no significant change in absolute conductance and conductance-voltage relationships of most disease variants as compared to wild type (WT), when expressed either alone or co-expressed with WT-KCNB2. However, variants c.1141A>G (p.Thr381Ala) and c.641C>T (p.Thr214Met) show complete abrogation of currents when expressed alone with the former exhibiting a left shift in activation midpoint when expressed alone or with WT-KCNB2. The variants we studied, nevertheless, show collective features of increased inactivation shifted to hyperpolarized potentials. We suggest that the effects of the variants on channel inactivation result in hyper-excitability of neurons, which contributes to disease manifestations.
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Channelopathies arise due to perturbations in ion channel function. In this study, we identify 10 variants in KCNB2 in individuals with neurodevelopmental disorders. Our data suggest that most KCNB2 variants show reduced potassium conductance due to either reduced functional expression or increased channel inactivation.
Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear.
We leveraged the International Study of Inflammation in COVID-19 (ISIC), a ...multicenter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy.
Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plasminogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 95% CI 0.78, 1.37). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels.
Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.
Young adult cancer survivors (YACS) are at elevated risk for chronic insomnia, even years after completing treatment. In addition to potential health consequences, insomnia can interrupt social, ...educational, and vocational development just as they are trying to "make up" for time lost to cancer. Cognitive behavioral therapy for insomnia (CBTI) is recommended as first-line treatment for insomnia but remains largely unavailable to YACS due to several barriers (ie, shortage of trained providers, geographic limitations, financial limitations). Traditional CBTI has not been adapted to meet YACS' unique developmental and circadian challenges. To improve availability of effective behavioral insomnia treatment for this population, we developed the Sleep Treatment Education Program for Young Adult Cancer Survivors (STEP-YA), a low-intensity educational intervention delivered virtually online.
In this phase 2 "proof of concept" trial, primary aims are to test the efficacy of STEP-YA to improve insomnia symptoms and mood in YACS and assess the utility of individualized coaching to improve treatment effects. A secondary aim will explore participant variables associated with clinically significant response to STEP-YA.
This 2-arm randomized prospective trial will enroll 74 off-treatment YACS aged 20 years to 39 years with clinically significant insomnia. Each participant completes the STEP-YA intervention in a 1-on-1 synchronous online session led by a trained interventionist following a structured outline. The 90-minute intervention presents educational information on the development of insomnia after cancer and offers specific suggestions for improving insomnia symptoms. During the session, participants review the suggestions and develop a personalized sleep action plan for implementing them. After the session, participants are randomized to either the coaching condition, in which they receive 2 telephone coaching sessions, or the no-coaching condition, which offers no subsequent coaching. The Insomnia Severity Index (ISI) and the Profile of Mood States: Short Form (POMS-SF) are assessed at baseline and 4 and 8 weeks postintervention.
Enrollment began in November 2022, with 28 participants currently enrolled. We anticipate recruitment will be completed in 2024. The primary endpoint is a change in ISI score from baseline to 8 weeks postintervention. The secondary endpoint is change in mood symptoms (POMS-SF) from baseline to 8 weeks postintervention. Change scores will be treated as continuous variables. Primary analyses will use ANOVA methods. A within-subjects analysis will examine if the STEP-YA intervention is associated with significant changes in insomnia and mood over time. A 2-way ANOVA will be used to evaluate the utility of coaching sessions to improve treatment effects.
Chronic insomnia has significant negative effects on YACS' medical, educational, and psychological functioning. STEP-YA aims to address their needs; study results will determine if the intervention warrants future effectiveness and dissemination studies and if individualized coaching is necessary for adequate treatment response.
ClinicalTrials.gov NCT05358951: https://clinicaltrials.gov/study/NCT05358951.
DERR1-10.2196/52315.
A major barrier to adeno-associated virus (AAV) gene therapy is the inability to re-dose patients due to formation of vector-induced neutralizing antibodies (Nabs). Tolerogenic nanoparticles ...encapsulating rapamycin (ImmTOR) provide long-term and specific suppression of adaptive immune responses, allowing for vector re-dosing. Moreover, co-administration of hepatotropic AAV vectors and ImmTOR leads to an increase of transgene expression even after the first dose. ImmTOR and AAV Anc80 encoding the methylmalonyl-coenzyme A (CoA) mutase (MMUT) combination was tested in a mouse model of methylmalonic acidemia, a disease caused by mutations in the MMUT gene. Repeated co-administration of Anc80 and ImmTOR was well tolerated and led to nearly complete inhibition of immunoglobulin (Ig)G antibodies to the Anc80 capsid. A more profound decrease of plasma levels of the key toxic metabolite, plasma methylmalonic acid (pMMA), and disease biomarker, fibroblast growth factor 21 (FGF21), was observed after treatment with the ImmTOR and Anc80-MMUT combination. In addition, there were higher numbers of viral genomes per cell (vg/cell) and increased transgene expression when ImmTOR was co-administered with Anc80-MMUT. These effects were dose-dependent, with the higher doses of ImmTOR providing higher vg/cell and mRNA levels, and an improved biomarker response. Combining of ImmTOR and AAV can not only block the IgG response against capsid, but it also appears to potentiate transduction and enhance therapeutic transgene expression in the mouse model.
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Kishimoto and colleagues extend their earlier findings showing that combining ImmTOR rapamycin-encapsulated nanoparticles with hepatotropic AAV vector leads to increased transduction, transgene expression, and suppression of IgG responses and therefore enables effective therapeutic AAV vector re-dosing in a mouse model of methylmalonic acidemia, an inborn metabolic disease.
High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD).
This study describes the molecular and clinical characterisation ...of 28 probands with NDD harbouring heterozygous
coding variants, occurring de novo for all those whose transmission could have been verified (26/28).
A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del).
encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations.
Our study establishes that de novo coding variants in
are involved in a novel monogenic form of NDD, highly similar to the recently reported
-related NDD.
Background: A history of diabetes mellitus and a diet high in glycemic load are both potential risk factors for pancreatic
cancer. Sugar-sweetened soft drinks are a prevalent source of readily ...absorbable sugars and have been associated with an increased
risk of obesity and diabetes. We investigated whether higher consumption of sugar-sweetened soft drinks increases the risk
of pancreatic cancer.
Methods: We examined the relation between consumption of sugar-sweetened soft drinks and the development of pancreatic cancer
in the Nurses' Health Study and the Health Professionals Follow-up Study. Among 88,794 women and 49,364 men without cancer
at baseline, we documented 379 cases of pancreatic cancer during up to 20 years of follow-up. Soft drink consumption was first
assessed at baseline (1980 for the women, 1986 for the men) and updated periodically thereafter.
Results: Compared with participants who largely abstained from sugar-sweetened soft drinks, those who consumed more than three
sugar-sweetened soft drinks weekly experienced overall a multivariate relative risk (RR) of pancreatic cancer of 1.13 95%
confidence interval (95% CI), 0.81-1.58; P for trend = 0.47. Women in the highest category of sugar-sweetened soft drink intake did experience a significant increase
in risk (RR, 1.57; 95% CI, 1.02-2.41; P for trend = 0.05), whereas there was no association between sweetened soft drink intake and pancreatic cancer among men.
Among women, the risk associated with higher sugar-sweetened soft drink was limited to those with elevated body mass index
(>25 kg/m 2 ; RR, 1.89; 95% CI, 0.96-3.72) or with low physical activity (RR, 2.02; 95% CI, 1.06-3.85). In contrast, consumption of diet
soft drinks was not associated with an elevated pancreatic cancer risk in either cohort.
Conclusion: Although soft drink consumption did not influence pancreatic cancer risk among men, consumption of sugar-sweetened
soft drinks may be associated with a modest but significant increase in risk among women who have an underlying degree of
insulin resistance.
In vitro experiments and limited animal studies suggest that aspirin and nonsteroidal anti-inflammatory drugs may inhibit pancreatic carcinogenesis. Because few studies have examined the association ...between aspirin use and pancreatic cancer in humans and the results have been inconsistent, we examined the relationship between aspirin use and the development of pancreatic cancer in the Nurses' Health Study.
Among 88 378 women without cancer at baseline, we documented 161 cases of pancreatic cancer during 18 years of follow-up. Aspirin use was first assessed at baseline in 1980 and updated biennially thereafter. All statistical tests were two-sided.
Participants were classified according to history of aspirin use. In a multivariable analysis, the risk of pancreatic cancer was not associated with current regular aspirin use (defined as two or more standard tablets per week; relative risk RR = 1.20, 95% confidence interval CI = 0.87 to 1.65), compared with use of fewer than two tablets per week. Increasing duration of regular aspirin use, compared with non-use, was associated with a statistically significant increase in risk: Women who reported more than 20 years of regular aspirin use had an increased risk of pancreatic cancer (RR = 1.58, 95% CI = 1.03 to 2.43; P(trend) =.01). Among women who reported aspirin use on at least two of three consecutive biennial questionnaires compared with consistent non-users of aspirin, the risk increased with dose (one to three tablets per week: RR = 1.11, 95% CI = 0.70 to 1.76; four to six tablets per week: RR = 1.29, 95% CI = 0.70 to 2.40; seven to 13 tablets per week: RR = 1.41, 95% CI = 0.76 to 2.61; and > or = 14 tablets per week: RR = 1.86, 95% CI = 1.03 to 3.35) (P(trend) =.02).
Extended periods of regular aspirin use appear to be associated with a statistically significantly increased risk of pancreatic cancer among women.
BACKGROUNDPrior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we ...assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline. METHODSPatients were identified using the RIKEE database and through clinical collaborators. Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings. FINDINGSDetailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment. R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects. Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits. INTERPRETATIONPatients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment. FUNDINGSupported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University of Antwerp, NINDS, and Chalk Family Foundation.
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