Intolerance of uncertainty does not significantly predict decisions about delayed, probabilistic rewards: A failure to replicate Luhmann, C. C., Ishida, K., & Hajcak, G. (2011).

Intolerance of Uncertainty (IU) is thought to lead to maladaptive behaviours and dysfunctional decision making, both in the clinical and healthy population. The seminal study reported by Luhmann and collaborators in 2011 showed that IU was negatively associated with choosing a delayed, but more certain and valuable, reward over choosing an immediate, but less certain and valuable, reward. These findings have been widely disseminated across the field of personality and individual differences because of their relevance to understand the role of IU in maladaptive behaviours in anxiety-related disorders. We conducted a study to replicate and extend Luhmann et al.'s results with a sample of 313 participants, which exceeded the size necessary (N = 266) to largely improve the statistical power of the original study by using the small telescopes approach. The results of our well powered study strongly suggest that the relationship between IU and the tendency to prefer an immediate, but less certain and less valuable reward is virtually negligible. Consequently, although this relationship cannot be definitely discarded, we conclude that it cannot be detected with Luhmann et al.'s (2011) decision-making task.

SLPI overexpression in hMSCs could be implicated in the HSC gene expression profile in AML.

Acute myeloid leukaemia (AML) is a severe haematological neoplasm that originates from the transformation of haematopoietic stem cells (HSCs) into leukaemic stem cells (LSCs). The bone marrow (BM) microenvironment, particularly that of mesenchymal stromal cells (hMSCs), plays a crucial role in the maintenance of HSCs. In this context, we explored whether alterations in the secretome of hMSCs derived from AML patients (hMSC-AML) could impact HSC gene expression. Proteomic analysis revealed that the secretome of coculture assays with hMSC-AMLs and HSC from healthy donor is altered, with increased levels of secretory leukocyte protease inhibitor (SLPI), a protein associated with important processes for maintenance of the haematopoietic niche that has already been described to be altered in several tumours. Increased SLPI expression was also observed in the BM plasma of AML patients. Transcriptome analysis of HSCs cocultured with hMSC-AML in comparison with HSCs cocultured with hMSC-HD revealed altered expression of SLPI target genes associated with the cell cycle, proliferation, and apoptosis. Important changes were identified, such as increased expression levels of CCNA2, CCNE2, CCND2, CD133 and CDK1 and decreased levels of CDKN2A and IGFBP3, among others. Overall, these findings suggest that the altered secretome of coculture assays with hMSC-AMLs and HSC from healthy donor, particularly increased SLPI expression, can contribute to gene expression changes in HSCs, potentially influencing important molecular mechanisms related to AML development and progression.

Characterisation of biocondensate microfluidic flow using array-detector FCS.

BACKGROUND: Biomolecular condensation via liquid-liquid phase separation (LLPS) is crucial for orchestrating cellular activities temporospatially. Although the rheological heterogeneity of biocondensates and the structural dynamics of their constituents carry critical functional information, methods to quantitatively study biocondensates are lacking. Single-molecule fluorescence research can offer insights into biocondensation mechanisms. Unfortunately, as dense condensates tend to sink inside their dilute aqueous surroundings, studying their properties via methods relying on Brownian diffusion may fail. METHODS: We take a first step towards single-molecule research on condensates of Tau protein under flow in a microfluidic channel of an in-house developed microfluidic chip. Fluorescence correlation spectroscopy (FCS), a well-known technique to collect molecular characteristics within a sample, was employed with a newly commercialised technology, where FCS is performed on an array detector (AD-FCS), providing detailed diffusion and flow information. RESULTS: The AD-FCS technology allowed characterising our microfluidic chip, revealing 3D flow profiles. Subsequently, AD-FCS allowed mapping the flow of Tau condensates while measuring their burst durations through the stationary laser. Lastly, AD-FCS allowed obtaining flow velocity and burst duration data, the latter of which was used to estimate the condensate size distribution within LLPS samples. CONCLUSION: Studying biocondensates under flow through AD-FCS is promising for single-molecule experiments. In addition, AD-FCS shows its ability to estimate the size distribution in condensate samples in a convenient manner, prompting a new way of investigating biocondensate phase diagrams. GENERAL SIGNIFICANCE: We show that AD-FCS is a valuable tool for advancing research on understanding and characterising LLPS properties of biocondensates.

MORC2 phosphorylation fine tunes its DNA compaction activity.

Variants in the poorly characterised oncoprotein, MORC2, a chromatin remodelling ATPase, lead to defects in epigenetic regulation and DNA damage response. The C-terminal domain (CTD) of MORC2, frequently phosphorylated in DNA damage, promotes cancer progression, but its role in chromatin remodelling remains unclear. Here, we report a molecular characterisation of full-length, phosphorylated MORC2, demonstrating its preference for binding open chromatin and functioning as a DNA sliding clamp. We identified a phosphate interacting motif within the CTD that dictates ATP hydrolysis rate and cooperative DNA binding. The DNA binding impacts several structural domains within the ATPase region. We provide the first visual proof that MORC2 induces chromatin remodelling through ATP hydrolysis-dependent DNA compaction, regulated by its phosphorylation state. These findings highlight phosphorylation of MORC2 CTD as a key modulator of chromatin remodelling, presenting it as a potential therapeutic target.

The lowdown on breakdown: Open questions in plant proteolysis.

Proteolysis, including post-translational proteolytic processing as well as protein degradation and amino acid recycling, is an essential component of the growth and development of living organisms. In this article, experts in plant proteolysis pose and discuss compelling open questions in their areas of research. Topics covered include the role of proteolysis in the cell cycle, DNA damage response, mitochondrial function, the generation of N-terminal signals (degrons) that mark many proteins for degradation (N-terminal acetylation, the Arg/N-degron pathway, and the chloroplast N-degron pathway), developmental and metabolic signaling (photomorphogenesis, abscisic acid and strigolactone signaling, sugar metabolism, and post-harvest regulation), plant responses to environmental signals (endoplasmic-reticulum associated degradation, chloroplast-associated degradation, drought tolerance, the growth-defense tradeoff)), and the functional diversification of peptidases. We hope these thought-provoking discussions help to stimulate further research.

Colchicine in acute heart failure: Rationale and design of a randomized double-blind placebo-controlled trial (COLICA).

AIMS: Heart failure (HF) elicits a pro-inflammatory state, which is associated with impaired clinical outcomes, but no anti-inflammatory therapies have demonstrated a clinical benefit yet. Inflammatory pathways related with the interleukin-1 axis are overactivated during episodes of acute HF. Colchicine, an anti-inflammatory drug with proven benefits in acute pericarditis and ischaemic heart disease, may target this inflammatory response. This study aims to assess the efficacy of colchicine in acute HF patients. METHODS: COLICA is a multicentre, randomized, double-blind, placebo-controlled trial enrolling 278 patients across 12 sites. Patients presenting with acute HF, clinical evidence of congestion requiring ≥40 mg of intravenous furosemide and N-terminal pro-B-type natriuretic peptide (NT-proBNP) >900 pg/ml, are eligible for participation. Patients are enrolled irrespective of left ventricular ejection fraction, HF type (new-onset or not) and setting (hospital or outpatient clinic). Patients are randomized 1:1 within the first 24 h of presentation to either placebo or colchicine, with an initial loading dose of 2 mg followed by 0.5 mg every 12 h for 8 weeks (reduced dose if <70 kg, >75 years old, or glomerular filtration rate <50 ml/min/1.73 m2). The primary efficacy endpoint is the time-averaged proportional change in NT-proBNP concentrations from baseline to week 8. Key secondary and exploratory outcomes include symptoms, diuretic use, worsening HF episodes, related biomarkers of cardiac stress and inflammation, total and cardiovascular readmissions, mortality and safety events. CONCLUSION: COLICA will be the first randomized trial testing the efficacy and safety of colchicine for acute HF.

Relative pedaling forces are low during cycling.

We quantified and compared the mechanical force demands relative to the maximum dynamic force (MDF) of 11 cyclists when pedaling at different intensities (ventilatory threshold, maximum lactate steady state, respiratory compensation point, and maximal aerobic power), cadences (free, 40, 60 and 80 rpm), and all-out resisted sprints. Relative force demands (expressed as %MDF) progressively increased with higher intensities (p < 0.001) and lower cadences (p < 0.001). Notwithstanding, relative force demands were low (<54 % MDF) for all conditions, even during the so-called 'torque training'. These results might be useful when programming on-bike resistance training to improve torque production capacity.

NF1+/ex42del miniswine model the cellular disruptions and behavioral presentations of NF1-associated cognitive and motor impairment.

Cognitive or motor impairment is common among individuals with neurofibromatosis type 1 (NF1), an autosomal dominant tumor-predisposition disorder. As many as 70% of children with NF1 report difficulties with spatial/working memory, attention, executive function, and fine motor movements. In contrast to the utilization of various Nf1 mouse models, here we employ an NF1+/ex42del miniswine model to evaluate the mechanisms and characteristics of these presentations, taking advantage of a large animal species more like human anatomy and physiology. The prefrontal lobe, anterior cingulate, and hippocampus from NF1+/ex42del and wild-type miniswine were examined longitudinally, revealing abnormalities in mature oligodendrocytes and astrocytes, and microglial activation over time. Imbalances in GABA: Glutamate ratios and GAD67 expression were observed in the hippocampus and motor cortex, supporting the role of disruption in inhibitory neurotransmission in NF1 cognitive impairment and motor dysfunction. Moreover, NF1+/ex42del miniswine demonstrated slower and shorter steps, indicative of a balance-preserving response commonly observed in NF1 patients, and progressive memory and learning impairments. Collectively, our findings affirm the effectiveness of NF1+/ex42del miniswine as a valuable resource for assessing cognitive and motor impairments associated with NF1, investigating the involvement of specific neural circuits and glia in these processes, and evaluating potential therapeutic interventions.

Mastoparan-7 adjuvanted COBRA H1 and H3 hemagglutinin influenza vaccines.

Adjuvants enhance, prolong, and modulate immune responses by vaccine antigens to maximize protective immunity and enable more effective immunization in the young and elderly. Most adjuvants are formulated with injectable vaccines. However, an intranasal route of vaccination may induce mucosal and systemic immune responses for enhancing protective immunity in individuals and be easier to administer compared to injectable vaccines. In this study, a next generation of broadly-reactive influenza hemagglutinin (HA) vaccines were developed using the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology. These HA vaccines were formulated with Mastoparan 7 (M7-NH2) mast cell degranulating peptide adjuvant and administered intranasally to determine vaccine-induced seroconversion of antibodies against a panel of influenza viruses and protection following infection with H1N1 and H3N2 viruses in mice. Mice vaccinated intranasally with M7-NH2-adjuvanted COBRA HA vaccines had high HAIs against a panel of H1N1 and H3N2 influenza viruses and were protected against both morbidity and mortality, with reduced viral lung titers, following challenge with an H1N1 influenza virus. Additionally, M7-NH2 adjuvanted COBRA HA vaccines induced Th2 skewed immune responses with robust IgG and isotype antibodies in the serum and mucosal lung lavages. Overall, this intranasally delivered M7-NH2 -adjuvanted COBRA HA vaccine provides effective protection against drifted H1N1 and H3N2 viruses.

Association of intrinsic capacity with functional decline and mortality in older adults: a systematic review and meta-analysis of longitudinal studies.

BACKGROUND: Together with environmental factors, intrinsic capacity (the composite of all the physical and mental capacities of an individual) has been proposed as a marker of healthy ageing. However, whether intrinsic capacity predicts major clinical outcomes is unclear. We aimed to explore the association of intrinsic capacity with functional decline and mortality in older adults. METHODS: In this systematic review and meta-analysis, we conducted a systematic search in MEDLINE (via PubMed), Scopus, and Web of Science from database inception to Feb 14, 2024, of observational longitudinal studies conducted in older adults (age ≥60 years) assessing the association of intrinsic capacity with impairment in basic activities of daily living (BADL) or instrumental activities of daily living (IADL) or risk of mortality. Estimates were extracted by two reviewers (JLS-S and W-HL) and were pooled using three-level meta-analytic models. The quality of each study was independently assessed by two authors (JLS-S and PLV) using the Newcastle-Ottawa Scale for longitudinal studies. Heterogeneity was evaluated using the I2 indicator at two levels: within-study (level 2) and between-study (level 3) variation. For associations between intrinsic capacity and IADL and BADL, we transformed data (standardised ß coefficients and odds ratios [ORs]) into Pearson product moment correlation coefficients (r) using Pearson and Digby formulas to allow comparability across studies. For associations between intrinsic capacity and risk of mortality, hazard ratios (HRs) with 95% CIs were extracted from survival analyses. This study is registered with PROSPERO, CRD42023460482. FINDINGS: We included 37 studies (206 693 participants; average age range 65·3-85·9 years) in the systematic review, of which 31 were included in the meta-analysis on the association between intrinsic capacity and outcomes; three studies (2935 participants) were included in the meta-analysis on the association between intrinsic capacity trajectories and longitudinal changes in BADL or IADL. Intrinsic capacity was inversely associated with longitudinal impairments in BADL (Pearson's r -0·12 [95% CI -0·19 to -0·04]) and IADL (-0·24 [-0·35 to -0·13]), as well as with mortality risk (hazard ratio 0·57 [95% CI 0·51 to 0·63]). An association was also found between intrinsic capacity trajectories and impairment in IADL (but not in BADL), with maintained or improved intrinsic capacity over time associated with a lower impairment in IADL (odds ratio 0·37 [95% CI 0·19 to 0·71]). There was no evidence of publication bias (Egger's test p>0·05) and there was low between-study heterogeneity (I2=18·4%), though within-study (I2=63·2%) heterogeneity was substantial. INTERPRETATION: Intrinsic capacity is inversely associated with functional decline and mortality risk in older adults. These findings could support the use of intrinsic capacity as a marker of healthy ageing, although further research is needed to refine the structure and operationalisation of this construct across settings and populations. FUNDING: None. TRANSLATIONS: For the Spanish and French translations of the abstract see Supplementary Materials section.

Neutrophils cultured ex vivo from CD34+ stem cells are immature and genetically tractable.

BACKGROUND: Neutrophils are granulocytes with essential antimicrobial effector functions and short lifespans. During infection or sterile inflammation, emergency granulopoiesis leads to release of immature neutrophils from the bone marrow, serving to boost circulating neutrophil counts. Steady state and emergency granulopoiesis are incompletely understood, partly due to a lack of genetically amenable models of neutrophil development. METHODS: We optimised a method for ex vivo production of human neutrophils from CD34+ haematopoietic progenitors. Using flow cytometry, we phenotypically compared cultured neutrophils with native neutrophils from donors experiencing emergency granulopoiesis, and steady state neutrophils from non-challenged donors. We carry out functional and proteomic characterisation of cultured neutrophils and establish genome editing of progenitors. RESULTS: We obtain high yields of ex vivo cultured neutrophils, which phenotypically resemble immature neutrophils released into the circulation during emergency granulopoiesis. Cultured neutrophils have similar rates of ROS production and bacterial killing but altered degranulation, cytokine release and antifungal activity compared to mature neutrophils isolated from peripheral blood. These differences are likely due to incomplete synthesis of granule proteins, as demonstrated by proteomic analysis. CONCLUSION: Ex vivo cultured neutrophils are genetically tractable via genome editing of precursors and provide a powerful model system for investigating the properties and behaviour of immature neutrophils.

Data-driven modeling of equatorial atmospheric waves: The role of moisture and nonlinearity on global-scale instabilities and propagation speeds.

The equatorial region of the Earth's atmosphere serves as both a significant locus for phenomena, including the Madden-Julian Oscillation (MJO), and a source of formidable complexity. This complexity arises from the intricate interplay between nonlinearity and thermodynamic processes, particularly those involving moisture. In this study, we employ a normal mode decomposition of atmospheric reanalysis ERA-5 datasets to investigate the influence of nonlinearity and moisture on amplitude growth, propagation speed, and mode coupling associated with equatorially trapped waves. We focus our analysis on global-scale baroclinic Kelvin and Rossby waves, recognized as crucial components contributing to the variability of the MJO. We examine the dependence of wave amplitudes on the background moisture field in the equatorial region, as measured by total column water vapor. Our analysis demonstrates the crucial role of moisture in exciting these waves. We further investigate the dependence of the propagation speed of the waves on their amplitudes and the background moisture field. Our analysis reveals a robust correlation between the phase speed of the normal modes and their corresponding amplitude, whereas a weaker correlation is found between the eigenmodes' phase speed and the moisture field. Hence, our findings suggest that moisture plays a role in exciting the global-scale Rossby-Kelvin structure of the MJO. In this context, the propagation speed of the eigenmodes is mainly influenced by their amplitudes, underscoring the significant role of nonlinearity in wave propagation.

Juvenile Hormone as a contributing factor in establishing midgut microbiota for fecundity and fitness enhancement in adult female Aedes aegypti.

Understanding the factors influencing mosquitoes' fecundity and longevity is important for designing better and more sustainable vector control strategies, as these parameters can impact their vectorial capacity. Here, we address how mating affects midgut growth in Aedes aegypti, what role Juvenile Hormone (JH) plays in this process, and how it impacts the mosquito's immune response and microbiota. Our findings reveal that mating and JH induce midgut growth. Additionally, the establishment of a native bacterial population in the midgut due to JH-dependent suppression of the immune response has important reproductive outcomes. Specific downregulation of AMPs with an increase in bacteria abundance in the gut results in increased egg counts and longer lifespans. Overall, these findings provide evidence of a cross-talk between JH response, gut epithelial tissue, cell cycle regulation, and the mechanisms governing the trade-offs between nutrition, immunity, and reproduction at the cellular level in the mosquito gut.

Effect of coenzyme Q10 supplementation on statin-related myopathic pain: a systematic review and meta-analysis of randomized controlled trials

INTRODUCTION: Coenzyme Q10 (CoQ10) has shown promising results as an adjuvant therapy to statins. However, the efficacy of this agent is still unclear. Hypothesis: The use of CoQ10 mitigates statin-related myopathic pain. METHODS: PubMed, Embase, and Cochrane databases were searched for randomized controlled trials (RCTs) comparing CoQ10 supplementation with placebo in patients taking statins. A random-effects model was employed to compute the mean difference (MD) with 95% confidence interval (CI). Statistical analysis was performed using R software 4.3.1. RESULTS: A total of 5 studies and 227 patients were included, of whom 48% were randomized to CoQ10 supplementation. Compared with placebo, CoQ10 had no effects on pain severity score (MD -0.94; 95% CI -3.80 to 1.91; p=0.5), and pain intensity score (MD -1.51; 95% CI -4.09 to 1.06; p = 0.2). Moreover, no association was found with low density lipoprotein cholesterol levels (MD -0.07; 95% CI -0.47 to 0.34; p = 0.7). CONCLUSIONS: In this meta-analysis of 5 RCTs, supplementation with CoQ10 did not yield statistically significant results. These findings suggest that CoQ10 has no impact on statin-related myopathic pain.

LANDMARK comparison of early outcomes of newer-generation Myval transcatheter heart valve series with contemporary valves (Sapien and Evolut) in real-world individuals with severe symptomatic native aortic stenosis: a randomised non-inferiority trial

BACKGROUND Transcatheter aortic valve implantation is an established, guideline-endorsed treatment for severe aortic stenosis. Precise sizing of the balloon-expandable Myval transcatheter heart valve (THV) series with the aortic annulus is facilitated by increasing its diameter in 1•5 mm increments, compared with the usual 3 mm increments in valve size. The LANDMARK trial aimed to show non-inferiority of the Myval THV series compared with the contemporary THVs Sapien Series (Edwards Lifesciences, Irvine, CA, USA) or Evolut Series (Medtronic, Minneapolis, MN, USA). METHODS In this prospective, multinational, randomised, open-label, non-inferiority trial across 31 hospitals in 16 countries (Germany, France, Sweden, the Netherlands, Italy, Spain, New Zealand, Portugal, Greece, Hungary, Poland, Slovakia, Slovenia, Croatia, Estonia, and Brazil), 768 participants with severe symptomatic native aortic stenosis were randomly assigned (1:1) to the Myval THV or a contemporary THV. Eligibility was primarily decided by the heart team in accordance with 2021 European Society of Cardiology guidelines. As per the criteria of the third Valve Academic Research Consortium, the primary endpoint at 30 days was a composite of all-cause mortality, all stroke, bleeding (types 3 and 4), acute kidney injury (stages 2­4), major vascular complications, moderate or severe prosthetic valve regurgitation, and conduction system disturbances resulting in a permanent pacemaker implantation. Non-inferiority of the study device was tested in the intention-to-treat population using a non-inferiority margin of 10•44% and assuming an event rate of 26•10%. This trial is registered with ClinicalTrials.gov, NCT04275726, and EudraCT, 2020-000137-40, and is closed to new participants. FINDINGS Between Jan 6, 2021, and Dec 5, 2023, 768 participants with severe symptomatic native aortic stenosis were randomly assigned, 384 to the Myval THV and 384 to a contemporary THV. 369 (48%) participants had their sex recorded as female, and 399 (52%) as male. The mean age of participants was 80•0 years (SD 5•7) for those treated with the Myval THV and 80•4 years (5•4) for those treated with a contemporary THV. Median Society of Thoracic Surgeons scores were the same in both groups (Myval 2•6% [IQR 1•7­4•0] vs contemporary 2•6% [1•7­4•0]). The primary endpoint showed non-inferiority of the Myval (25%) compared with contemporary THV (27%), with a risk difference of ­2•3% (one-sided upper 95% CI 3•8, pnon-inferiority<0•0001). No significant difference was seen in individual components of the primary composite endpoint. INTERPRETATION In individuals with severe symptomatic native aortic stenosis, the Myval THV met its primary endpoint at 30 days.

Influence of Preterm Birth and Low Birthweight on Physical Fitness: A Systematic Review, Meta-Analysis, and Meta-Regression.

BACKGROUND: Preterm birth and low birthweight (LBW) might be associated with reduced physical fitness, although evidence remains inconclusive. OBJECTIVE: To examine the influence of preterm birth and LBW on physical fitness, as well as to assess whether variables such as gestational age, birthweight, or age at assessment moderate these effects. METHODS: PubMed, Scopus, and PsycINFO were systematically searched from inception to 7 December 2023 for case-control and cohort studies analyzing the association between preterm birth or LBW (or gestational age or birthweight as continuous variables) with at least one physical fitness-related outcome (i.e., cardiorespiratory fitness (CRF), muscle strength, flexibility, speed, agility). Random-effects meta-analysis and meta-regression models were used to estimate the pooled effect size, as well as to examine potential associations between the magnitude of the effect and gestational age, birthweight, or age at assessment. RESULTS: Fifty-two studies (n = 920,603 participants, average age ranging from 4.7 to 34.4 years) were included. Preterm birth was associated with reduced CRF (standardized mean difference (SMD) = -0.38, 95% confidence interval (CI) = -0.51 to -0.25) and muscle strength (SMD = -0.44, 95% CI = -0.79 to -0.08). LBW was associated with reduced CRF (SMD = -0.40, 95% CI = -0.64 to -0.17), muscle strength (SMD = -0.18, 95% CI = -0.24 to -0.13), flexibility (SMD = -0.11, 95% CI = -0.22 to -0.01), and agility (SMD = -0.99, 95% CI = -1.91 to -0.07). Meta-regression analyses showed that a lower gestational age or birthweight were associated with larger reductions in physical fitness, whereas no consistent association was found for the age at assessment. CONCLUSION: Both preterm birth and LBW seem associated with reduced physical fitness regardless of age, with larger reductions overall observed in individuals with lower gestational age or birthweight. These findings might support the implementation of preventive strategies (e.g., fitness monitoring and physical exercise interventions) in these populations through the life course. PROSPERO registration: CRD42021231845.

Variable Penetrance and Expressivity of a Rare Pore Loss-of-Function Mutation (p.L889V) of Nav1.5 Channels in Three Spanish Families.

A novel rare mutation in the pore region of Nav1.5 channels (p.L889V) has been found in three unrelated Spanish families that produces quite diverse phenotypic manifestations (Brugada syndrome, conduction disease, dilated cardiomyopathy, sinus node dysfunction, etc.) with variable penetrance among families. We clinically characterized the carriers and recorded the Na+ current (INa) generated by p.L889V and native (WT) Nav1.5 channels, alone or in combination, to obtain further insight into the genotypic-phenotypic relationships in patients carrying SCN5A mutations and in the molecular determinants of the Nav1.5 channel function. The variant produced a strong dominant negative effect (DNE) since the peak INa generated by p.L889V channels expressed in Chinese hamster ovary cells, either alone (-69.4 ± 9.0 pA/pF) or in combination with WT (-62.2 ± 14.6 pA/pF), was significantly (n ≥ 17, p < 0.05) reduced compared to that generated by WT channels alone (-199.1 ± 44.1 pA/pF). The mutation shifted the voltage dependence of channel activation and inactivation to depolarized potentials, did not modify the density of the late component of INa, slightly decreased the peak window current, accelerated the recovery from fast and slow inactivation, and slowed the induction kinetics of slow inactivation, decreasing the fraction of channels entering this inactivated state. The membrane expression of p.L889V channels was low, and in silico molecular experiments demonstrated profound alterations in the disposition of the pore region of the mutated channels. Despite the mutation producing a marked DNE and reduction in the INa and being located in a critical domain of the channel, its penetrance and expressivity are quite variable among the carriers. Our results reinforce the argument that the incomplete penetrance and phenotypic variability of SCN5A loss-of-function mutations are the result of a combination of multiple factors, making it difficult to predict their expressivity in the carriers despite the combination of clinical, genetic, and functional studies.

Reducing delivery insurance costs through risk score model for food delivery company.

In this paper, we propose a novel pricing model for delivery insurance in a food delivery company in Latin America, with the aim of reducing the high costs associated with the premium paid to the insurer. To achieve this goal, a thorough analysis was conducted to estimate the probability of losses based on delivery routes, transportation modes, and delivery drivers' profiles. A large amount of data was collected and used as a database, and various statistical models and machine learning techniques were employed to construct a comprehensive risk profile and perform risk classification. Based on the risk classification and the estimated probability associated with it, a new pricing model for delivery insurance was developed using advanced mathematical algorithms and machine learning techniques. This new pricing model took into account the pattern of loss occurrence and high and low-risk behaviors, resulting in a significant reduction of insurance costs for both the contracting company and the insurer. The proposed pricing model also allowed for greater flexibility in insurance contracting, making it more accessible and appealing to delivery drivers. The use of estimated loss probabilities and a risk score for the pricing of delivery insurance proved to be a highly effective and efficient alternative for reducing the high costs associated with insurance, while also improving the profitability and competitiveness of the food delivery company in Latin America.