DNA methylation changes in genes involved in inflammation and depression in fibromyalgia: a pilot study

Objectives: The present pilot study aims to investigate DNA methylation changes of genes related to fibromyalgia (FM) development and its main comorbid symptoms, including sleep impairment, inflammation, depression and other psychiatric disorders. Epigenetic modifications might trigger or perpetuate complex interplay between pain transduction/transmission, central pain processing and experienced stressors in vulnerable individuals. Methods: We conducted DNA methylation analysis by targeted bisulfite NGS sequencing testing differential methylation in 112 genomic regions from leukocytes of eight women with FM and their eight healthy sisters as controls. Results: Tests for differentially methylated regions and cytosines brought focus on the GRM2 gene, encoding the metabotropic glutamate receptor2. The slightly increased DNA methylation observed in the GRM2 region of FM patients may confirm the involvement of the glutamate pathway in this pathological condition. Logistic regression highlighted the simultaneous association of methylation levels of depression and inflammation-related genes with FM. Conclusions: Altogether, the results evidence the glutamate pathway involvement in FM and support the idea that a combination of methylated and unmethylated genes could represent a risk factor to FM or its consequence, more than single genes. Further studies on the identified biomarkers could contribute to unravel the causative underlying FM mechanisms, giving reliable directions to research, improving the diagnosis and effective therapiesThis study was supported by Spanish Government Funding (Ministerio de Economía y Competitividad: grant PSI2013-45818-R). The genotyping service was carried out at CEGEN-PRB3-ISCIII; it is supported by grant PT17/0019, of the PE I + D + i 2013–2016, funded by ISCIII and ERDF. MCG and LAN are part of the Center for Neuroplasticity and Pain (CNAP) which is supported by the Danish National Research Foundation (DNRF121)S

Enrichment of B cell receptor signaling and epidermal growth factor receptor pathways in monoclonal gammopathy of undetermined significance: a genome-wide genetic interaction study

Background: Recent identification of 10 germline variants predisposing to monoclonal gammopathy of undetermined significance (MGUS) explicates genetic dependency of this asymptomatic precursor condition with multiple myeloma (MM). Yet much of genetic burden as well as functional links remain unexplained. We propose a workflow to expand the search for susceptibility loci with genome-wide interaction and for subsequent identification of genetic clusters and pathways. Methods: Polygenic interaction analysis on 243 cases/1285 controls identified 14 paired risk loci belonging to unique chromosomal bands which were then replicated in two independent sets (case only study, 82 individuals; case/control study 236 cases/ 2484 controls). Further investigation on gene-set enrichment, regulatory pathway and genetic network was carried out with stand-alone in silico tools separately for both interaction and genome-wide association study-detected risk loci. Results: Intronic-PREX1 (20q13.13), a reported locus predisposing to MM was confirmed to have contribution to excess MGUS risk in interaction with SETBP1, a well-established candidate predisposing to myeloid malignancies. Pathway enrichment showed B cell receptor signaling pathway (P < 5.3 × 10− 3) downstream to allograft rejection pathway (P < 5.6 × 10− 4) and autoimmune thyroid disease pathway (P < 9.3 × 10− 4) as well as epidermal growth factor receptor regulation pathway (P < 2.4 × 10− 2) to be differentially regulated. Oncogene ALK and CDH2 were also identified to be moderately interacting with rs10251201 and rs16966921, two previously reported risk loci for MGUS. Conclusions: We described novel pathways and variants potentially causal for MGUS. The methodology thus proposed to facilitate our search streamlines risk locus-based interaction, genetic network and pathway enrichment analyses

Well-posedness for degenerate third order equations with delay and applications to inverse problems

[EN] In this paper, we study well-posedness for the following third-order in time equation with delay <disp-formula idoperators defined on a Banach space X with domains D(A) and D(B) such that t)is the state function taking values in X and u(t): (-, 0] X defined as u(t)() = u(t+) for < 0 belongs to an appropriate phase space where F and G are bounded linear operators. Using operator-valued Fourier multiplier techniques we provide optimal conditions for well-posedness of equation (0.1) in periodic Lebesgue-Bochner spaces Lp(T,X), periodic Besov spaces Bp,qs(T,X) and periodic Triebel-Lizorkin spaces Fp,qs(T,X). A novel application to an inverse problem is given.The first, second and third authors have been supported by MEC, grant MTM2016-75963-P. The second author has been supported by AICO/2016/30. The fourth author has been supported by MEC, grant MTM2015-65825-P.Conejero, JA.; Lizama, C.; Murillo-Arcila, M.; Seoane Sepúlveda, JB. (2019). Well-posedness for degenerate third order equations with delay and applications to inverse problems. Israel Journal of Mathematics. 229(1):219-254. https://doi.org/10.1007/s11856-018-1796-8S2192542291K. Abbaoui and Y. Cherruault, New ideas for solving identification and optimal control problems related to biomedical systems, International Journal of Biomedical Computing 36 (1994), 181–186.M. Al Horani and A. Favini, Perturbation method for first- and complete second-order differential equations, Journal of Optimization Theory and Applications 166 (2015), 949–967.H. Amann, Operator-valued Fourier multipliers, vector-valued Besov spaces, and applications, Mathematische Nachrichten 186 (1997), 5–56.U. A. Anufrieva, A degenerate Cauchy problem for a second-order equation. A wellposedness criterion, Differentsial’nye Uravneniya 34 (1998), 1131–1133; English translation: Differential Equations 34 (1999), 1135–1137.W. Arendt and S. Bu, The operator-valued Marcinkiewicz multiplier theorem and maximal regularity, Mathematische Zeitschrift 240 (2002), 311–343.W. Arendt and S. Bu, Operator-valued Fourier multipliers on periodic Besov spaces and applications, Proceedings of the Edinburgh Mathematical Society 47 (2004), 15–33.W. Arendt, C. Batty and S. Bu, Fourier multipliers for Holder continuous functions and maximal regularity, Studia Mathematica 160 (2004), 23–51.V. Barbu and A. Favini, Periodic problems for degenerate differential equations, Rendiconti dell’Istituto di Matematica dell’Università di Trieste 28 (1996), 29–57.A. Bátkai and S. Piazzera, Semigroups for Delay Equations, Research Notes in Mathematics, Vol. 10, A K Peters, Wellesley, MA, 2005.S. Bu, Well-posedness of second order degenerate differential equations in vector-valued function spaces, Studia Mathematica 214 (2013), 1–16.S. Bu and G. Cai, Periodic solutions of third-order degenerate differential equations in vector-valued functional spaces, Israel Journal of Mathematics 212 (2016), 163–188.S. Bu and G. Cai, Well-posedness of second-order degenerate differential equations with finite delay in vector-valued function spaces, Pacific Journal of Mathematics 288 (2017), 27–46.S. Bu and Y. Fang, Periodic solutions of delay equations in Besov spaces and Triebel–Lizorkin spaces, Taiwanese Journal of Mathematics 13 (2009), 1063–1076.S. Bu and J. Kim, Operator-valued Fourier multipliers on periodic Triebel spaces, Acta Mathematica Sinica 21 (2005), 1049–1056.G. Cai and S. Bu, Well-posedness of second order degenerate integro-differential equations with infinite delay in vector-valued function spaces, Mathematische Nachrichten 289 (2016), 436–451.R. Chill and S. Srivastava, Lp-maximal regularity for second order Cauchy problems, Mathematische Zeitschrift 251 (2005), 751–781.R. Denk, M. Hieber and J. Prüss, R-boundedness, Fourier multipliers and problems of elliptic and parabolic type, Memoirs of the American Mathematical Society 166 (2003).O. Diekmann, S. A. van Giles, S. M. Verduyn Lunel and H.-O. Walther, Delay Equations, Applied Mathematical Sciences, Vol. 110, Springer, New York, 1995.K. J. Engel and R. Nagel, One-Parameter Semigroups for Linear Evolution Equations, Graduate Texts in Mathematics, Vol. 194, Springer, New York, 2000.M. Fabrizio, A. Favini and G. Marinoschi, An optimal control problem for a singular system of solid liquid phase-transition, Numerical Functional Analysis and Optimization 31 (2010), 989–1022.A. Favini and G. Marinoschi, Periodic behavior for a degenerate fast diffusion equation, Journal of Mathematical Analysis and Applications 351 (2009), 509–521.A. Favini and G. Marinoschi, Identification of the time derivative coefficients in a fast diffusion degenerate equation, Journal of Optimization Theory and Applications 145 (2010), 249–269.A. Favini and A. Yagi, Degenerate differential equations in Banach spaces, Monographs and Textbooks in Pure and Applied Mathematics, Vol. 215, Marcel Dekker, New York, 1999.X. L. Fu and M. Li, Maximal regularity of second-order evolution equations with infinite delay in Banach spaces, Studia Mathematica 224 (2014), 199–219.G. C. Gorain, Boundary stabilization of nonlinear vibrations of a flexible structure in a bounded domain in Rn, Journal of Mathematical Analysis and Applications 319 (2006), 635–650.P. Grisvard, Équations différentielles abstraites, Annales Scientifiques de l’école Normale Superieure 2 (1969), 311–395.J. K. Hale and W. Huang, Global geometry of the stable regions for two delay differential equations, Journal of Mathematical Analysis and Applications 178 (1993), 344–362.Y. Hino, S. Murakami and T. Naito, Functional Differential Equations with Infinite Delay, Lecture Notes in Mathematics, Vol. 1473, Springer, Berlin, 1991.B. Kaltenbacher, I. Lasiecka and M. Pospieszalska, Well-posedness and exponential decay of the energy in the nonlinear Moore-Gibson-Thomson equation arising in high intensity ultrasound, Mathematical Models & Methods in Applied Sciences 22 (2012), 1250035.V. Keyantuo and C. Lizama, Fourier multipliers and integro-differential equations in Banach spaces, Journal of the London Mathematical Society 69 (2004), 737–750.V. Keyantuo and C. Lizama, Maximal regularity for a class of integro-differential equations with infinite delay in Banach spaces, Studia Mathematica 168 (2005), 25–50.V. Keyantuo, C. Lizama and V. Poblete, Periodic solutions of integro-differential euations in vector-valued function spaces, Journal of Differential Equations 246 (2009), 1007–1037.C. Lizama, Fourier multipliers and periodic solutions of delay equations in Banach spaces, Journal of Mathematical Analysis and Applications 324 (2006), 921–933.C. Lizama and V. Poblete, Maximal regularity of delay equations in Banach spaces, Studia Mathematica 175 (2006), 91–102.C. Lizama and R. Ponce, Periodic solutions of degenerate differential equations in vector valued function spaces, Studia Mathematica 202 (2011), 49–63.C. Lizama and R. Ponce, Maximal regularity for degenerate differential equations with infinite delay in periodic vector-valued function spaces, Proceedings of the Edinburgh Mathematical Society 56 (2013), 853–871.R. Marchand, T. Mcdevitt and R. Triggiani, An abstract semigroup approach to the third-order Moore–Gibson–Thompson partial differential equation arising in highintensity ultrasound: structural decomposition, spectral analysis, exponential stability, Mathematical Methods in the Applied Sciences 35 (2012), 1896–1929.V. Poblete, Solutions of second-order integro-differential equations on periodic Besov spaces, Proceedings of the Edinburgh Mathematical Society 50 (2007), 477–492.V. Poblete and J. C. Pozo, Periodic solutions of an abstract third-order differential equation, Studia Mathematica 215 (2013), 195–219.J. Prüss, Evolutionary Integral Equations and Applications, Monographs in Mathematics, Vol. 87, Birkhäuser, Heidelberg, 1993.G. A. Sviridyuk and V. E. Fedorov, Linear Sobolev type Equations and Degenerate Semigroups of Operators, Inverse and Ill-posed Problems Series, VSP, Utrecht, 2003.L. Weis, Operator-valued Fourier multiplier theorems and maximal Lp-regularity, Mathematische Annalen 319 (2001), 735–758

Behavioural syndrome in a solitary predator is independent of body size and growth rate.

Models explaining behavioural syndromes often focus on state-dependency, linking behavioural variation to individual differences in other phenotypic features. Empirical studies are, however, rare. Here, we tested for a size and growth-dependent stable behavioural syndrome in the juvenile-stages of a solitary apex predator (pike, Esox lucius), shown as repeatable foraging behaviour across risk. Pike swimming activity, latency to prey attack, number of successful and unsuccessful prey attacks was measured during the presence/absence of visual contact with a competitor or predator. Foraging behaviour across risks was considered an appropriate indicator of boldness in this solitary predator where a trade-off between foraging behaviour and threat avoidance has been reported. Support was found for a behavioural syndrome, where the rank order differences in the foraging behaviour between individuals were maintained across time and risk situation. However, individual behaviour was independent of body size and growth in conditions of high food availability, showing no evidence to support the state-dependent personality hypothesis. The importance of a combination of spatial and temporal environmental variation for generating growth differences is highlighted

Individual and country-level variables associated with the medicalization of birth: Multilevel analyses of IMAgiNE EURO data from 15 countries in the WHO European region

Objective: To investigate potential associations between individual and country-level factors and medicalization of birth in 15 European countries during the COVID-19 pandemic. Methods: Online anonymous survey of women who gave birth in 2020–2021. Multivariable multilevel logistic regression models estimating associations between indicators of medicalization (cesarean, instrumental vaginal birth [IVB], episiotomy, fundal pressure) and proxy variables related to care culture and contextual factors at the individual and country level. Results: Among 27 173 women, 24.4% (n = 6650) had a cesarean and 8.8% (n = 2380) an IVB. Among women with IVB, 41.9% (n = 998) reported receiving fundal pressure. Among women with spontaneous vaginal births, 22.3% (n = 4048) had an episiotomy. Less respectful care, as perceived by the women, was associated with higher levels of medicalization. For example, women who reported having a cesarean, IVB, or episiotomy reported not feeling treated with dignity more frequently than women who did not have those interventions (odds ratio [OR] 1.37; OR 1.61; OR 1.51, respectively; all: P< 0.001). Country-level variables contributed to explaining some of the variance between countries. Conclusion: We recommend a greater emphasis in health policies on promotion of respectful and patient-centered care approaches to birth to enhance women's experiences of care, and the development of a European-level indicator to monitor medicalization of reproductive care

Reversal of Synapse Degeneration by Restoring Wnt Signaling in the Adult Hippocampus

Synapse degeneration occurs early in neurodegenerative diseases and correlates strongly with cognitive decline in Alzheimer's disease (AD). The molecular mechanisms that trigger synapse vulnerability and those that promote synapse regeneration after substantial synaptic failure remain poorly understood. Increasing evidence suggests a link between a deficiency in Wnt signaling and AD. The secreted Wnt antagonist Dickkopf-1 (Dkk1), which is elevated in AD, contributes to amyloid-β-mediated synaptic failure. However, the impact of Dkk1 at the circuit level and the mechanism by which synapses disassemble have not yet been explored. Using a transgenic mouse model that inducibly expresses Dkk1 in the hippocampus, we demonstrate that Dkk1 triggers synapse loss, impairs long-term potentiation, enhances long-term depression, and induces learning and memory deficits. We decipher the mechanism involved in synapse loss induced by Dkk1 as it can be prevented by combined inhibition of the Gsk3 and RhoA-Rock pathways. Notably, after loss of synaptic connectivity, reactivation of the Wnt pathway by cessation of Dkk1 expression completely restores synapse number, synaptic plasticity, and long-term memory. These findings demonstrate the remarkable capacity of adult neurons to regenerate functional circuits and highlight Wnt signaling as a targetable pathway for neuronal circuit recovery after synapse degeneration

Quality of health care around the time of childbirth during the COVID-19 pandemic: Results from the IMAgiNE EURO study in Norway and trends over time

Objective: To describe maternal perception of the quality of maternal and newborn care (QMNC) in facilities in Norway during the first year of COVID-19 pandemic. Methods: Women who gave birth in a Norwegian facility from March 1, 2020, to October 28, 2021, filled out a structured online questionnaire based on 40 WHO standards-based quality measures. Quantile regression analysis was performed to assess changes in QMNC index over time. Results: Among 3326 women included, 3085 experienced labor. Of those, 1799 (58.3%) reported that their partner could not be present as much as needed, 918 (29.8%) noted inadequate staff numbers, 183 (43.6%) lacked a consent request for instrumental vaginal birth (IVB), 1067 (34.6%) reported inadequate communication from staff, 78 (18.6%) reported fundal pressure during IVB, 670 (21.7%) reported that they were not treated with dignity, and 249 (8.1%) reported experiencing abuse. The QMNC index increased gradually over time (3.68 points per month, 95% CI, 2.83– 4.53 for the median), with the domains of COVID-19 reorganizational changes and experience of care displaying the greatest increases, while provision of care was stable over time. Conclusion: Although several measures showed high QMNC in Norway during the first year of the COVID-19 pandemic, and a gradual improvement over time, several findings suggest that gaps in QMNC exist. These gaps should be addressed and monitored

Altered processing of sensory stimuli in patients with migraine

Migraine is a cyclic disorder, in which functional and morphological brain changes fluctuate over time, culminating periodically in an attack. In the migrainous brain, temporal processing of external stimuli and sequential recruitment of neuronal networks are often dysfunctional. These changes reflect complex CNS dysfunction patterns. Assessment of multimodal evoked potentials and nociceptive reflex responses can reveal altered patterns of the brain's electrophysiological activity, thereby aiding our understanding of the pathophysiology of migraine. In this Review, we summarize the most important findings on temporal processing of evoked and reflex responses in migraine. Considering these data, we propose that thalamocortical dysrhythmia may be responsible for the altered synchronicity in migraine. To test this hypothesis in future research, electrophysiological recordings should be combined with neuroimaging studies so that the temporal patterns of sensory processing in patients with migraine can be correlated with the accompanying anatomical and functional changes

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery