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Mutations in ANXA11 cause amyotrophic lateral sclerosis (ALS) and have recently been identified as a cause of multisystem proteinopathy and adult-onset muscular dystrophy. These conditions are adult-onset diseases and result from the substitution of Aspartate 40 (Asp40) for an apolar residue in the intrinsically disordered domain (IDD) of ANXA11. Some ALS-related variants are known to affect ANXA11 IDD; however, the mechanism by which the myopathy occurs is unknown.Genetic analysis was performed using WES-trio. For the study of variant pathogenicity, we used recombinant proteins, muscle biopsy, and fibroblasts.Here we describe an individual with severe and rapidly progressive childhood-onset oculopharyngeal muscular dystrophy who carries a new ANXA11 variant at position Asp40 (p.Asp40Ile; c.118_119delGAinsAT). p.Asp40Ile is predicted to enhance the aggregation propensity of ANXA11 to a greater extent than other changes affecting this residue. In vitro studies using recombinant ANXA11p.Asp40Ile showed abnormal phase separation and confirmed this variant is more aggregation-prone than the ALS-associated variant ANXA11p.Asp40Gly . The study of the patient's fibroblasts revealed defects in stress granules dynamics and clearance, and muscle histopathology showed a myopathic pattern with ANXA11 protein aggregates. Super-resolution imaging showed aggregates expressed as pearl strips or large complex structures in the sarcoplasm, and as layered subsarcolemmal chains probably reflecting ANXA11 multifunctionality.We demonstrate common pathophysiology for disorders associated with ANXA11 Asp40 allelic variants. Clinical phenotypes may result from different deleterious impacts of variants upon ANXA11 stability against aggregation, and differential muscle or motor neuron dysfunction expressed as a temporal and tissue-specific continuum.© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Lysine-specific demethylase 1 (LSD1) inhibitor; Neuroendocrine tumor; Non-Hodgkin lymphoma Tumor neuroendocrino; Linfoma no Hodgkin; Inhibidores de desmetilasa-1 específica a lisina Tumor neuroendocrí; Limfoma no Hodgkin; Inhibidor de la desmetilasa-1 específica a la lisina Background CC-90011 is an oral, potent, selective, reversible inhibitor of lysine-specific demethylase 1 (LSD1) that was well tolerated, with encouraging activity in patients who had advanced solid tumors or relapsed/refractory marginal zone lymphoma. The authors present long-term safety and efficacy and novel pharmacodynamic and pharmacokinetic data from the first-in-human study of CC-90011. Methods CC-90011-ST-001 (ClincalTrials.gov identifier NCT02875223; Eudract number 2015–005243-13) is a phase 1, multicenter study in which patients received CC-90011 once per week in 28-day cycles. The objectives were to determine the safety, maximum tolerated dose, and/or recommended phase 2 dose (primary) and to evaluate preliminary efficacy and pharmacokinetics (secondary). Results Sixty-nine patients were enrolled, including 50 in the dose-escalation arm and 19 in the dose-expansion arm. Thrombocytopenia was the most common treatment-related adverse event and was successfully managed with dose modifications. Clinical activity with prolonged, durable responses were observed, particularly in patients who had neuroendocrine neoplasms. In the dose-escalation arm, one patient with relapsed/refractory marginal zone lymphoma achieved a complete response (ongoing in cycle 58). In the dose-expansion arm, three patients with neuroendocrine neoplasms had stable disease after nine or more cycles, including one patient who was in cycle 46 of ongoing treatment. CC-90011 decreased levels of secreted neuroendocrine peptides chromogranin A, progastrin-releasing peptide, and RNA expression of the blood pharmacodynamic marker monocyte-to-macrophage differentiation–associated. Conclusions The safety profile of CC-90011 suggested that its reversible mechanism of action may provide an advantage over other irreversible LSD1 inhibitors. The favorable tolerability profile, clinical activity, durable responses, and once-per-week dosing support further exploration of CC-90011 as monotherapy and in combination with other treatments for patients with advanced solid tumors and other malignancies. This study was supported by Bristol Myers Squibb, Princeton, New Jersey, USA. Writing and editorial assistance was provided by Bio Connections, LLC, funded by Bristol Myers Squibb.

Stress cardiac MRI permits comprehensive evaluation of patients with known or suspected chronic coronary syndromes (CCS). The impact of sex on the use of invasive cardiac angiography (ICA) after vasodilator stress cardiac MRI is unclear.To evaluate the impact of sex on ICA use after vasodilator stress cardiac MRI.Retrospective.A total of 6229 consecutive patients (age [mean ± standard deviation] 65.2 ± 11.5 years, 38.1% women).A 5-T; a steady-state free-precession cine sequence; stress first-pass perfusion imaging; late enhancement imaging.Patients underwent vasodilator stress cardiac MRI for known or suspected CCS. The ischemic burden (at stress first-pass perfusion imaging) was computed (17-segment model).Multivariate logistic regression was used to evaluate the potential differential association between ischemic burden and use of cardiac MRI-related ICA across sex.A total of 1109 (17.8%) patients were referred to ICA, among which there were significantly more men (762, 19.7%) than women (347, 14.6%). Overall, after multivariate adjustment, female sex was not associated with lower use of ICA (odds ratio [OR] = 0.99; confidence interval [CI] 95%: 0.84-1.18, P = 0.934). However, significant sex differences were detected across ischemic burden. Whereas women with nonischemic vasodilator stress cardiac MRI (0 ischemic segments) were less commonly submitted to ICA (OR = 0.49; CI 95%: 0.35-0.69) in patients with ischemia (1 ischemic segment), adjusted use of ICA was more frequent in women than men (OR = 1.27; CI 95%: 1.1-1.5).In patients with known or suspected CCS submitted to undergo vasodilator stress cardiac MRI, cardiac MRI-related ICA may be overused in men without ischemia. Furthermore, ICA referral in patients with negative ischemia resulted in greater odds of revascularization in men.3 TECHNICAL EFFICACY: Stage 5.

Hydropeaking negatively affects fish assemblages, but knowledge gaps still constrain our ability to rank and mitigate the impacts of different hydropower operation regimes at particular power plants. This is especially relevant for species and rivers for which the effects of hydropeaking are less investigated, such as the Iberian Cypriniformes and Mediterranean rivers. Recognizing the potential of the hydropeaking tool method (HT) developed for salmonids to systematically assess hydropeaking impacts, we adapted it for Iberian Cypriniformes. The general tool framework developed for the salmonids was kept for the Cypriniformes, with the combined use of factors describing the hydromorphological effects and factors related with fish vulnerability to assess hydropeaking impact. Effect and vulnerability factors were developed for Iberian cyprinids and leuciscids establishing preliminary thresholds for each indicator with three different levels of hydropeaking impact on the targeted taxa. The proposed factors and thresholds were critically reviewed and ranked by experts on Iberian Cypriniformes ecology and Mediterranean rivers functioning. Overall, the timing and distribution of peaking events were ranked higher by the experts in the effect factors, whereas the population size of barbel and smaller native Cypriniformes, as well as the degree of limitations in recruitment, were ranked higher in the vulnerability factors. Although there was some divergence in the expert opinions, a final set of effect and vulnerability factors was established, that retained most of the ones proposed for the salmonids, but included new ones, particularly for vulnerability. The present study provided a comprehensive, straightforward, and systematic assessment tool for evaluating hydropeaking impacts on Iberian Cypriniformes. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No. 727830, http://www.fithydro.eu/

This chapter explores how citizen reporters mobilized in the quests to assist failing mediatic infrastructures and to create transparency devices that morally exhorted traditional media workers to react properly to the turmoil and against disinformation. While these newfangled projects are ingenious, it argues that their innovations are also indicative of what Chilean citizen journalists and digital activists thought was missing from the already large ecology of media organizations in the country with regard to enacting authentic journalistic principles. Digital or online journalism is uninterrupted in its transformation of the ways in which information and communication technologies are being used by media workers. FastCheck is making the process of fact-checking both popular and transparent, incentivizing citizens to participate actively in such an endeavor. Both professional journalism and citizen-generated reporting have shown a positive impact on the political involvement of their audiences and on a better understanding of politics in general.

Plasmids are extra-chromosomal genetic elements that encode a wide variety of phenotypes and can be maintained in bacterial populations through vertical and horizontal transmission, thus increasing bacterial adaptation to hostile environmental conditions like those imposed by antimicrobial sub-stances. To circumvent the segregational instability resulting from randomly distributing plasmids between daughter cells upon division, non-transmissible plasmids tend to be carried in multiple copies per cell, with the added benefit of exhibiting increased gene dosage and resistance levels. But carrying multiple copies also results in a high metabolic burden to the bacterial host, therefore reducing the overall fitness of the population. This trade-off poses an existential question for plasmids: What is the optimal plasmid copy number? In this manuscript, we address this question by postulating and analyzing a population genetics model to evaluate the interaction between selective pressure, the number of plasmid copies carried by each cell, and the metabolic burden associated with plasmid bearing in the absence of selection for plasmid-encoded traits. Parameter values of the model were estimated experimentally usingEscherichia coliK12 carrying a multicopy plasmid encoding for a fluorescent protein andblaTEM-1, a gene conferring resistance toβ-lactam antibiotics. By numerically determining the optimal plasmid copy number for constant and fluctuating selection regimes, we show that plasmid copy number is a highly optimized evolutionary trait that depends on the rate of environmental fluctuation and balances the benefit between increased stability in the absence of selection with the burden associated with carrying multiple copies of the plasmid.

Simultaneous optical microscopy and electric transport measurements on La0.7Sr0.3MnO3 nanobridges, grown on SrTiO3 (STO), show direct evidence of directional oxygen vacancy migration under large voltage bias. Comparative study on discontinuous structures, with voltages applied across a micron-scale gap, demonstrates that high electric fields induce electrolytic modifications confined to the anode. Extensive electromigration is shown to induce the formation of linear surface scars on the STO substrate, following well defined crystallographic directions. The reproducible triggering of these surface dislocations is demonstrated, unveiling their thermal rather than electrical origin and it is shown that they do not represent electroformed conduction channels. High-resolution scanning transmission electron microscopy imaging reveals that the scars correspond to nanometer scale steps caused by (101) gliding planes in the STO caused by the proliferation of edge dislocations and local lattice expansion. These findings shed light on selective electrically-controlled atom migration and its role in structural modification of functional oxides, opening a unique avenue for ionotronic device design., This work was supported by the Fonds de la Recherche Scientifique - FNRS under the grants CDR J.0176.22 and PDR T.0204.21, and the COST action SUPERQUMAP (CA 21144). The authors acknowledge financial support from the Spanish Ministry of Economy and Competitiveness through the Severo Ochoa Programme for Centres of Excellence in R&D (FUNFUTURE CEX2019-000917-S), HTSUPERFUN project (PID2021-124680OB-100), cofinanced by the European Regional Development Fund and from the Catalan Government with 2017 SGR 1519. A.F. thanks the Spanish Ministry of Economy for his FPI Spanish grant (BES-2016-077310). H.W. acknowledges financial support from the China Scholarship Council (CSC). S.M. acknowledges support from FRS-FNRS Research Fellowship ASP under the grant 1.A.320.21F. Authors acknowledge the SEM-FIB microscopy service of the Universidad de Málaga and the ICTS-CNME for offering access to their instruments and expertise., With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).

Objective Surgery is the standard treatment for most tumors in the prestyloid parapharyngeal space (PPS) but it can be a challenging procedure because of the anatomical complexity of the area. Prestyloid surgery can be performed with various lateral approaches or with a medial approach using transoral robotic surgery (TORS)—either alone or in combination with a transcervical incision. We have retrospectively compared our center's results with lateral and medial approaches. Methods Between 2015 and 2020, 28 patients with prestyloid PPS tumors underwent surgery at our center: 14 with lateral approaches, including transcervical, transcervical‐parotid, and transcervical‐mandibular, and 14 with medial approaches (12 with TORS and two with TORS plus a transcervical incision). We compared surgical time, postsurgical complications, length of hospital stay, need for feeding tube, and relapse‐free survival in the two patient groups. Results Pleomorphic adenoma was the most frequent tumor and 60.7% of the tumors were benign. Tumor volume and maximum length were similar in the two groups of patients. Intraoperative image guidance and ultrasound were used in 33% of TORS. TORS was associated with less surgical time, fewer complications, and shorter hospital stays. Recurrence rates were similar in the two groups. Conclusion The medial approach by TORS offers superior results in prestyloid tumors than the open lateral approach and can be refined by intraoperative guidance. Level of Evidence: 4, Retrospective analysis of prestyloid parapharyngeal tumors patients comparing lateral surgical approach vs medial (TORS). Internal carotid artery position and parotid gland involvement are crucial points to consider in choosing a medial or lateral approach in prestyloid tumors. We can recommend the use of TORS approach in selected cases on experienced hands.

Foundational debates about public service provision originate with the study of private lighthouses in England and Wales. We provide a new empirical assessment of cost and technical efficiency of competing lighthouse organizations in the early 1800s. Those with more private control charged ships higher fees and had greater operating costs. Lights with more local representation and funding provided lights of more local use and were most cheaply maintained. Our results help explain why government promoted nonprofit organizations to run lighthouses over private operators. We provide new insights into the role of private enterprise and nonprofit organizations in public service provision.

Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype-phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy-number variant and whole-exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine-rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD. LAY SUMMARY: Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD.

Polypropylene; Polyvinylidene fluoride; Stress urinary incontinence Polipropileno; Fluoruro de polivinilideno; Incontinencia urinaria de esfuerzo Polipropilè; Fluorur de polivinilidè; Incontinència urinària d'esforç Aims: To compare the effectiveness and safety of polypropylene (PP) and polyvinylidene fluoride (PVDF) transobturator tapes (TOT) for the treatment of female stress urinary incontinence (SUI). Methods: This is a multicentre randomized trial. Women with SUI or stress-predominant mixed urinary incontinence and scheduled for a TOT procedure were randomized to PP or PVDF slings. The primary outcome was 1-year cure or improvement rate using composite criteria. Complications were also compared. Relationships with outcomes were analyzed using multivariable logistic regressions models. Results: From April 2016 to January 2018 285 participants were randomized. PP and PVDF slings showed similar high cure or improvement rate (91.0% vs. 95.6%, p = .138). Improvement in validated questionnaires was also similar. PVDF slings were associated with a lower rate of de novo urgency incontinence (adjusted odds ratio = 0.35; 95% confidence interval = 0.15-0.80). We found no statistical differences in complications rates, although a higher incidence of long-term pain events were observed in the PP group. The study is underpowered to find differences in specific complications owing to the low number of events. Conclusion: PP and PVDF TOTs are equally effective, although PVDF is associated with fewer cases of de novo urgency incontinence. Further studies are needed to give robust conclusions on safety profiles.

Funding: This work was supported in part by an unrestricted grant from Vifor Pharma and Proyectos de Investigación de la Sección de Insuficiencia Cardiaca 2017 from Sociedad Española de Cardiología. The mechanisms underlying the beneficial effect of ferric carboxymaltose (FCM) in patients with heart failure (HF) and iron deficiency (ID) have not been completely characterized. The Myocardial-IRON trial was a double-blind, randomized trial that evaluated myocardial iron repletion following FCM vs. placebo in 53 patients with HF and ID. In this post hoc analysis, we evaluated whether treatment with FCM was associated with cardiac magnetic resonance changes in left and right ventricular function (LVEF and RVEF, respectively) at different points of systolic dysfunction. We included patients from the Myocardial-IRON trial with left and right ventricular systolic dysfunction (LVSD and RVSD, respectively) at enrolment. Linear mixed regression models were used to evaluate changes at 7 and 30 days on LVEF and RVEF at cardiac magnetic resonance. At enrolment, 27 (50.9%) and 38 (71.7%) patients had LVEF < 40% (LVSD) or

The footwear industry is closely related to adhesives as footwear manufacturing involves transformation and assembly of various components made up of several materials where different adhesives play a key role. The proper choice of adhesive is crucial to ensure the bond strength required. Moreover, the large variety of materials used in the footwear industry require specially formulated adhesives. The present review gives an overview of the substrates used as footwear materials and discusses the adhesives most commonly used in the footwear manufacturing process. Surface treatments used prior to bonding process are also reviewed, highlighting their importance. Footwear adhesives requirements are also reviewed in this paper where the joining of the upper to the sole is the most demanding process in terms of peel resistance. Future trends in footwear adhesives will be related to the use of more sustainable adhesives. From this perspective, water-based and hot-melt adhesives are also included in this paper.

There is a debate about whether coastal shipping experienced substantial productivity growth prior to the advent of steam power. To study changes over the long eighteenth century, this article uses thousands of coastal journey times culled from Board of Trade crew lists between 1835 and 1844 and coastal port books for the mid‐to‐late 1600s, along with a newly digitized coastal network. Comparisons between matched samples show that journey speeds, defined as miles sailed per day, were significantly higher in the crew lists compared to the port books, and that voyage cycle times, defined as days between starting two identical voyages, were substantially lower. The study also shows that voyage times in the east coast coal trade were substantially lower around 1840 than around 1700, but the difference was much smaller when peace years are compared. These new data imply that total factor productivity growth in the east coast coal trade was significant, especially if one accounts for gains from peace after 1815. The findings contribute to the larger literature studying the rate and sources of productivity growth during the industrial revolution.

13 páginas,1 figura, 3 tablas, 1 apéndice. Se extraen los autores pertenecientes a The CIBERER network que trabajan en Centros del CSIC del Appendix A, CIBER (Center for Biomedical Network Research; Centro de Investigación Biomédica En Red) is a public national consortium created in 2006 under the umbrella of the Spanish National Institute of Health Carlos III (ISCIII). This innovative research structure comprises 11 different specific areas dedicated to the main public health priorities in the National Health System. CIBERER, the thematic area of CIBER focused on rare diseases (RDs) currently consists of 75 research groups belonging to universities, research centers, and hospitals of the entire country. CIBERER's mission is to be a center prioritizing and favoring collaboration and cooperation between biomedical and clinical research groups, with special emphasis on the aspects of genetic, molecular, biochemical, and cellular research of RDs. This research is the basis for providing new tools for the diagnosis and therapy of low-prevalence diseases, in line with the International Rare Diseases Research Consortium (IRDiRC) objectives, thus favoring translational research between the scientific environment of the laboratory and the clinical setting of health centers. In this article, we intend to review CIBERER's 15-year journey and summarize the main results obtained in terms of internationalization, scientific production, contributions toward the discovery of new therapies and novel genes associated to diseases, cooperation with patients' associations and many other topics related to RD research., This study has been funded by Instituto de Salud Carlos III (ISCIII) and Spanish Ministry of Science and Innovation