The monks of San Millán: Investigating the transition between pre-monastic and monastic diet using carbon and nitrogen isotope ratios in incremental dentine

YesFrom the early Medieval period, Christian monasteries were wealthy and powerful, and played a central role in both religious and political life. Those who entered the monasteries did so at the age of 7-8 years and were drawn from a wide range of social strata. From that point, they were subject to the dietary rules imposed by the rules of each monastic order. In order to assess the origins and diet of 10 monks who lived in the monastery of San Millán de la Cogolla Yuso (La Rioja, Spain) during the 17th – 18th century, collagen from small sections of human dentine (representing the childhood diet) and from ribs (an average of the last 5 - 10 years of adult diet) was measured to establish lifetime variations in the isotope ratios of carbon (δ13C) and nitrogen (δ15N). Bulk collagen δ13C (overall mean= -18.2‰ +/-0.4) and δ15N (overall mean= 12.6‰ +/-0.8) values from the ribs suggest 2 adult cohorts: one with a diet based on C3 plants and a high intake of protein from meat or dairy products and some marine resources and a second cohort with some C4 plant consumption alongside meat and dairy. Data from the dentine sections revealed different dietary patterns during the period of tooth formation among the monks, suggesting that 4 of them entered the monastery after consuming lower status diets during childhood.This paper was written with the support of a PhD grant (BES-2015-075176) from the project CoChange (HAR2014-51830-P) lead by Prof. Pablo Arias

Garnet-clinopyroxene bearing assemblages in the 'upper catazonal unit' of the Cabo Ortega! Complex (NW Spain)

[Resumen] Se han estudiado los siguientes materiales de la 'unidad catazonal superior' del Complejo del Cabo Ortegal conteniendo asociaciones con granate-clinopiroxeno: eclogitas, granulitas básicas, intercalaciones gneísicas en las granulitas, piroxenitas con granate, gneises de la aureola de contacto de las rocas ultramáficas, metabasitas de la 'formación Candelaria' y 'carbonatitas'. Los datos termobarométricos obtenidos sugieren que, mientras que los minerales de algunos de estos materiales han sufrido importantes reajustes composicionales durante los procesos de retromorfosis (e. g. granulitas con distena, intercalaciones gneísicas en granulitas, -intercalaciones u1tramáficas en gneises, etc.), otros han conservado elementos mineralógicos con la composición alcanzada durante el episodio metamórfico que originó la formación de las asociaciones con granate-clinopiroxeno. Este segundo grupo de materiales puede subdividirse en dos categorías: 1) aquellos materiales en los que la asociación granate-clinopiroxeno se formó en torno a los 800 oC y 15 ± 1. 5 kbar (eclogitas 'tipo-I', granulitas de la 'formación Bracariza', piroxenitas con granate de los macizos de rocas u1tramáficas 'carbonatitas'), y, 11) aquellos en los que dicha asociaci6n se formó a unos 700 oC y la misma P aproximadamente (eclogitas y granulitas intercaladas en las formaciones gneísicas). Aunque las diferencias no son muy importantes, es posible que los dos conjuntos litológicos representen dos gradientes metamórficos distintos y, por tanto, la existencia en dicha 'unidad' de materiales con diferentes historias tectono-metamórficas.[Abstract] The following materials from the 'uper' catazonal unit' of the Cabo Ortegal Complex, containing garnet-clinopyroxene assemblages, have been studied: eclogites, basic granulites, gneissic intercalations within granulites, garnetbearing pyroxenites, gneisses from the contact aureole of the ultramafic rocks, metabasites from the 'Candelaria formation' and 'carbonatites'. The thermobarometric data obtained from this study suggest that the minerals from several of those materials underwent strong compositional readjustements during the subsequent retromorphic events (e. g. the kyanite-bearing granulites, the gneissic intercalations in granulites, the u1tramafic intercalations in gneisses, etc.). The remaining materials have preserved mineral compositions attained during the metamorphic episode that produced the garnetclinopyroxene assemblages; these materials may be classified as follows: 1) those in which the garnet-clinopyroxene assemblage formed at ca. 800 oC and 15 ± ± 1,5 kbar ('type-I' eclogites, granulites from the 'Bacariza formation', garnetbearing pyroxenites from the ultramafic massifs and 'carbonatites'), and, 11) those where the same association developed at ca 700 oC and more or less the same P conditions (eclogites and granulites intercaled in gneisses). Although these differences in P and Tare not very important, it is possible that these two groups represent two different metamorphic gradients, and therefore the existence in this 'unit' of the Complex of two lithological sub-units with different tectono-metamorphic histories

Structural analysis of APOB variants, p.(Arg3527Gln), p.(Arg1164Thr) and p.(Gln4494del), causing Familial Hypercholesterolaemia provides novel insights into variant pathogenicity

Free PMC Article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4672294/Familial hypercholesterolaemia (FH) is an inherited autosomal dominant disorder resulting from defects in the low-density lipoprotein receptor (LDLR), in the apolipoprotein B (APOB) or in the proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. In the majority of the cases FH is caused by mutations occurring within LDLR, while only few mutations in APOB and PCSK9 have been proved to cause disease. p.(Arg3527Gln) was the first mutation in APOB being identified and characterized. Recently two novel pathogenic APOB variants have been described: p.(Arg1164Thr) and p.(Gln4494del) showing impaired LDLR binding capacity, and diminished LDL uptake. The objective of this work was to analyse the structure of p.(Arg1164Thr) and p.(Gln4494del) variants to gain insight into their pathogenicity. Secondary structure of the human ApoB100 has been investigated by infrared spectroscopy (IR) and LDL particle size both by dynamic light scattering (DLS) and electron microscopy. The results show differences in secondary structure and/or in particle size of p.(Arg1164Thr) and p.(Gln4494del) variants compared with wild type. We conclude that these changes underlie the defective binding and uptake of p.(Arg1164Thr) and p.(Gln4494del) variants. Our study reveals that structural studies on pathogenic variants of APOB may provide very useful information to understand their role in FH disease

Preconditioned iterative methods for convection diffusion and related boundary value problems

AbstractWe develop and analyze preconditioners for the iterative solution of the system of equations arising from the discretization of multi-dimensional singularity perturbed boundary value problems. This includes a class of convection diffusion models. The choice of preconditioner is crucial for the efficient solution of the system of equations. In particular, it is necessary to choose a preconditioner that substantially reduces the condition number κ both for small grid size h and for large values of the parameter K multiplying the convection terms. A class of preconditioners is analyzed that is inexpensive to implement and for which κ = 0(1) as h→0 and κ = (1 + K12) as K → ∞ for some convection diffusion problems with positive definite symmetric part. This result is then used to develop an algorithm with work estimate 0(1 + K12as K → ∞ for a more general class of convection diffusion problems including those with indefinite symmetric part. Numerical experiments using a symmetric multigrid preconditioner demonstrate the effectiveness of the numerical method even for large problems

MLb-LDLr: A Machine Learning Model for Predicting the Pathogenicity of LDLr Missense Variants

Untreated familial hypercholesterolemia (FH) leads to atherosclerosis and early cardiovascular disease. Mutations in the low-density lipoprotein receptor (LDLr) gene constitute the major cause of FH, and the high number of mutations already described in the LDLr makes necessary cascade screening or in vitro functional characterization to provide a definitive diagnosis. Implementation of high-predicting capacity software constitutes a valuable approach for assessing pathogenicity of LDLr variants to help in the early diagnosis and management of FH disease. This work provides a reliable machine learning model to accurately predict the pathogenicity of LDLr missense variants with specificity of 92.5% and sensitivity of 91.6%. © 2021 The Author

All-or-none amyloid disassembly via chaperone-triggered fibril unzipping favors clearance of α-synuclein toxic species

11 pags., 5 figs.α-synuclein aggregation is present in Parkinson’s disease and other neuropathologies. Among the assemblies that populate the amyloid formation process, oligomers and short fibrils are the most cytotoxic. The human Hsc70-based disaggregase system can resolve α-synuclein fibrils, but its ability to target other toxic assemblies has not been studied. Here, we show that this chaperone system preferentially dis-aggregates toxic oligomers and short fibrils, while its activity against large, less toxic amyloids is severely impaired. Biochemical and kinetic characterization of the disassembly process reveals that this behavior is the result of an all-or-none abrupt solubilization of individual aggregates. High-speed atomic force microscopy explicitly shows that disassembly starts with the destabilization of the tips and rapidly progresses to completion through protofilament unzipping and depolymerization without accumulation of harmful oligomeric intermediates. Our data provide molecular insights into the selective processing of toxic amyloids, which is critical to identify potential therapeutic targets against increasingly prevalent neurodegenerative disorders.This work was supported by MCI/AEI/FEDER, UE (Grants PGC2018-101282-B-I00 to J.M.G.V, PGC2018-096335-B-100 to N.C., and PID2019-111068GB-I00 to A.M.), MINECO/FEDER, UE (Grants RYC-2012-12068 and BFU2015-64119-P to N.C.), and by the Basque Government (Grant IT1201-19 to A.M. and A.P.). A.C. also acknowledges funding from MCIU, PID2019-111096GA-I00; MCIU/AEI/FEDER MINECOG19/P66 , RYC2018-024686-I, and Basque Government T1270-19. L.S. acknowledges support from the University of California, Davis. A.F. thanks a predoctoral fellowship from the Basque Government. The technical and human support provided by the microscopy service of SGIker (UPV/EHU/ERDF, EU) is acknowledged. We thank J. M. Valpuesta and J. Cuellar for the visualization of α-syn oligomers by E

Safety study of transcranial static magnetic field stimulation (tSMS) of the human cortex

Transcranial static magnetic field stimulation (tSMS) in humans reduces cortical excitability. Objective: The objective of this study was to determine if prolonged tSMS (2 h) could be delivered safely in humans. Safety limits for this technique have not been described. Methods: tSMS was applied for 2 h with a cylindric magnet on the occiput of 17 healthy subjects. We assessed tSMS-related safety aspects at tissue level by measuring levels of neuron-specific enolase (NSE,a marker of neuronal damage) and S100 (a marker of glial reactivity and damage). We also included an evaluation of cognitive side effects by using a battery of visuomotor and cognitive tests. Results: tSMS did not induce any significant increase in NSE or S100. No cognitive alteration was detected. Conclusions: Our data indicate that the application of tSMS is safe in healthy human subjects, at least within these parameter

Remote ischemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity

Aims: Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. Methods and results: Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischaemic preconditioning (RIPC, 3 cycles of 5 min leg ischaemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at Weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at Weeks 6, 8, 12, and 16, being sacrifice after that. In Study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6. In Study 1, left ventricular ejection fraction (LVEF) depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at Week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5 ± 9.1% vs. 32.5 ± 8.7%, P = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at Week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs. Conclusion: In a translatable large-animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC.Fil: Galán Arriola, Carlos. Centro de Investigacion Biomedica En Red.; EspañaFil: Villena Gutiérrez, Rocio. Centro de Investigacion Biomedica En Red.; EspañaFil: Higuero Verdejo, María I.. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: Díaz Rengifo, Iván A.. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: Pizarro, Gonzalo. Centro de Investigacion Biomedica En Red.; EspañaFil: López, Gonzalo J.. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: de Molina Iracheta, Antonio. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: Pérez Martínez, Claudia. Universidad de Leon. Facultad de Veterinaria; ArgentinaFil: García, Rodrigo Damián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Medicina y Biología Experimental de Cuyo; ArgentinaFil: González Calle, David. Centro de Investigacion Biomedica En Red.; EspañaFil: Lobo, Manuel. Centro de Investigacion Biomedica En Red.; EspañaFil: Sánchez, Pedro L.. Centro de Investigacion Biomedica En Red.; EspañaFil: Oliver, Eduardo. Centro de Investigacion Biomedica En Red.; EspañaFil: Córdoba, Raúl. Hospital Fundacion Jimenez Diaz; EspañaFil: Fuster, Valentin. Centro Nacional de Investigaciones Cardiovasculares; EspañaFil: Sánchez González, Javier. No especifíca;Fil: Ibanez, Borja. Centro de Investigacion Biomedica En Red.; Españ

Familial hypercholesterolemia and elevated lipoprotein(a) : double heritable risk and new therapeutic opportunities

Vuorio A, Watts GF, Schneider WJ, Tsimikas S, Kovanen PT (Mehilainen Airport Health Centre, Vantaa; University of Helsinki, Helsinki, Finland; University of Western Australia, Perth, Australia; Royal Perth Hospital, Perth, Australia; Medical University of Vienna, Vienna, Austria; University of California San Diego, La Jolla, CA, USA; Wihuri Research Institute, Helsinki, Finland). Familial hypercholesterolemia and elevated lipoprotein(a): double heritable risk and new therapeutic opportunities (Review). J Intern Med 2020; 287: 2-18. There is compelling evidence that the elevated plasma lipoprotein(a) [Lp(a)] levels increase the risk of atherosclerotic cardiovascular disease (ASCVD) in the general population. Like low-density lipoprotein (LDL) particles, Lp(a) particles contain cholesterol and promote atherosclerosis. In addition, Lp(a) particles contain strongly proinflammatory oxidized phospholipids and a unique apoprotein, apo(a), which promotes the growth of an arterial thrombus. At least one in 250 individuals worldwide suffer from the heterozygous form of familial hypercholesterolemia (HeFH), a condition in which LDL-cholesterol (LDL-C) is significantly elevated since birth. FH-causing mutations in the LDL receptor gene demonstrate a clear gene-dosage effect on Lp(a) plasma concentrations and elevated Lp(a) levels are present in 30-50% of patients with HeFH. The cumulative burden of two genetically determined pro-atherogenic lipoproteins, LDL and Lp(a), is a potent driver of ASCVD in HeFH patients. Statins are the cornerstone of treatment of HeFH, but they do not lower the plasma concentrations of Lp(a). Emerging therapies effectively lower Lp(a) by as much as 90% using RNA-based approaches that target the transcriptional product of the LPA gene. We are now approaching the dawn of an era, in which permanent and significant lowering of the high cholesterol burden of HeFH patients can be achieved. If outcome trials of novel Lp(a)-lowering therapies prove to be safe and cost-effective, they will provide additional risk reduction needed to effectively treat HeFH and potentially lower the CVD risk in these high-risk patients even more than currently achieved with LDL-C lowering alone.Peer reviewe