Search

Uncertainty quantification is crucial for any measurement technique. The present work aims at validating a priori estimates of displacement uncertainties. Images acquired prior to fourteen thermomechanical tests were analyzed via FE-based stereocorrelation to determine actual displacement uncertainties, which were compared to a priori estimates. For the studied experimental database, a very good agreement was observed between a priori and a posteriori estimates of standard displacement uncertainties. [ABSTRACT FROM AUTHOR]

Objective: There is extensive literature indicating that inflammatory pathways are affected in Alzheimer's disease (AD). We examined whether plasma exchange with albumin replacement (PE-Alb) can impact the inflammatory status of AD patients and alter the relationship between inflammatory mediators and cognitive measures., Methods: Serum and cerebrospinal fluid (CSF) samples from 142 AD patients participating in the AMBAR trial (14-month schedule of PE-Alb treatment vs. placebo [sham PE-Alb]) were analyzed for changes from baseline for 19 inflammatory mediators (6 inflammatory cytokines, 9 chemokines, and 4 vascular injury indicators) at representative time points across the AMBAR study (lasting effects) as well as in pre- versus post-PE-Alb procedure (acute effects). Association between mediator changes and clinical outcomes reported in the AMBAR study (cognitive, functional, behavioral function, and global change tests) was assessed., Results: PE-Alb significantly reduced IFN-γ, eotaxin, MIP-1α and ICAM-1 levels in serum, and eotaxin-3 and MIP-1β levels in CSF, at various time points during treatment (p < 0.05; false discovery rate-corrected). Vascular injury indicators were the mediators mostly affected by post- versus pre-PE-Alb level reduction. Increased serum MIP-1α levels were associated with worsening in ADAS-Cog, CDR-sb, and ADCS-CGIC scores in the placebo group, but not in the PE-Alb-treated group., Interpretation: Peripheral intervention could affect AD by reducing inflammatory mediators in both peripheral and central compartments. Changes in MIP-1α due to PE-Alb were associated with changes in clinical outcomes., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Small RNAs (sRNAs) are bioactive molecules that can be detected in biofluids, reflecting physiological and pathological states. In plasma, sRNAs are found within extracellular vesicles (EVs) and in extravesicular compartments, offering potential sources of highly sensitive biomarkers. Deep sequencing strategies to profile sRNAs favor the detection of microRNAs (miRNAs), the best-known class of sRNAs. Phospho-RNA-seq, through the enzymatic treatment of sRNAs with T4 polynucleotide kinase (T4-PNK), has been recently developed to increase the detection of thousands of previously inaccessible RNAs. In this study, we investigated the value of phospho-RNA-seq on both the EVs and extravesicular plasma subfractions. Phospho-RNA-seq increased the proportion of sRNAs used for alignment and highlighted the diversity of the sRNA transcriptome. Unsupervised clustering analysis using sRNA counts matrices correctly classified the EVs and extravesicular samples only in the T4-PNK treated samples, indicating that phospho-RNA-seq stresses the features of sRNAs in each plasma subfraction. Furthermore, T4-PNK treatment emphasized specific miRNA variants differing in the 5'-end (5'-isomiRs) and certain types of tRNA fragments in each plasma fraction. Phospho-RNA-seq increased the number of tissue-specific messenger RNA (mRNA) fragments in the EVs compared with the extravesicular fraction, suggesting that phospho-RNA-seq favors the discovery of tissue-specific sRNAs in EVs. Overall, the present data emphasizes the value of phospho-RNA-seq in uncovering RNA-based biomarkers in EVs.

Functional telomeres in yeast lacking telomerase can be restored by rare Rad51- or Rad59-dependent recombination events that lead to type I and type II survivors, respectively. We previously proposed that polySUMOylation of proteins and the SUMO-targeted ubiquitin ligase Slx5-Slx8 are key factors in type II recombination. Here, we show that SUMOylation of Rad52 favors the formation of type I survivors. Conversely, preventing Rad52 SUMOylation partially bypasses the requirement of Slx5-Slx8 for type II recombination. We further report that SUMO-dependent proteasomal degradation favors type II recombination. Finally, inactivation of Rad59, but not Rad51, impairs the relocation of eroded telomeres to the Nuclear Pore complexes (NPCs). We propose that Rad59 cooperates with non-SUMOylated Rad52 to promote type II recombination at NPCs, resulting in the emergence of more robust survivors akin to ALT cancer cells. Finally, neither Rad59 nor Rad51 is required by itself for the survival of established type II survivors., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Dengue is endemic in Brazil. The dengue surveillance system's reliance on passive reporting may underestimate disease incidence and cannot detect asymptomatic/pauci-symptomatic cases. In this 3-year prospective cohort study (NCT01391819) in 5- to 13-year-old children from nine schools in Fortaleza ( N = 2,117), we assessed dengue virus (DENV) infection seroprevalence by IgG indirect ELISA at yearly visits and disease incidence through active and enhanced passive surveillance. Real-time quantitative polymerase chain reaction (RT-qPCR) and DENV IgM/IgG capture ELISA were used for diagnosis. We further characterized confirmed and probable cases with a plaque reduction neutralization test. At enrollment, 54.1% (95% CI: 46.6, 61.4) of children were DENV IgG positive. The annual incidence of laboratory-confirmed symptomatic dengue cases was 11.0 (95% CI: 7.3, 14.7), 18.1 (10.4, 25.7), and 10.2 (0.7, 19.7), and of laboratory-confirmed or probable dengue cases with neutralizing antibody profile evocative of dengue exposure was 13.2 (6.6, 19.9), 18.7 (5.3, 32.2), and 8.4 (2.4, 19.2) per 1,000 child-years in 2012, 2013, and 2014, respectively. By RT-qPCR, we identified 14 DENV-4 cases in 2012-2013 and seven DENV-1 cases in 2014. During the course of the study, 32.8% of dengue-naive children experienced a primary infection. Primary inapparent dengue infection was detected in 20.3% (95% CI: 13.6, 29.1) of dengue-naive children in 2012, 8.7% (6.9, 10.9) in 2013, and 5.1% (4.4, 6.0) in 2014. Our results confirmed the high dengue endemicity in Fortaleza, with active and enhanced passive surveillance detecting three to five times more cases than the National System of Disease Notification.

The Nuclear Pore Complex (NPC) has emerged as an important hub for processing various types of DNA damage. Here, we uncover that fusing a DNA binding domain to the NPC basket protein Nup1 reduces telomere relocalization to nuclear pores early after telomerase inactivation. This Nup1 modification also impairs the relocalization to the NPC of expanded CAG/CTG triplet repeats. Strikingly, telomerase negative cells bypass senescence when expressing this Nup1 modification by maintaining a minimal telomere length compatible with proliferation through rampant unequal exchanges between sister chromatids. We further report that a Nup1 mutant lacking 36 C-terminal residues recapitulates the phenotypes of the Nup1-LexA fusion indicating a direct role of Nup1 in the relocation of stalled forks to NPCs and restriction of error-prone recombination between repeated sequences. Our results reveal a new mode of telomere maintenance that could shed light on how 20% of cancer cells are maintained without telomerase or ALT.

We are a European academic group of family doctors and we propose a definition of flexibility in family medicine. A review of the literature shows that flexibility and complexity are emerging concepts in the field of family practice. The outcomes of a workshop at the WONCA-Europe congress in 2014 are discussed. The flexibility is a capability of the general practitioner to deal with complex clinical situations in a biomedical and societal changing world. Flexibility is framed by ethics. It could improve the quality of care, be useful against burnout and used in medical research. In conclusion, family medicine should adopt a specific definition of the flexibility describing its specificity, a useful and teachable capacity.

Problem Addressed: For some family medicine supervisors working in rural and remote areas, access to face-to-face training is problematic. They need distance training programs designed specifically for them., Objective of Program: To study the advantages, disadvantages, and feasibility of a training program for these supervisors that is delivered over the Internet., Program Description: This was a pilot project for international on-line training consisting of a platform of courses and a collaborative type of Web conferencing that ran for 2 hours each week for 5 weeks. The training focused on the acquisition of teaching skills and the use of information and communications technology, and included discussions on topics related to practising and teaching in rural areas., Conclusion: Such a program is feasible and economical. The main difficulties are recruiting participants, keeping them in the program, and the amount of time spent on development and supervision. Participants who persevered reported high levels of satisfaction. The content of this type of training, barriers to participation, and the role of distance education in rural supervisor training programs remain to be explored.