As the cold of winter begins to make its presence felt in the north Murcia town of Moratalla everything is now prepared for the Beer and Tapas Festival which opens at 12.00 midday on both the 16th and 17th November at the Recinto Ferial (click for map) The tapas on offer are prepared by the catering wing of Dilka Eventos and the wide variety of beers to sample includes various brewed by both San Miguel and Mahou there is also a delicious dessert prepared by Cremoso Postres For more upcoming events in the Region of Murcia go to the What’s on section of Murcia Today Sign up for the Spanish News Today Editors Roundup Weekly Bulletin and get an email with all the week’s news straight to your inbox (List price   3  months 12 Bulletins)  and thank you for choosing CamposolToday.com to publicise your organisation’s info or event Camposol Today is a website set up by Murcia Today specifically for residents of the urbanisation in Southwest Murcia providing news and information on what’s happening in the local area which is the largest English-speaking expat area in the Region of Murcia When submitting text to be included on Camposol Today please abide by the following guidelines so we can upload your article as swiftly as possible: Send an email to editor@camposoltoday.com or contact@murciatoday.com Attach the information in a Word Document or Google Doc Also attach a photo to illustrate your article 4vs3CSUN Photo by: John FajardoBadillo Clinches 4-3 Win For Beach Tennis Over CSUN2/15/2025 7:17:00 PM | Women's Tennis Long Beach State won four of six singles matches to grab the win over the Matadors Match Recap: Women's Tennis | 4/4/2025 9:35:00 PM Thanks for visiting The use of software that blocks ads hinders our ability to serve you the content you came here to enjoy We ask that you consider turning off your ad blocker so we can deliver you the best experience possible while you are here Metrics details The ability to exfoliate layered materials down to the single layer limit has presented the opportunity to understand how a gradual reduction in dimensionality affects the properties of bulk materials Here we use this top–down approach to address the problem of superconductivity in the two-dimensional limit The transport properties of electronic devices based on 2H tantalum disulfide flakes of different thicknesses are presented We observe that superconductivity persists down to the thinnest layer investigated (3.5 nm) we find a pronounced enhancement in the critical temperature from 0.5 to 2.2 K as the layers are thinned down which allows us to attribute this phenomenon to an enhancement of the effective electron–phonon coupling constant This work provides evidence that reducing the dimensionality can strengthen superconductivity as opposed to the weakening effect that has been reported in other 2D materials so far we explore 2D superconductivity in few-molecular-layer tantalum disulphide flakes of different thicknesses which have been mechanically exfoliated onto Si/SiO2 substrates we observe that superconductivity persists down to the thinnest layer investigated (3.5 nm with a pronounced increase in the critical temperature (Tc) from 0.5 K (bulk crystal) to ∼2.2 K when the thickness of the layer is decreased In search of the origin of these observations we perform density functional theory (DFT) calculations and construct a simple tight binding model to study the change in the electronic band structure and density of states (DOSs) at the Fermi level as a function of reduced thickness We ascribe the enhancement to an increase in the effective coupling constant (λeff) for reduced thicknesses we find that a rapid integration of freshly exfoliated flakes into final devices and their immediate transfer to vacuum conditions for measurement also permits retaining the pristine properties of most TaS2 samples (vide infra) (a) Ball and stick model of the crystal structure of the 2H polytype of TaS2 The dashed prism encloses the content of a single unit cell and the metal coordination geometry is highlighted by the red polyhedron (b) Atomic force microscopy image of two devices fabricated on a 3.5-nm 2H-TaS2 flake The full colour scale of the topograph corresponds to a height of 100 nm (c) Line profile of the flake taken at the location of the white dotted line in b 5 nm/70 nm) electrodes were evaporated onto selected flakes by employing standard e-beam lithography techniques (see Methods for details) All transport measurements were made using a four terminal current bias configuration in a temperature range of 20 mK to 4 K in a dilution fridge Temperature dependence of three selected devices spanning the range of thicknesses studied (a) Current–voltage (I–V) characteristics as a function of temperature for a bulk-like 14.9 nm device (b) Resistance (zero bias numerical derivative) versus temperature for the 14.9 nm device (c) I–V characteristics as a function of temperature for a 5.8-nm device (d) Resistance versus temperature for the 5.8-nm device (e) I–V characteristics as a function of temperature for a 4.2-nm device (f) Resistance versus temperature for the 4.2-nm device Perpendicular external magnetic field dependence at 30 mK for three selected devices spanning the range of thicknesses studied (a) Resistance (zero bias numerical derivative) versus applied field for a bulk-like (b) Zero bias resistance versus applied field for the 14.9-nm device (c) Resistance (zero bias numerical derivative) versus applied field for the 5.8-nm device (d) Zero bias resistance versus applied field for the 5.8-nm device (e) Resistance versus applied field for the 4.2-nm device (f) Zero bias resistance versus applied field for the 4.2-nm device (a) Variation of Tc as a function of the thickness of the TaS2 flakes Devices exhibiting a non-zero residual resistance below Tc are plotted in red The error bars are given by the temperatures at 10 and 90% of the normal state resistance The solid black line marks the bulk Tc of 600 mK The black dotted line is an exponential trend line fit to the data starting at the bulk limit (b) Variation of Bc2 as a function of flake thickness The red circles mark the same devices in a having residual resistance The black solid line indicates the bulk limit upper critical field of 110 mT The grey solid line plots the GL coherence lengths devices as thin as 4.5 nm still maintain an RRR of 10 indicating pristine thin samples even below our bulk limit of 10 nm although substrate interactions have led to the interesting Tc enhancements found in epitaxial grown FeSe on STO we rule out such effects as the TaS2 flakes presented here are weakly coupled to the substrate This suggests a deeper mechanism as opposed to simple substrate interaction intercalation or degradation reported in previous studies We find that the DOS at the Fermi level is not appreciably affected by the CDW for reduced thicknesses to determine if such a competition with CDWs could be playing a role one could search for direct evidence of such suppression in STM studies of thin flakes below the 10-nm bulk limit observed here where λ is the electron–phonon coupling constant is a term that represents the renormalized repulsive Coulomb interaction In usual 3D superconductors characterized by a featureless—hence constant—DOS the projection on the Fermi level of the high-energy degrees of freedom gives rise to a pseudo-potential of the form μ*=μ/(1+μ ln(W/ω0)) with ω0 the characteristic phonon frequency W the system bandwidth and μ the bare Coulomb repulsion with a DOS characterized by a van Hove singularity near the Fermi level the renormalization of the bare μ can be significantly larger than in a 3D material This effect is therefore strongly dependent on the number of layers we have reported 2D superconductivity in 2H-TaS2 in atomically thin layers In contrast to other van der Waals superconductors such as NbSe2 we find that the Tc of this material is strongly enhanced from the bulk value as the thickness is decreased In addition to a possible charge-density wave origin we propose a model in which this enhancement arises from an enhancement of the effective coupling constant Our results provide evidence of an unusual effect of the reduction of dimensionality on the properties of a superconducting 2D crystal and unveil another aspect of the exotic manifestation of superconductivity in atomically thin transition metal dichalcogenides Polycrystalline 2H-TaS2 was synthesized by heating stoichiometric quantities of Ta and S in an evacuated quartz ampoule at 900 °C for 9 days The growth of large single crystals from the polycrystalline sample was achieved by employing a three-zone furnace The powder sample was placed in the leftmost zone of the furnace and the other two zones were initially brought to 875 °C and kept at that temperature for 1 day the temperature of the source zone was risen to 800 °C during the course of 3 h The temperature of the centre zone was then gradually cooled down at a speed of 1 °C min−1 until a gradient of 125 °C was finally established between the leftmost (875 °C) and centre (750 °C) zones A gradient of 50 °C was also set between the rightmost and growth zones This temperature gradient was maintained for 120 h and the furnace was then switched off and left to cool down naturally The crystals were then thoroughly rinsed with diethyl ether and stored under an N2 atmosphere Contact pads and optical markers are first created on the surface of the Si/SiO2 substrates to locate and design contacts to the transferred flakes The contacts (chromium−5 nm/ gold−70 nm) are then patterned with standard e-beam lithography (Vistec metal deposition (AJA International) and subsequent lift-off in warm acetone pattern the electrodes and load into the dilution fridge within a few hours In that respect and even after minimizing the fabrication time all attempts to contact flakes with thicknesses below 3.5 nm were unsuccessful because of sample degradation How to cite this article: Navarro-Moratalla Enhanced superconductivity in atomically thin TaS2 Possibility of vortex-antivortex pair dissociation in two-dimensional superconductors Onset of superconductivity in the two-dimensional limit Superconducting-insulating transition in two-dimensional α-MoGe thin films Superconductor-insulator transitions in the two-dimensional limit Superconductivity modulated by quantum size effects Fate of the Josephson effect in thin-film superconductors Superconductivity at the two-dimensional limit Superconductivity in one-atomic-layer metal films grown on Si(111) Boron nitride substrates for high-quality graphene electronics Substrate-induced bandgap opening in epitaxial graphene Size effects in superconducting thin films coupled to a substrate Phonon-mediated superconductivity in graphene by lithium deposition Chiral superconductivity from repulsive interactions in doped graphene Electric double-layer capacitance between an ionic liquid and few-layer graphene The transition metal dichalcogenides discussion and interpretation of the observed optical Electronic properties of intercalation complexes of the transition metal dichalcogenides Solvent exfoliation of transition metal dichalcogenides: dispersibility of exfoliated nanosheets varies only weakly between compounds Coexistence of superconductivity and magnetism by chemical design Hybrid magnetic/superconducting materials obtained by insertion of a single-molecule magnet into TaS2 layers Transfer printing by kinetic control of adhesion to an elastomeric stamp Frictional characteristics of atomically thin sheets Atomically thin MoS2: a new direct-gap semiconductor Emerging photoluminescence in monolayer MoS2 Ultralow thermal conductivity in disordered Superconductivity in ultrathin NbSe2 Layers Electric field effect on superconductivity in atomically thin flakes of NbSe2 Superconductivity in two-dimensional NbSe2 field effect transistors Films of iron chalcogenide superconductors Electronic origin of high-temperature superconductivity in single-layer FeSe superconductor Phase diagram and electronic indication of high-temperature superconductivity at 65 K in single-layer FeSe films Superconductivity at the border of electron localization and itinerancy Quality heterostructures from two dimensional crystals unstable in air by their assembly in inert atmosphere Strongly enhanced charge-density-wave order in monolayer NbSe2 Ising pairing in superconducting NbSe2 atomic layers Nature of the quantum metal in a two-dimensional crystalline superconductor and anomalous metallic behavior in 2D transition metal dichalcogenides Chiral charge order in the superconductor 2H-TaS2 Ultrafast switching to a stable hidden quantum state in an electronic crystal Zero-bias conductance peak in detached flakes of superconducting 2H-TaS2 probed by scanning tunneling spectroscopy Realization and electrical characterization of ultrathin crystals of layered transition-metal dichalcogenides Chemistry of the Elements Elsevier Butterworth-Heinemann (1997) Two-Dimensional Materials: from Hybrid Magnetic Multilayers to Superconducting Single Layers PhD thesis Universitat de Valencia (2013) Método y sistema de exfoliación micromecánica por vía seca de materiales laminares bidimensionales Dynamic measurements of the low-temperature specific heat of 2H—TaS2 single crystals in magnetic fields Self-heating in normal metals and superconductors Critical-field enhancement and reduced dimensionality in superconducting layer compounds Superconductivity in Layered Compounds with Variable Interlayer Spacings Suppression of superconductivity in epitaxial NbN ultrathin films Tuning the charge density wave and superconductivity in CuxTaS2 Raman spectroscopic studies of MX2-type layered compounds Experimental observation of the quantum Hall effect and Berry's phase in graphene Electrical transport properties in 2H-NbS2 On the preparation and characterization of ‘NaOH.TaS2’ Order parameter fluctuations at a buried quantum critical point Calculation of the superconducting state parameters with retarded electron-phonon interaction Electric-field-induced superconductivity at 9.4 K in a layered transition metal disulphide MoS2 Superconducting dome in a gate-tuned band insulator Interactions and superconductivity in heavily doped MoS2 The SIESTA method for ab initio order-N materials simulation Generalized gradient approximation made simple Linear-scaling ab-initio calculations for large and complex systems Special points for Brillouin-zone integrations Download references Financial support from the EU (ELFOS project and ERC Advanced Grant SPINMOL) the Spanish MINECO (Excellence Unit “María de Maeztu” MDM-2015-0538 Project Consolider-Ingenio in Molecular Nanoscience and projects MAT2011–25046 and MAT2014–57915-R Dutch organization for Fundamental Research on Matter (FOM) NWO/OCW and the Comunidad Autonoma de Madrid (MAD2D-CM -S2013/MIT-3007- and NANOFRONTMAG-CM -S2013/MIT-2850) and the Generalitat Valenciana (Prometeo Program) are gratefully acknowledged AC-G acknowledges financial support from the BBVA Foundation through the fellowship ‘I Convocatoria de Ayudas Fundacion BBVA a Investigadores Innovadores y Creadores Culturales’ (‘Semiconductores ultradelgados: hacia la optoelectronica flexible’) from the MINECO (Ramón y Cajal 2014 program RYC-2014-01406) and from the MICINN (MAT2014-58399-JIN) We are grateful to the Electronic Microscopy team at Central Support Service in Experimental Research (SCSIE Spain) for their kind and constant support Present address: Present address: Department of Physics Present address: Present address: Valencia Nanophotonics Technology Center Present address: Present address: Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA- Nanociencia) Island and Eugenio Coronado: These authors contributed equally to this work Elena Pinilla-Cienfuegos & Eugenio Coronado Departamento de Física de la Materia Condensada Gabino Rubio-Bollinger & Nicolás Agraït Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA- Nanociencia) The manuscript was written through contributions of all authors All authors have given approval to the final version of the manuscript designed and performed the measurements and prepared the manuscript; S.M.-V helped with the preparation and characterization of samples and contributed to the edition of the manuscript created the theoretical model with contributions from J.A.S.-G supervised the theoretical analysis and edited the manuscript carried out optical microcopy measurements model and interpret supervised the study and edited the manuscript The authors declare no competing financial interests Supplementary Notes 1-6 and Supplementary References (PDF 1103 kb) Reprints and permissions Download citation Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing newsletter — what matters in science You don't have permission to access the page you requested What is this page?The website you are visiting is protected.For security reasons this page cannot be displayed The town of Moratalla in the far north-west of Murcia is well-known for the quality of the oil produced from its numerous olive plantations and over the weekend of February 22 and 23 a series of events are being held to celebrate this important part of the local economy and cuisine 10.00 to 14.00 and 16.00 to 19.00: Market of local produce in the Plaza del Ayuntamiento 12.30 and 18.00: Visit to a recently restored olive press to watch how the oil is obtained and taste the Extra Virgin Olive Oil. Registration online here 19.30: Screening of a documentary film in the Teatro Trieta Directed by José Luis López-Linares the film shows the importance of olive oil tourism in the province of Jaén providing fascinating insights into the production process and how the local oil is appreciated by chefs and consumers 11.00 to 12.00: A walk in the olive groves, enjoying the sights, scents and sounds of the countryside. Registration online here 10.00 to 14.00: Cooking competition, registration online here Hello, and thank you for choosing CamposolToday.com to publicise your organisation’s info or event. Camposol Today is a website set up by Murcia Today specifically for residents of the urbanisation in Southwest Murcia, providing news and information on what’s happening in the local area, which is the largest English-speaking expat area in the Region of Murcia. When submitting text to be included on Camposol Today, please abide by the following guidelines so we can upload your article as swiftly as possible: Who is the organisation running the event? Is it necessary to book beforehand, or can people just show up on the day? Also attach a photo to illustrate your article, no more than 100kb Fibroblasts from Alzheimer’s patients with APOE 3/4 + G206D-PSEN1 mutation and homozygous APOE ε4 were used to study the effects of APOE polymorphism and PSEN1 mutation on the autophagy pathway, mitochondrial network fragmentation, superoxide anion levels, lysosome clustering, and p62/SQSTM1 levels. The findings suggest that all these modifications could eventually contribute to the neuronal degeneration that underlies the pathogenesis of Alzheimer’s disease. Further research in this area may help to develop targeted therapies for the treatment of Alzheimer’s disease. Alzheimer's Disease and Related Dementias Volume 15 - 2023 | https://doi.org/10.3389/fnagi.2023.1087072 This article is part of the Research TopicInsights in Alzheimer’s Disease and Related Dementias: 2022View all 6 articles Introduction: Alzheimer’s disease remains the most common neurodegenerative disorder depicted mainly by memory loss and the presence in the brain of senile plaques and neurofibrillary tangles This disease is related to several cellular alterations like the loss of synapses changes in the autophagic pathway have turned out to be a key factor in the early development of the disease The aim of this research is to determine the impact of the APOE allele ε4 and G206D-PSEN1 on the underlying mechanisms of Alzheimer’s disease Methods: Fibroblasts from Alzheimer’s patients with APOE 3/4 + G206D-PSEN1 mutation and homozygous APOE ε4 were used to study the effects of APOE polymorphism and PSEN1 mutation on the autophagy pathway Results: We observed that the APOE allele ε4 in homozygosis induces mitochondrial network fragmentation that correlates with an increased colocalization with p62/SQSTM1 G206D-PSEN1 mutation causes an impairment of the integrity of mitochondrial networks triggering high superoxide anion levels and thus making APOE 3/4 + PSEN1 fibroblasts more vulnerable to cell death induced by oxidative stress PSEN1 mutation induces accumulation and clustering of lysosomes that along with an increase of global p62/SQSTM1 Conclusion: The findings suggest that all these modifications could eventually contribute to the neuronal degeneration that underlies the pathogenesis of Alzheimer’s disease Further research in this area may help to develop targeted therapies for the treatment of Alzheimer’s disease Fibroblasts were maintained in DMEM (Lonza fibroblasts were treated with tert-Butyl hydroperoxide (tBHP Experiments were conducted in all fibroblasts in parallel Features of recruited patients and control subjects used in this study We assessed cell viability using the resazurin assay a fluorometric method to estimate cell metabolic activity Only viable cells with healthy mitochondria can reduce non-fluorescent resazurin to resorufin (λemission = 585 nm) thanks to the electrons transferred by mitochondrial enzymes non-viable cells cannot perform this reduction and do not spawn a fluorescent signal Fibroblasts were seeded at 62,500 cells/cm2 in a MW96 plate and then incubated with different treatments Spain) was added at 40 μg/μl and incubated in darkness for 30 min at 37°C the fluorescence emission signal (585 nm) was detected with the plate reader FLUOstar Omega (BMG LABTECH A superoxide anion was detected using the fluorescent probe dihydroethidium (DHE Spain) to measure the intracellular ROS content Fibroblasts were seeded in MW6 plates at 20,800 cells/cm2 and then incubated with tBHP 300 μM for 1 h and incubated in the darkness for 30 min at 37°C with DHE 1 μM cells were centrifuged again and resuspended in PBS 1X Twenty thousand events were acquired with CytoFLEX Flow Cytometer (Beckman Coulter Western Blot experiments were performed with cell lysates of the fibroblasts under basal conditions and after a 4 h treatment with EBSS (Earle’s Balanced Salt Solution cells were treated with chloroquine (CQ) 50 μM 4 h Cells were lysed in lysis buffer (50 mM Tris HCl pH 7.4 Supernatants were obtained after a 30 min centrifugation and the protein concentration was quantified with the BCA Assay Kit (Sigma) 5–12 μg of protein lysates were loaded onto a SDS-electrophoresis gel and then transferred to nitrocellulose membranes The membranes were blocked with appropriate 5–10% BSA or skim milk they were incubated with primary antibodies for TOM20 (Santa Cruz Biotechnology 1:30000) and β-tubulin (Cell Signaling Technology The appropriate secondary infrared dye-conjugated antibodies (α-mouse IRDye 800 CW and α-rabbit IRDye 680 LT 1:15000) were detected by Odyssey Infrared Imaging System (LI-COR Biosciences a minimum of 3 independent experiments were carried out Total DNA was isolated from fibroblasts using the Quick-DNA Miniprep Plus Kit (Zymo Research, Irvine, CA, United States), following the manufacturer’s instructions. The Mitochondrial DNA (mtDNA) and the nuclear DNA (nDNA) content were determined by using specific primers for the mitochondrial tRNALeu(UUR) and 16S rRNA genes and for the nuclear β-2-microglobulin (β2M) gene, respectively (Venegas et al., 2011) Quantitative PCR was carried out with SYBR Green Master Mix (Applied Biosystems and the fluorescence amplification cycles were used to calculate the mtDNA: nDNA ratio for each sample Fibroblasts (7,400 cells/cm2) were seeded on gelatin-coated round glass coverslips (12 mm) in MW24 plates and subsequently fixed with 4% paraformaldehyde or methanol, as appropriate. Immunohistochemistry was done as previously described (Ruiz-DeDiego et al., 2015) After a 1 h blocking step with 10% BSA/0.1% Triton/PBS fibroblasts were incubated with primary antibodies for p62/SQSTM1 (Progen 1:200) and LAMP1 (Santa Cruz Biotechnology fibroblasts were incubated with secondary antibodies conjugated to Alexa Fluor 594 or 488 Fibroblasts were counterstained with DAPI (Thermo Fisher Scientific coverslips were mounted with Prolong® Gold (Life Technologies Images were acquired with a SP5 laser confocal microscope (Leica Fibroblasts were seeded in round gelatin-coated glass coverslips at a density of 7,400 cells/cm2 fibroblasts were incubated with 70 nM lysoTracker Red DND-99 probe (Invitrogen Spain; λem = 590 nm) for 30 min at 37°C fibroblasts were fixed with 3% paraformaldehyde (PFA) for 30 min at RT washed with glycine and stained with 25 μg/ml Filipin (Sigma; λem = 400–484 nm) for free cholesterol detection the round covers were mounted with Prolong® Gold reagent (Life Technologies Spain) and observed using the fluorescence microscope (Leica A specific lentivirus was used to analyze the complexity of the fibroblasts’ mitochondrial networks of fibroblasts. Specifically, we used a plasmid with mtDsRed red fluorescent protein (pWPXL-mtDsRed, λex = 580 nm/λem 630/60 nm; Clayton et al., 2012) from the Instituto de Investigaciones Biomédicas of Barcelona Constructions in the pWPXL lentiviral vector contain a target sequence of the subunit IV of the mitochondrial protein cytochrome oxidase HEK293T cells were used as packaging cells to obtain these lentiviruses These cells contain the SV40 virus T antigen which allows an episomal replication of plasmids containing the origin of replication of this virus The fibroblasts were seeded at 70,500 cells/cm2 in 100 mm plates and transfected with the following plasmid mix: pMD2.G (viral envelope) Lentiviral particles were collected twice: 8 h and 16 h after removing the transfection medium the medium containing the lentiviral particles was ultracentrifuged at 20,000 rpm and 16°C for 2 h and the pellet was resuspended in PBS and tittered by qPCR Fibroblasts of all genotypes were seeded in round gelatin-coated glass coverslips (2,000 cells/cm2) and transduced with the lentiviral particles containing the plasmid pWPXL-mtDsRed to obtain 43 integrations/cell Cells were fixed with 4% paraformaldehyde 36 h later and used for p62/SQSTM1 immunocytochemistry we mounted coverslips with fibroblasts using Prolong Gold (Thermo Fisher Scientific Images were captured and assessed with a SP5 laser confocal microscope (Leica The area analyzed in each image corresponds to a region of interest (ROI) of 150 × 150 pixels located in a perinuclear region of the cell At least 6 cells per subject were examined We performed at least 3 independent experiments per assay to obtain all data We normalized the data acquired to control values as appropriate The statistical analysis of the results was carried out with GraphPad Prism 6.0 (Graphpad software Data distribution was evaluated using the D’Agostino and Pearson test One or two-way ANOVA parametric tests were used to compare results between different fibroblast lines and treatments In cases where the data had a non-Gaussian distribution we applied the Kruskal-Wallis test and Dunn’s post-hoc Statistical significance was set at a p-value of P < 0.05 fibroblasts carrying the PSEN1 mutation show decreased viability APOE 4/4 and APOE 3/3 genotypes appear to be more resistant to oxidative stress Vulnerability of fibroblasts to tert-butyl (tBHP) induced oxidative stress and increased production of ROS species in APOE 3/4 + PSEN1 fibroblasts (A) Percentage of the viability of fibroblasts from AD patients compared to controls and to respective basal conditions (B) Quantification of DHE signal measured as the percentage of DHE positive cells by the mean fluorescence intensity in the fibroblasts under basal conditions and after 1 h treatment with 300 μM tBHP (C) Representative graph of events versus fluorescence intensity of the DHE probe obtained by flow cytometry from control and APOE 3/4 + PSEN1 fibroblasts Samples were processed in parallel; data represent the mean ± SEM of at least n = 3 independent experiments for all cell lines *P < 0.05; **P < 0.01; ***P < 0.005 vs Control; #P < 0.05; ##P < 0.01; ###P < 0.005; ####P < 0.0001 vs Representative images and quantification of total free cholesterol and free cholesterol levels inside the lysosomes of control and AD fibroblasts (A) Representative confocal images of control and AD fibroblasts stained with LysoTracker (acid compartments (B) Integrated density (IntDen = intensity*μm2) quantification of Filipin in the total cell area (C) Integrated density (IntDen = intensity*μm2) quantifications of Filipin in the area occupied by LysoTracker staining Samples were processed in parallel; data represent mean ± SEM of n = 2 independent experiments with a minimum of 80 cells per genotype analyzed ***P < 0.005 vs Alterations in mitochondrial morphology in fibroblasts of AD patients (A) Representative western blots of TOM20 levels after treatment with EBSS for 4 h Samples were processed in parallel; data represent mean ± SEM of n = 3 independent experiments calculated with the levels of the mtDNA genes tRNALeu(UUR) (left) and 16S rRNA (right) after treatment with EBSS for 4 h Data represent mean ± SEM of n = 3 independent experiments (D) Representative confocal images of mtDsRed stained mitochondria in control and AD fibroblasts and examples of the skeletonization of the networks obtained with the MiNA plug-in for ImageJ (E–I) Analysis of different parameters related to the complexity of the mitochondrial networks Samples were processed in parallel; data represent mean ± SEM of n = 6 images for all cell lines *P < 0.05; **P < 0.01 vs Remarkably, APOE 3/4 + PSEN1 genotype also produces a significant decline in the length of the mitochondrial branches (Figure 3G), in the cellular area occupied by mitochondria (mitochondrial footprint, Figure 3H) and in the size of the mitochondrial networks but not being significant in this latter case (Figure 3I) All these results suggest that the mitochondrial network’s morphology and integrity are compromised in all fibroblasts from AD patients and that these changes are much more evident in APOE 3/4 + PSEN1 fibroblasts and in APOE 4/4 Since mitophagy could be induced in AD fibroblasts to eliminate damaged mitochondria, specifically in those with the ε4 allele (APOE 4/4 and APOE 3/4+PSEN1), we first performed a p62/SQSTM1 immunofluorescence in all fibroblasts (Figure 4A). The quantification of the fluorescence integrated density (IntDen) of p62/SQSTM1 showed an increase in APOE 4/4 and APOE 3/4 + PSEN1 fibroblasts (Figure 4B) Mitochondria and p62/SQSTM1 colocalization in AD fibroblasts (A) Representative images of mtDsRed-labeled mitochondria and immunofluorescence for p62/SQSTM1 in AD fibroblasts (APOE 4/4 and APOE 3/4 + PSEN1) Nuclei are stained with DAPI (B) Integrated density (IntDen = intensity*μm2) quantifications of p62/SQSTM1 (C) Quantitation of mtDsRed and p62/SQSTM1 colocalization with Manders’ Coefficients (tM1 and tM2) Samples are processed in parallel; data represent mean ± SEM of n = 6 images for all cell lines **P < 0.01; ***P < 0.005; ****P < 0.0001 vs the morphological changes may not be due to an increased effective mitophagy (A) Representative western blots of p-mTOR and p-ULK levels under baseline and nutrient deprivation conditions (EBSS treatment for 4 h) (B) Quantitative densitometry of p-mTOR (normalized against β-tubulin and total mTOR levels) (C) Quantitative densitometry of p-ULK (normalized against β-tubulin and total ULK levels) (D) Representative Western blot of Beclin-1 levels (E) Quantitative densitometry of Beclin-1 (normalized against β-actin) (F) Representative Western blot of LC3-II and LC3I levels under baseline and chloroquine (CQ) treatment conditions (G) Quantitative densitometry of LC3-II (normalized against β-actin) (G′) Quantitative densitometry of LC3II (normalized against LC3I) relative to the ratio from untreated controls Samples are processed in parallel; data represent mean ± SEM of n = 3 independent experiments for all cell lines Control; **P < 0.01 vs probably indicating some lysosomal disturbance this increase of perinuclear clustered lysosomes is potentiated in APOE 3/4 + PSEN1 fibroblasts lysosomal clustering in APOE 3/4 + PSEN1 fibroblasts and perinuclear clustered lysosomes in all AD fibroblasts (A) Representative images of LAMP1 (a lysosome marker) immunofluorescence in AD fibroblasts (APOE 4/4 (B) Integrated density (IntDen = intensity*μm2) of LAMP1 (C) Lysosomal clustering index (number of clustered lysosomes / number of individual lysosomes) APOE 3/3; &&&&P < 0.0001 vs (D) Representative images of LysoTracker staining Arrows indicate the zoomed areas in the top right corner of each image (E) The proportion of fibroblasts of each genotype presenting lysosomal aggregates Samples are processed in parallel; data represent mean ± SEM of a minimum of 80 cells per genotype analyzed the PI3K class III complex is also activated The activations of ULK1 and Beclin1 are essential for the formation of the phagophore which engulfs the charge that will be degraded the now-called autophagosome fuses with the lysosome to form the autophagolysosome The mutation in PSEN1 induces a significant disruption of mitochondrial networks in APOE 3/4 + PSEN1 fibroblasts and an accumulation of lysosomes and higher levels of superoxide anion inside these cells which are more vulnerable to oxidative stress this could be a possible explanation for our APOE 4/4 results and further studies regarding this are still needed to clarify this question All these alterations could contribute eventually to the neuronal degeneration that underlies the pathogenesis of Alzheimer’s disease a limitation of our study is that the PSEN1 study is based on a single fibroblast cell line the conclusion drawn cannot be generalized; nevertheless it opens the possibility of having mutation-specific treatments in the future This work constitutes an interesting characterization of the mitochondrial status and autophagy mechanisms in patients’ fibroblasts that could offer new targets for developing AD biomarkers and therapies The raw data supporting the conclusions of this article will be made available by the authors The studies involving human participants were reviewed and approved by the Human Research Ethics Committees of CSIC and CIBERNED (Instituto de Salud Carlos III) The patients/participants provided their written informed consent to participate in this study PG-S and RM were responsible for all aspects of the project including the conceptualization and design of the study and EJ-E performed experiments and acquired and analyzed data All authors revised the final version of the manuscript and took responsibility for its content This work was supported by grants from the Spanish Ministries of Science and Innovation (SAF2016-78207-R and PID2019-111693RB-I00) from the European Union’s Horizon 2020 Research and Innovation Program (AND-PD and by NextGenerationEU/PRTR (MICIN/CSIC/PTI+ NeuroAging) Social Services and Equality (PI2019/09-3) and CIBERNED Instituto de Salud Carlos III (CB06/05/0055 from the Scientific Image and Microscopy Unit of Cajal Institute for designing custom-written scripts for all image analysis in this manuscript; the laboratory of Dr Joan Comella at the Hospital Vall d’Hebron (Barcelona Catalina Requejo for revising the manuscript for literature updates and Eva Díaz-Guerra for their experimental help The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher The pleiotropic role of p53 in functional/dysfunctional neurons: Focus on pathogenesis and diagnosis of Alzheimer’s disease Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: Cross talk Attenuation of the lysosomal death pathway by lysosomal cholesterol accumulation APOE genotype effects on Alzheimer’s disease onset and epidemiology PubMed Abstract | CrossRef Full Text | Google Scholar Lysosome-associated membrane protein 1 (LAMP-1) in Alzheimer’s disease Ursodeoxycholic acid improves mitochondrial function and redistributes Drp1 in fibroblasts from patients with either sporadic or familial Alzheimer’s disease A quarter century of APOE and Alzheimer’s disease: Progress to date and the path forward Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy and ROS: A mitochondrial love-hate triangle The mitochondrial-lysosomal axis theory of aging Mitochondrial dysfunction contributes to the pathogenesis of Alzheimer’s disease Apolipoprotein E genotyping method by Real Time PCR a fast and cost-effective alternative to the TaqMan® and FRET assays Calvo-Rodriguez Mitochondria and calcium in Alzheimer’s disease: From cell signaling to neuronal cell death Expression changes in mitochondrial genes affecting mitochondrial morphology and neuronal cell death found in brains of alzheimer’s disease patients Cellular cholesterol homeostasis and Alzheimer’s disease The association of tau with mitochondrial dysfunction in Alzheimer’s disease NP1 regulates neuronal activity-dependent accumulation of BAX in mitochondria and mitochondrial dynamics cause endo-lysosomal dysfunction in PSEN-deficient cells Mitochondria–lysosome crosstalk: From physiology to neurodegeneration Molecular basis of familial and sporadic Alzheimer’s disease Effect of chronic stress present in fibroblasts derived from patients with a sporadic form of AD on mitochondrial function and mitochondrial turnover APOE4 is associated with cognitive and pathological heterogeneity in patients with Alzheimer’s disease: A systematic review APOE4 expression is associated with impaired autophagy and mitophagy in astrocytes Fernández-Calle APOE in the bullseye of neurodegenerative diseases: Impact of the APOE genotype in Alzheimer’s disease pathology and brain diseases The contribution of altered neuronal autophagy to neurodegeneration The WD40 domain of ATG16L1 is required for its non-canonical role in lipidation of LC3 at single membranes García-Sanz N370S -GBA1 mutation causes lysosomal cholesterol accumulation in Parkinson’s disease García-Sanz Cholesterol and multilamellar bodies: Lysosomal dysfunction in GBA -Parkinson disease García-Sanz The role of cholesterol in α−synuclein and lewy body pathology in GBA1 Parkinson’s disease Alterations in mitochondrial number and function in Alzheimer’s disease fibroblasts PubMed Abstract | CrossRef Full Text | Google Scholar The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics The neurobiology and age-related prevalence of the ε4 allele of apolipoprotein e in Alzheimer’s disease cohorts Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by two-pore channel 2 inhibition Ageing as a risk factor for neurodegenerative disease Altered γ-secretase processing of APP disrupts lysosome and autophagosome function in monogenic Alzheimer’s disease The role of lysosomes in a broad disease-modifying approach evaluated across transgenic mouse models of Alzheimer’s disease and Parkinson’s disease and models of mild cognitive impairment Pharmacological modulators of autophagy activate a parallel noncanonical pathway driving unconventional LC3 lipidation ApoE4-induced cholesterol dysregulation and its brain cell type-specific implications in the pathogenesis of Alzheimer’s disease Mitochondrial reticulum network dynamics in relation to oxidative stress Selective autophagy mediated by autophagic adapter proteins PubMed Abstract | CrossRef Full Text | Google Scholar Axonal degeneration in Alzheimer’s disease: When signaling abnormalities meet the axonal transport system Apolipoprotein E ε4 count affects age at onset of Alzheimer disease but not lifetime susceptibility: The cache county study Dissection of the autophagosome maturation process by a novel reporter protein Inhibition of cholesterol metabolism underlies synergy between mTOR pathway inhibition and chloroquine in bladder cancer cells and APOE4 Confer disparate phenotypes in human iPSC-derived microglia Lysosomal positioning coordinates cellular nutrient responses Endosomal-lysosomal and autophagy pathway in Alzheimer’s disease: A systematic review and meta-analysis PubMed Abstract | CrossRef Full Text | Google Scholar ApoE lipidation as a therapeutic target in Alzheimer’s disease Larramona-Arcas Sex-dependent calcium hyperactivity due to lysosomal-related dysfunction in astrocytes from APOE4 versus APOE3 gene targeted replacement mice mitochondria and oxidative stress: Cross-talk and redox signalling Presenilin 1 maintains lysosomal Ca2+ homeostasis via TRPML1 by regulating vATPase-mediated lysosome acidification Lysosomal proteolysis and autophagy require presenilin 1 and are disrupted by alzheimer-related PS1 mutations Imaging of macrophage mitochondria dynamics in vivo reveals cellular activation phenotype for diagnosis ApoE4 (Δ272–299) induces mitochondrial-associated membrane formation and mitochondrial impairment by enhancing GRP75-modulated mitochondrial calcium overload in neuron Lysosome trafficking and signaling in health and neurodegenerative diseases APOE4 causes widespread molecular and cellular alterations associated with Alzheimer’s disease phenotypes in human iPSC-derived brain cell types Apolipoprotein E and Alzheimer disease: Risk Alterations in cholesterol metabolism as a risk factor for developing Alzheimer’s disease: Potential novel targets for treatment Detrimental effects of apolipoprotein E4: Potential therapeutic targets in Alzheimers disease Martín-Maestro Slower dynamics and aged mitochondria in sporadic Alzheimer’s disease Martín-Maestro Mitophagy failure in fibroblasts and iPSC-derived neurons of Alzheimer’s disease-associated presenilin 1 mutation Lag-time in Alzheimer’s disease patients: A potential plasmatic oxidative stress marker associated with ApoE4 isoform Ca2+ dyshomeostasis disrupts neuronal and synaptic function in Alzheimer’s Disease Compromised autophagy and neurodegenerative diseases Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease Protein aggregation and dysfunction of autophagy-lysosomal pathway: A vicious cycle in lysosomal storage diseases Chronically increased oxidative stress in fibroblasts from Alzheimer’s disease patients causes early senescence and renders resistance to apoptosis by oxidative stress PSEN1 mutant iPSC-derived model reveals severe astrocyte pathology in Alzheimer’s disease The use of fibroblasts as a valuable strategy for studying mitochondrial impairment in neurological disorders Neuronal apolipoprotein E4 expression results in proteome-wide alterations and compromises bioenergetic capacity by disrupting mitochondrial function Significance of mitochondrial activity in neurogenesis and neurodegenerative diseases Altered cholesterol ester cycle in skin fibroblasts from patients with Alzheimer’s disease Mitochondrial bioenergetics is altered in fibroblasts from patients with sporadic Alzheimer’s disease Mitochondrial dysfunction in Alzheimer’s disease: Role in pathogenesis and novel therapeutic opportunities PubMed Abstract | CrossRef Full Text | Google Scholar Amyloid-like aggregating proteins cause lysosomal defects in neurons via gain-of-function toxicity Activation of DREAM (downstream regulatory element antagonistic modulator) reduces L-DOPA-induced dyskinesias in mice Presenilin mutations deregulate mitochondrial Ca2+ homeostasis and metabolic activity causing neurodegeneration in Caenorhabditis elegans The interplay between apolipoprotein E4 and the autophagic–endocytic–lysosomal axis Altered mitochondrial dynamics and function in APOE4-expressing astrocytes Mitochondrial dysfunction as a driver of cognitive impairment in Alzheimer’s disease Impaired mitochondrial biogenesis contributes to mitochondrial dysfunction in Alzheimer’s disease The Effects of APOE4 on mitochondrial dynamics and proteins in vivo Lupeol alters viability of SK-RC-45 (Renal cell carcinoma cell line) by modulating its mitochondrial dynamics Amyloid precursor protein and mitochondria PubMed Abstract | CrossRef Full Text | Google Scholar Mitochondria and mitochondrial cascades in Alzheimer’s disease PubMed Abstract | CrossRef Full Text | Google Scholar Szybińska P53 dysfunction in neurodegenerative diseases - the cause or effect of pathological changes Lysosomal exocytosis: The extracellular role of an intracellular organelle Direct transcriptional effects of apolipoprotein E Lysosomal TPCN (two pore segment channel) inhibition ameliorates beta-amyloid pathology and mitigates memory impairment in Alzheimer disease and metabolism in neuronal health and disease Defects in mitochondrial dynamics and metabolomic signatures of evolving energetic stress in mouse models of familial Alzheimer’s disease Identification of a mutant-like conformation of p53 in fibroblasts from sporadic Alzheimer’s disease patients A simple ImageJ macro tool for analyzing mitochondrial network morphology in mammalian cell culture Cholesterol metabolism is a druggable axis that independently regulates tau and amyloid-β in iPSC-derived Alzheimer’s disease neurons A bird’s-eye view of the multiple biochemical mechanisms that propel pathology of Alzheimer’s Disease: Recent advances and mechanistic perspectives on how to halt the disease progression targeting multiple pathways Real-time quantitative PCR analysis of mitochondrial DNA content An analysis of the neurological and molecular alterations underlying the pathogenesis of Alzheimer’s disease Dual dynamics of mitochondrial permeability transition pore opening Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: Recent advances Intracellular and plasma membrane cholesterol labeling and quantification using filipin and GFP-D4 Cholesterol as a causative agent in Alzheimer disease: A debatable hypothesis CrossRef Full Text | Google Scholar Amelioration of Alzheimer’s disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow Alzheimer’s disease presenilin-1 mutation sensitizes neurons to impaired autophagy flux and propofol neurotoxicity: Role of calcium dysregulation Effect of ApoE isoforms on mitochondria in Alzheimer disease Defective mitophagy and the etiopathogenesis of Alzheimer’s disease Abnormal mitochondrial dynamics in the pathogenesis of Alzheimer’s disease Moratalla R and García-Sanz P (2023) APOE ε4 allele alters mitochondrial networks and their degradation in Alzheimer’s disease Copyright © 2023 Costa-Laparra, Juárez-Escoto, Vicario, Moratalla and García-Sanz. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Rosario Moratalla, bW9yYXRhbGxhQGNhamFsLmNzaWMuZXM=; Patricia García-Sanz, cGF0cmljaWEuZ2FyY2lhLnNhbnpAanVudGFkZWFuZGFsdWNpYS5lcw== †Present addresses: Patricia García-Sanz Andalusian Public Foundation Progress and Health-FPS Spain; Instituto de Biomedicina de Sevilla (IBiS)/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla ‡These authors share last authorship Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish Match Recap: Women's Tennis | 3/16/2025 6:30:00 PM Thanks for visiting As the heirs of the late Marchioness of Moratalla squabble over her estate Click here to listen to the audio recording of this article you doubtless already knew of the Marchioness of Moratalla With an estate unofficially estimated to be worth $175 million she didn’t have the same galactic fortune as racer breeders such as Dubai’s Sheikh Mohammed (whose Godolphin dominates the sport) or Chanel’s Wertheimer brothers with more than 5,000 wins credited to her stable Establishing herself in the equestrian world in the early 1980s María de la Soledad Cabeza de Vaca y Leighton was of Spanish-aristocratic and wealthy-English heritage but chose France for her base of operations You couldn’t blame her for wanting to make a home for herself in the velvety hills of the French Basque Country where her secluded Domaine de Coumères could be found not too far from the home region of the trainer Maurice Labrouche But she and her estate managers just didn’t love the taxes It was so much more advantageous to stay domiciled in Switzerland where her mother had already set up the family trusts Match Recap: Women's Tennis | 4/24/2025 2:56:00 PM Thanks for visiting which is dominated by the medieval castle and impressive churches begins at 11.00 on Saturday March 22 at the main entrance to the Town Hall and the route through the old town centre includes the castle the churches of La Asunción and San Francisco and the Teatro Trieta a visit is included to the Museo del Tambor which commemorates the celebratory drumming which takes place throughout the town on Maundy Thursday Comfortable clothing and footwear are recommended Further information is available from the tourist office of Moratalla (Calle Barrio Nuevo For more upcoming events in the Region of Murcia go to the What’s on section of Murcia Today Metrics details Recent findings of structural glasses with extremely high kinetic and thermodynamic stability have attracted much attention The question has been raised as to whether the well-known low-temperature “glassy anomalies” (attributed to the presence of two-level systems [TLS] and the “boson peak”) persist or not in these ultrastable glasses of much lower configurational entropy we study a particular type of ultrastable glass which can be prepared by physical vapor deposition in a highly-stable state with different degrees of layering and molecular orientation and also as a conventional glass and in crystalline state After a thorough characterization of the different samples prepared we have measured their specific heat down to 0.4 K Whereas the conventional glass exhibits the typical glassy behaviour and the crystal the expected Debye cubic dependence at very low temperatures a strong depletion of the TLS contribution is found in both kinds of ultrastable glass regardless of their layering and molecular ordering Glasses are liquids that have been supercooled out of thermodynamic equilibrium The glass transition in the laboratory is a kinetic transition when thermodynamic magnitudes are measured the glass transition looks like a second-order phase transition with finite discontinuities in second derivatives of the Gibbs free energy in contrast to the first-order divergence for the melting of a crystal glass transitions are typically observed as a jump in heat capacity with a small overshoot depending on the employed heating rate there are complicated unsolved questions related to this apparent phase transition the deviation from the equilibrium curve occurs at a lower glass-transition temperature Tg This is a serious problem to consider it a proper phase transition temperature since the glass is in a non-equilibrium state by isothermal annealing of a glass below Tg (or simply by aging at room temperature) the thermodynamic magnitudes can be relaxed to lower where an underlying thermodynamic phase transition might occur many experiments were devoted to investigating whether those low-temperature anomalous excitations would gradually decrease or even disappear when decreasing enthalpy and entropy of the glass by means of typical annealing or aging stabilization processes Due to the obvious limitations of time (many millions of years are expected to be necessary to stabilize a glass with minimal entropy) the obtained results from those modest thermal treatments were usually unclear or even contradictory the very nature of computer glasses is not straightforwardly related to that of real structural glasses the major source of noise and decoherence in superconducting circuits typically made from aluminum or niobium comes from the losses generated by these TLS or atomic tunneling excitations within the amorphous oxide layers encasing them we have studied TPD glasses grown by PVD in three different conditions: anisotropic glass with the highest stability (deposited at 285 K); isotropic glass but also with high stability (deposited at 300 K); and isotropic conventional glass (deposited at Tg = 333 K) Control samples grown simultaneously with the ones for low-temperature measurements were characterized by Differential scanning calorimetry (DSC) ultraviolet/visible (UV/Vis) spectroscopy and high-resolution Brillouin spectroscopy (HRBS) DSC curves for stable glasses deposited at 0.85 Tg (black lines) and 0.9 Tg (red lines) where Tg is the glass transition temperature Both first upscans at 10 K/min up to 380 K −exposing the thermodynamic history of the stable glass− and second upscans −after the sample has transformed into the conventional glass by cooling the liquid at −10 K/min− are depicted The corresponding devitrification temperatures Ton of each case (assessing the degree of kinetic stability) are graphically shown Wide-angle XRD spectra for the two stable glasses with the corresponding deposition temperatures indicated in the legend and the one of the conventional glass (CG) deposited at Tg = 333 K Blue dotted lines mark the positions of the main diffraction peaks Solid red squares (right scale): devitrification onset temperature (Ton) measured by calorimetry on TPD glasses grown at different deposition temperatures Solid stars correspond to samples obtained by cooling from the liquid state The uncertainty in the Sz value is obtained from the standard deviation of three absorption measures per each deposition temperature after error propagation of the maximum absorption value in the UV-Vis spectra where \(A\) is the absorption of the deposited film and \({A}_{{iso}}\) is the absorption of a film that has exactly the same number of molecules as the original one This is obtained after annealing the vapor deposited film during 30 s at 350 K (Tg + 27 K) in Ar atmosphere A value of Sz = −0.5 corresponds to a transition dipole moment of the molecule aligned parallel to the substrate then indicating horizontal orientation of the molecule; Sz = 0 means that the molecules are randomly oriented and Sz = 1 that molecules are preferentially aligned with the long axis perpendicular to the substrate Sound velocity as a function of temperature for the differently prepared glasses as indicated in the legend: a longitudinal sound velocity vL; b transverse sound velocity vT In the case of the conventional glass the darker symbols represent a cooling run and the less dark ones represent a heating run In the case of the anisotropic ultrastable glasses (USG) both symbols (darker and less dark ones) represent two different cooling runs It is to be stressed that data in anisotropic glasses refers only to the sound velocity measured in the direction of the acoustic vector (see the Sound velocity subsection for more details) Errors associated with the data points are calculated from the frequency error values obtained from the non-linear fits to the peaks in the Brillouin spectra and are below 1% for vL and about 2.5% for vT making them smaller than the symbols in the plot especially for the more anisotropic glass (0.85 Tg) This finding will be supported by the specific heat data to be discussed below Specific heat for the three different glasses (conventional, isotropic ultrastable glass and anisotropic ultrastable glass) and the reference crystal of TPD (see the symbols in the legend) plotted in a Debye-reduced Cp/T 3 plot. Error associated with the data points was calculated using one standard deviation and is of the size of the data points. Specific-heat data below 2 K for the three different glasses and the reference crystal of TPD (see the symbols in the legend) in a Cp/T vs T 2 plot. Dashed lines show the corresponding least-squares fits: quadratic, below 2 K for the glasses; linear, below 1 K for the crystal. Error associated with the data points was calculated using one standard deviation and is of the size of the data points. Glassy specific-heat excess (subtracting its value for the crystal state) for the three different glasses (see legend) in: a Cp/T 3 representation; b Cp/T vs T 2 representation at the lowest temperatures Dashed lines show the least squares linear fits performed to determine the corresponding linear coefficients As mentioned above, in Fig. 5 the whole of our specific-heat data is plotted as Cp/T 3 versus temperature in a log scale where deviations from the expected cubic behavior for crystals at the lowest temperatures are more easily observed and analyzed data appear noisier than in other representations due to the T 3 factor in the denominator conventional glass has a significant linear coefficient whereas the stable glasses show a clear depletion of TLS especially the most stable glass deposited at 0.85 Tg for which its presence is null within experimental error In order to enhance and better visualize the glassy features of the specific heat, we have subtracted the reference crystal value from the total Cp(T) of each glass sample, as depicted in Fig. 7 The left panel (a) shows this glassy excess ΔCp,glassy over the crystal curve in the Cp/T 3 plot while the right panel (b) shows the lowest-temperature data in a Cp/T vs T 2 plot the ordinary or conventional glass (grown at Tg) exhibited the expected glassy features namely a linear term in the specific heat due to the presence of TLS and a boson peak Cp/T 3 slightly below 3 K the most novel finding in this work has been obtained from preparing and studying an intermediate glass state (the glass deposited at 0.9 Tg) which is almost as stable as the 0.85 Tg one but almost as isotropic as the conventional glass it shows a linear term in Cp much smaller than that of the conventional glass although not strictly zero within experimental error what we attribute to the slightly lesser stability than the 0.85 Tg glass the density of TLS appears to inversely correlate with the degree of stability and is independent of the anisotropy the vibrational Debye-like background of Cp dominating above 1 K of this isotropic/stable glass is very similar to that of the conventional glass but clearly higher than that of the anisotropic glass of 0.85 Tg Hence this vibrational background around the boson peak seems to be governed by the molecular ordering influencing the network structure The sample grown at Tdep =333 K is equivalent from the thermodynamic (onset and fictive temperature) and structural (XRD and Sz parameter) points of view to a conventional (−10 K/min) liquid-cooled glass the low-temperature specific heat of the reference crystal state was also measured respectively) are both isotropic within the experimental uncertainty This technique provides information about the electronic transitions in the range of ultraviolet-visible wavelengths As each electronic transition has associated a transition dipole moment the molecular orientation of the glass may yield variations on the intensity of the transition This scattering geometry allows the observation of the longitudinal and transverse phonons whereas in the pure Backscattering geometry the transverse phonons in principle do not couple to the electromagnetic field of the incoming light As it is shown in Supplementary Fig. 1 the acoustic wave vector q2αA is related to the scattering angle (2α) as: being α the angle of incidence and λ0 the laser wavelength It is not dependent on the refractive index of the sample where fL,T is the measured Brillouin frequency shift of the longitudinal (L) or transverse (T) phonons a 1 kΩ resistor chip (used as a heater) and a thermal sensor were also fixed on the sapphire support in very good thermal contact with the samples The calorimetric cell was connected to the controlled thermal sink through a thin PtW wire chosen to have relaxation times of tens of seconds All data are available in the main text or the supplementary materials as well as from the corresponding author on reasonable request Amorphous Solids: Low Temperature Properties Low temperature properties of amorphous materials: through a glass darkly Relaxation in glassforming liquids and amorphous solids Supercooled liquids and the glass transition Structural glasses and supercooled liquids: theory Perspective: supercooled liquids and glasses Impact of jamming criticality on low-temperature anomalies in structural glasses Low-Temperature and Vibrational Properties of Disordered Solids: A Half-Century of “Anomalies” of Glasses (World Scientific Viscous liquids and the glass transition: a potential energy barrier picture A topographic view of supercooled liquids and glass formation Ultrastable glasses: new perspectives for an old problem The nature of the glassy state and the behavior of liquids at low temperatures Are universal “anomalous” properties of glasses at low temperatures truly universal Thermal conductivity and specific heat of thin-film amorphous silicon Excess specific heat in evaporated amorphous silicon Hydrogen-free amorphous silicon with no tunneling states Organic glasses with exceptional thermodynamic and kinetic stability Stability of thin film glasses of toluene and ethylbenzene formed by vapor deposition: an in situ nanocalorimetric study Correction: Stability of thin film glasses of toluene and ethylbenzene formed by vapor deposition: an in situ nanocalorimetric study Perspective: Highly stable vapor-deposited glasses Suppression of tunneling two-level systems in ultrastable glasses of indomethacin Depletion of two-level systems in ultrastable computer-generated glasses Microscopic observation of two-level systems in a metallic glass model Low-temperature thermal properties of a hyperaged geological glass Two-level systems and boson peak remain stable in 110-million-year-old amber glass Do two-level systems and boson peak persist or vanish in hyperaged geological glasses of amber Highly stable glasses of celecoxib: influence on thermo-kinetic properties microstructure and response towards crystal growth Birefringent stable glass with predominantly isotropic molecular orientation Anisotropic vapor-deposited glasses: hybrid organic solids Surface equilibration mechanism controls the molecular packing of glassy molecular semiconductors at organic interfaces Transformation kinetics of vapor-deposited thin film organic glasses: the role of stability and molecular packing anisotropy Enhanced electrical properties and air stability of amorphous organic thin films by engineering film density Influence of vapor deposition on structural and charge transport properties of Ethylbenzene films Emergence of a substrate-temperature-dependent dielectric process in a prototypical vapor deposited hole-transport glass Evidence of thermal transport anisotropy in stable glasses of vapor deposited organic molecules Role of molecular layering in the enhanced mechanical properties of stable glasses Superconducting circuits for quantum information: an outlook Towards understanding two-level-systems in amorphous solids: insights from quantum circuits Acoustic properties of metallic glasses at low temperatures: tunneling systems and their dephasing Low Energy Excitations in Disordered Solids Ch Kinetic arrest of front transformation to gain access to the bulk glass transition in ultrathin films of vapour-deposited glasses Emergence of equilibrated liquid regions within the glass Structural characterization of vapor-deposited glasses of an organic hole transport material with X-ray scattering The structure and energetics of TPD ground and excited states Asymmetry between absorption and photoluminescence line shapes of TPD: spectroscopic fingerprint of the twisted biphenyl core Structure and Properties of Oriented Polymers Molecular orientation in small-molecule organic light-emitting diodes Tunable molecular orientation and elevated thermal stability of vapor-deposited organic semiconductors Simple model-free estimation of orientation order parameters of vacuum-deposited and spin-coated amorphous films used in organic light-emitting diodes Are the calorimetric and elastic Debye temperatures of glasses really different Low-temperature specific heat of glasses and disordered crystals in Low-Temperature and Vibrational Properties of Disordered Solids: A Half-Century of “Anomalies” of Glasses (ed Influence of molecular shape on the thermal stability and molecular orientation of vapor-deposited organic semiconductors A new Brillouin scattering technique for the investigation of acoustic and opto-acoustic properties: application to polymers Heat capacity measurements on small samples at low temperatures Low-temperature calorimetry on molecular glasses and crystals Low-temperature specific heat of graphite and CeSb2: validation of a quasi-adiabatic continuous method Download references Castilla for unvaluable help with the 3He cryostat acknowledge financial support from PID2021-127498NB-I00/AEI/FEDER/10.13039/501100011033 also from MCIN/AEI/10.13039/ 501100011033 through the “María de Maeztu” Program for Units of Excellence in R&D (CEX2018-000805-M) as well as from the Autonomous Community of Madrid through program S2018/NMT-4321 (NANOMAGCOST-CM) The ICN2 is funded by the CERCA program/Generalitat de Catalunya The ICN2 was supported by the “Severo Ochoa” Centres of Excellence Program funded by the Spanish Research Agency (AEI received funds from the PID2021-127033OB-C21/MCIN/AEI/10.13039/501100011033 research project of the Spanish Ministerio de Ciencia e Innovación Cristian Rodríguez-Tinoco & Javier Rodríguez-Viejo Catalan Institute of Nanoscience and Nanotechnology (ICN2) Instituto de Ciencia de Materiales de Madrid (ICMM-CSIC) conceived the idea and proposed the experiments implemented the experimental setups for low-temperature calorimetry under the supervision of M.A.R. performed the calorimetric and structural characterizations and their data analysis conducted the Brillouin light scattering measurements and obtained the sound velocity data conducted the specific-heat measurements at low temperature and their data analysis with the input of M.A.R All authors contributed to the writing and editing of the manuscript The authors declare no competing interests reviewer(s) for their contribution to the peer review of this work Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s42005-023-01398-4 Sorry, a shareable link is not currently available for this article. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. volume 5 - 2011 | https://doi.org/10.3389/fnana.2011.00051 This article is part of the Research TopicStriatal Signaling: Two Decades of ProgressView all 18 articles Parkinson’s disease is a common neurodegenerative disorder caused by the degeneration of midbrain substantia nigra dopaminergic neurons that project to the striatum Despite extensive investigation aimed at finding new therapeutic approaches remains the most effective and commonly used treatment chronic treatment and disease progression lead to changes in the brain’s response to L-DOPA resulting in decreased therapeutic effect and the appearance of dyskinesias L-DOPA-induced dyskinesia (LID) interferes significantly with normal motor activity and persists unless L-DOPA dosages are reduced to below therapeutic levels controlling LID is one of the major challenges in Parkinson’s disease therapy LID is the result of intermittent stimulation of supersensitive D1 dopamine receptors located in the very severely denervated striatal neurons Through increased coupling to Gαolf resulting in greater stimulation of adenylyl-cyclase D1 receptor stimulation activates extracellular signal-regulated kinase and triggers a signaling pathway involving mammalian target for rapamycin and modifications of histones that results in changes in translation sensitization of D1 receptor signaling causes a widespread increase in the metabolic response to D1 agonists and changes in the activity of basal ganglia neurons that correlate with the severity of LID different studies suggest that dyskinesias may share mechanisms with drug abuse and long term memory involving D1 receptor activation Here we review evidence implicating D1 receptor signaling in the genesis of LID analyze mechanisms that may translate enhanced D1 signaling into dyskinetic movements and discuss the possibility that the mechanisms underlying LID are not unique to the Parkinson’s disease brain Here we review animal studies investigating the mechanisms of LID with a focus on rodent models and D1 receptor signaling mechanisms Additional mechanisms involving D2 family receptors may contribute to the expression of LID especially when dyskinetic movements are induced by D2-like agonists in animals previously exposed to L-DOPA these findings show that LID is related to specific D1R-dependent changes in gene expression in striatonigral MSNs neurons that selectively express dynorphin and D1 receptor Genetic inactivation of dopamine D1 receptor blocks striatal molecular changes induced by chronic L-DOPA administration in hemiparkinsonian mice Photomicrographs of adjacent coronal striatal sections from WT (top) and D1R−/− (bottom) hemiparkinsonian mice treated with L-DOPA Chronic L-DOPA treatment induced marked FosB and p-ERK expression in the striatal areas that are devoid of TH-immunoreactive fibers in WT mice but not in the striatum of D1R−/− mice It has been possible to follow the signaling cascade involved in LID downstream to translation and transcription mechanisms Finally, some changes in transcription may be related to a switch in gene expression control from cAMP-response element binding transcription factor (CREB) dominance to ΔFosB dependence. In the intact striatum, prodynorphin transcription is mediated by CREB, but L-DOPA induction of prodynorphin transcription in parkinsonian rats is under the control of ΔFosB and JunD (Andersson et al., 2001) Thus, it seems likely that D2R subtype regulation of striatopallidal neurons may modulate LID expression. This is illustrated in a study by Gold et al. (2007) aimed at modulating D2 receptor signaling in LID Modifying the expression of regulator of G-protein signaling (RSG) 9-2 a protein that inhibits D2 receptor interaction with G proteins regulated LID: RSG 9-2 knockouts showed increased susceptibility to LID whereas overexpression of RSG 9-2 reduced LID in MPTP-lesioned monkeys the effects of modifying RSG 9-2 expression on motor function were not specific to LID suggesting that striatal D2R subtype signaling allows an increase in motor output that results in more severe dyskinesia when the main LID signaling cascade It is worth considering whether the effects of D3R preferring drugs in LID result from their ability to modulate D1R-D3R membrane interactions rather than from their antagonist/partial agonist action at the ligand binding site no study has yet taken advantage of engineered mice expressing florescent proteins in D1R- or D2R–MSNs to establish how L-DOPA impacts on plasticity in each striatal output pathway Top row diagrams: sensitivity of direct and indirect-pathway MSNs to dopamine receptor stimulation in a naive patient (left) in a patient that is finding benefit under L-DOPA therapy (middle) The naive parkinsonian brain has hyperactive and hypoactive indirect and direct pathways respectively and may respond weakly to a first challenge with L-DOPA Repeated D1 receptor stimulation may reinstate a balance between the direct and indirect pathways and produce clinical benefit (middle) the complete loss of dopamine buffering capacity results in pulsatile stimulation of D1 receptors induction of D3 receptor expression in direct-pathway MSNs and amplification of D1 receptor signaling Bottom row diagrams: repeated pulsatile stimulation of D1 receptors in direct-pathway MSNs produces a multiplicative gain in the motor response to L-DOPA which is reflected in a change of the slope and an increase in the maximal attainable response (left) This would progressively impel the patient to the threshold for induction of dyskinesia D2 receptor stimulation in indirect-pathway MSNs may not drive the patient through the dyskinesia threshold but may have an additive effect if the patient is above threshold (right) once direct-pathway MSNs have crossed threshold stimulation of over-expressed D3 receptors may also have multiplicative gain effects it is not clear how such receptor reorganization is related to alterations in synaptic plasticity or to other functional changes associated with LID suggesting that mGluR5 plays a more important control over ERK1/2 than the NMDA receptor in the parkinsonian condition D1 receptor activation may result in exaggerated ERK1/2 phosphorylation through multiple mechanisms In addition to alterations in functional plasticity, indirect evidence suggests that LID is associated with structural changes in neurons. Activity-regulated cytoskeletal-associated protein (arc) is markedly up-regulated in direct pathway MSNs in rats with 6-OHDA lesion treated chronically with L-DOPA, though it is not clear that this change is selectively associated with the development of LID (Sgambato-Faure et al., 2005) Although changes in arc expression and function are frequently involved in synaptic remodeling further work is necessary to assess such changes in LID further suggesting that D3R stimulation acts by potentiating D1R signaling in LID Importantly, it seems that metabolic changes are not restricted to motor areas. A 2-deoxyglucose accumulation study conducted in MPTP-lesioned non-human primates revealed increased metabolic activity in limbic and cognitive territories of the striatum only in L-DOPA-treated animals that had developed dyskinesia (Guigoni et al., 2005) The studies by Filion et al. (1991) and Boraud et al. (2001) show that D2-like agonists induce dyskinesia and changes in pallidal activity similar to those produced by apomorphine In both studies the same monkeys were repeatedly challenged with a mixed D1/D2 agonist and a selective D2-like agonist thus the D2 agonist effects were taking place in a primed brain both apomorphine and D2-like receptor agonists induced increases in activity in the external pallidal segment which could have contributed to reducing neuronal firing in the internal pallidum D2/D3 agonist-induced dyskinesia probably shares circuit mechanisms with LID Further work correlating the activity of direct- and indirect-pathway striatal MSNs to the degree of dopamine denervation and dyskinesia scores is necessary to determine the circuit mechanisms involved in LID the data indicate that a good buffering capacity of dopamine concentration in the extracellular space may preclude sensitization to L-DOPA and attenuate the activation of already sensitized postsynaptic dyskinesia machinery This is not to say that supersensitivity of D1R signaling does not contribute to LID. Supersensitivity may explain why the molecular changes associated to LID are several-fold more widespread and intense than those induced by psychostimulants. However, an almost complete loss of presynaptic dopaminergic terminals (implying a loss of buffering capacity) is a prerequisite for D1R signaling supersensitivity (Pavon et al., 2006; Darmopil et al., 2009) D1R supersensitivity and the loss of buffering capacity conspire together in LID sequential “waves” of dopamine at different time points are critical for long term memory storage in the hippocampus supporting the important role of D1R in learning and memory at least some components of the signaling cascade implicated in LID are also active in the hippocampus at times when D1 receptor stimulation contributes to memory persistence An intriguing possibility is that phasic D1R stimulation is critical for inducing components of the signaling cascade that produce physiological increases in synaptic strength. Even in the striatum, where tonic dopamine levels are relatively high, it is believed that the low affinity of D1R is not activated except during physiological surges of dopamine induced by burst firing of the dopaminergic neurons (Gonon, 1997) physiological surges of dopamine in the extracellular space could be involved in D1R promotion of memory storage in different brain areas Longer-lasting and more marked non-physiological D1R stimulation induced by cocaine and psychostimulants in the dopamine-intact brain or by L-DOPA in the brain that has lost the buffering capacity of striatal dopaminergic terminals may induce abnormal plasticity and behavioral alterations This hypothesis can be interrogated by studying the behavioral consequences of intermittent stimulation of dopamine receptors after manipulating dopamine buffering capacity in specific brain areas Ruiz De Diego for their help with the figures and art work Funded by grants from the Spanish Ministerios de Ciencia e Innovación y de Sanidad y Política Social Striatal fosB expression is causally linked with L-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson’s disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text cAMP response element-binding protein is required for dopamine-dependent gene expression in the intact but not the dopamine-denervated striatum Pubmed Abstract | Pubmed Full Text The blood-brain barrier is intact after levodopa-induced dyskinesias in parkinsonian primates – evidence from in vivo neuroimaging studies Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Increased D1 dopamine receptor signaling in levodopa-induced dyskinesia Pubmed Abstract | Pubmed Full Text | CrossRef Full Text restores striatal equilibrium in a rat model of Parkinsonism CrossRef Full Text Distinct subclasses of medium spiny neurons differentially regulate striatal motor behaviors Pubmed Abstract | Pubmed Full Text | CrossRef Full Text BDNF is essential to promote persistence of long-term memory storage Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Aberrant striatal plasticity is specifically associated with dyskinesia following levodopa treatment Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Involvement of hippocampal cAMP/cAMP-dependent protein kinase signaling pathways in a late memory consolidation phase of aversively motivated learning in rats Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pharmacological analysis demonstrates dramatic alteration of D1 dopamine receptor neuronal distribution in the rat analog of L-DOPA-induced dyskinesia Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Striatal overexpression of DeltaJunD resets L-DOPA-induced dyskinesia in a primate model of Parkinson disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dopamine and memory: modulation of the persistence of memory for novel hippocampal NMDA receptor-dependent paired associates Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Is striatal dopaminergic receptor imbalance responsible for levodopa-induced dyskinesia Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dopamine agonist-induced dyskinesias are correlated to both firing pattern and frequency alterations of pallidal neurones in the MPTP-treated monkey Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Induction of dopamine D3 receptor expression as a mechanism of behavioral sensitization to levodopa Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Involvement of the direct striatonigral pathway in levodopa-induced sensitization in 6-hydroxydopamine-lesioned rats Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Parsing molecular and behavioral effects of cocaine in mitogen- and stress-activated protein kinase-1-deficient mice Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pubmed Abstract | Pubmed Full Text Pharmacologically modulated fMRI – cortical responsiveness to levodopa in drug-naive hemiparkinsonian patients Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Levodopa-induced dyskinesia: a pathological form of striatal synaptic plasticity Dopamine and cAMP-regulated phosphoprotein 32 kDa controls both striatal long-term depression and long-term potentiation Long-term synaptic depression in the striatum: physiological and pharmacological characterization Pubmed Abstract | Pubmed Full Text Role of striatal L-DOPA in the production of dyskinesia in 6-hydroxydopamine lesioned rats Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Maladaptive striatal plasticity in L-DOPA-induced dyskinesia Pubmed Abstract | Pubmed Full Text Distinct roles of D1 and D5 dopamine receptors in motor activity and striatal synaptic plasticity Pubmed Abstract | Pubmed Full Text Unilateral dopamine denervation blocks corticostriatal LTP Pubmed Abstract | Pubmed Full Text Dopamine and N-methyl-D-aspartate receptor interactions in the neostriatum Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Persistent increase in olfactory type G-protein alpha subunit levels may underlie D1 receptor functional hypersensitivity in Parkinson’s disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Modification of parkinsonism: chronic treatment with L-dopa Pubmed Abstract | Pubmed Full Text | CrossRef Full Text dopamine: insights from Parkinson’s disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Development of dyskinesias induced by treatment for Parkinson’s disease: potential role of first exposure to L-DOPA (or phenomenon of priming) Pubmed Abstract | Pubmed Full Text Genetic inactivation of dopamine D1 but not D2 receptors inhibits L-DOPA-induced dyskinesia and histone activation Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Tyrosine hydroxylase cells appearing in the mouse striatum after dopamine denervation are likely to be projection neurones regulated by L-DOPA Pubmed Abstract | Pubmed Full Text | CrossRef Full Text de la Fuente-Fernández Levodopa-induced changes in synaptic dopamine levels increase with progression of Parkinson’s disease: implications for dyskinesias Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Mapping the effects of three dopamine agonists with different dyskinetogenic potential and receptor selectivity using pharmacological functional magnetic resonance imaging Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Behavioral sensitization to different dopamine agonists in a parkinsonian rodent model of drug-induced dyskinesias Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Chronic alterations in dopaminergic neurotransmission produce a persistent elevation of deltaFosB-like protein(s) in both the rodent and primate striatum Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Spatial learning deficit in dopamine D1 receptor knockout mice Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pubmed Abstract | Pubmed Full Text Inhibition of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) signaling in the striatum reverts motor symptoms associated with L-dopa-induced dyskinesia Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1) controls activation of extracellular signal-regulated kinase (ERK) signaling in the striatum and long-term behavioral responses to cocaine Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Effects of dopamine agonists on the spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Reciprocal regulation of dopamine D1 and D3 receptor function and trafficking by heterodimerization Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Loss of synaptic D1 dopamine/N-methyl-D-aspartate glutamate receptor complexes in L-DOPA-induced dyskinesia in the rat Pubmed Abstract | Pubmed Full Text A critical interaction between NR2B and MAGUK in L-DOPA induced dyskinesia Pubmed Abstract | Pubmed Full Text | CrossRef Full Text D1 dopamine receptor supersensitivity in the dopamine-depleted striatum results from a switch in the regulation of ERK1/2/MAP kinase Pubmed Abstract | Pubmed Full Text RGS9-2 negatively modulates L-3,4-dihydroxyphenylalanine-induced dyskinesia in experimental Parkinson’s disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Prolonged and extrasynaptic excitatory action of dopamine mediated by D1 receptors in the rat striatum in vivo Pubmed Abstract | Pubmed Full Text D(1) dopamine receptor agonists are more effective in alleviating advanced than mild parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys Pubmed Abstract | Pubmed Full Text D1 but not D5 dopamine receptors are critical for LTP and LTP-Induced arc and zif268 expression in the hippocampus Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Chronic treatment with atypical neuroleptics induces striosomal FosB/DeltaFosB expression in rats Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Potential therapeutic use of the selective dopamine D1 receptor agonist A-86929: an acute study in parkinsonian levodopa-primed monkeys Pubmed Abstract | Pubmed Full Text D1 receptor blockade improves L-dopa-induced dyskinesia but worsens parkinsonism in MPTP monkeys Pubmed Abstract | Pubmed Full Text Altered D(1) dopamine receptor trafficking in parkinsonian and dyskinetic non-human primates Pubmed Abstract | Pubmed Full Text | CrossRef Full Text and associative basal ganglia domains in L-3,4-dihydroxyphenylalanine-induced dyskinesia Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dissociation of metabolic and neurovascular responses to levodopa in the treatment of Parkinson’s disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Atypical and typical neuroleptic treatments induce distinct programs of transcription factor expression in the striatum Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Molecular dissection of dopamine receptor signaling Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized 33 controlled trial Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Effect of the D3 dopamine receptor partial agonist BP897 [N-[4-(4-(2-methoxyphenyl) piperazinyl) butyl]-2-naphthamide] on L-3,4-dihydroxyphenylalanine-induced dyskinesias and parkinsonism in squirrel monkeys Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dopamine D3 receptors in the basal ganglia of the common marmoset and following MPTP and L-DOPA treatment Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Molecular mechanisms of L-DOPA-induced dyskinesia Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Transition to addiction is associated with a persistent impairment in synaptic plasticity Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Expression of the transcription factor deltaFosB in the brain controls sensitivity to cocaine Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson’s disease models Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Striatal plasticity and basal ganglia circuit function Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Evaluation of the D3 dopamine receptor selective antagonist PG01037 on L-DOPA-dependent abnormal involuntary movements in rats Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Cabergoline and pramipexole fail to modify already established dyskinesias in an animal model of parkinsonism Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Regulation of histone acetylation during memory formation in the hippocampus Pubmed Abstract | Pubmed Full Text | CrossRef Full Text L-DOPA-induced dopamine efflux in the striatum and the substantia nigra in a rat model of Parkinson’s disease: temporal and quantitative relationship to the expression of dyskinesia Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Differential involvement of D1 and D2 dopamine receptors in L-DOPA-induced angiogenic activity in a rat model of Parkinson’s disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Neurotransmitter roles in synaptic modulation plasticity and learning in the dorsal striatum Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Neuronal recordings in Parkinson’s disease patients with dyskinesias induced by apomorphine Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pharmacological validation of a mouse model of L-DOPA-induced dyskinesia Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Identification of dopamine D1-D3 receptor heteromers Indications for a role of synergistic D1-D3 receptor interactions in the striatum Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Regulation of gene expression and cocaine reward by CREB and DeltaFosB Pubmed Abstract | Pubmed Full Text | CrossRef Full Text DeltaFosB: a molecular switch for long-term adaptation in the brain Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Antagonism of metabotropic glutamate receptor type 5 attenuates L-DOPA-induced dyskinesia and its molecular and neurochemical correlates in a rat model of Parkinson’s disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text improves parkinsonian-like motor dysfunction but does not affect L-DOPA-induced dyskinesia in 6-hydroxydopamine hemi-lesioned rats Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Apomorphine induces changes in GPi spontaneous outflow in patients with Parkinson’s disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Cellular responses to psychomotor stimulant and neuroleptic drugs are abnormal in mice lacking the D1 dopamine receptor CrossRef Full Text Network-level changes in expression of inducible Fos-Jun proteins in the striatum during chronic cocaine treatment and withdrawal CrossRef Full Text Levodopa in Parkinson’s disease: neurotoxicity issue laid to rest Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Levodopa induces a cytoplasmic localization of D1 dopamine receptors in striatal neurons in Parkinson’s disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Clinical pharmacology of levodopa-induced dyskinesia Pubmed Abstract | Pubmed Full Text Pharmacokinetics and pharmacodynamics of levodopa Pubmed Abstract | Pubmed Full Text | CrossRef Full Text O’Carroll Dopaminergic modulation of the persistence of one-trial hippocampus dependent memory Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Levodopa in the treatment of Parkinson’s disease: current controversies Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Drug insight: Continuous dopaminergic stimulation in the treatment of Parkinson’s disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Sudden appearance of invalidating dyskinesia-dystonia and off fluctuations after the introduction of levodopa in two dopaminomimetic drug naive patients with stage IV Parkinson’s disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Associative learning and CA3-CA1 synaptic plasticity are impaired in D1R null Drd1a-/- mice and in hippocampal siRNA silenced Drd1a mice Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Internal globus pallidus discharge is nearly suppressed during levodopa-induced dyskinesias Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Levodopa in Parkinsonism: potentiation of central effects with a peripheral inhibitor Pubmed Abstract | Pubmed Full Text | CrossRef Full Text ERK phosphorylation and FosB expression are associated with L-DOPA-induced dyskinesia in hemiparkinsonian mice Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Loss of bidirectional striatal synaptic plasticity in L-DOPA-induced dyskinesia Pubmed Abstract | Pubmed Full Text Expression of D(3) receptor messenger RNA and binding sites in monkey striatum and substantia nigra after nigrostriatal degeneration: effect of levodopa treatment Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dopamine agonists: what is the place of the newer compounds in the treatment of Parkinson’s disease Development of dyskinesias in a 5-year trial of ropinirole and L-dopa Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Induction by dopamine D1 receptor agonist ABT-431 of dyskinesia similar to levodopa in patients with Parkinson disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Metabolic interactions between glutamatergic and dopaminergic neurotransmitter systems are mediated through D(1) dopamine receptors Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dopamine controls persistence of long-term memory storage Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Pharmacological modulation of glutamate transmission in a rat model of L-DOPA-induced dyskinesia: effects on motor behavior and striatal nuclear signaling Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Sánchez-Pernaute In vivo evidence of D3 dopamine receptor sensitization in parkinsonian primates and rodents with L-DOPA-induced dyskinesias Pubmed Abstract | Pubmed Full Text | CrossRef Full Text L-DOPA activates ERK signaling and phosphorylates histone H3 in the striatonigral medium spiny neurons of hemiparkinsonian mice CrossRef Full Text Inhibition of mTOR signaling in Parkinson’s disease prevents L-DOPA-induced dyskinesia CrossRef Full Text CrossRef Full Text Critical involvement of cAMP/DARPP-32 and extracellular signal-regulated protein kinase signaling in L-DOPA-induced dyskinesia Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor lovastatin reduces severity of L-DOPA-induced abnormal involuntary movements in experimental Parkinson’s disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Sgambato-Faure Coordinated and spatial upregulation of arc in striatonigral neurons correlates with L-dopa-induced behavioral sensitization in dyskinetic rats Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dichotomous dopaminergic control of striatal synaptic plasticity Pubmed Abstract | Pubmed Full Text | CrossRef Full Text A phosphatase cascade by which rewarding stimuli control nucleosomal response Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dopamine and synaptic plasticity in dorsal striatal circuits controlling action selection Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dopamine-dependent synaptic plasticity in striatum during in vivo development Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dopamine D1 and D2 receptor contributions to L-DOPA-induced dyskinesia in the dopamine-depleted rat Pubmed Abstract | Pubmed Full Text | CrossRef Full Text MAPK cascade signalling and synaptic plasticity Pubmed Abstract | Pubmed Full Text | CrossRef Full Text The effects of L-DOPA on regional cerebral glucose utilization in rats with unilateral lesions of the substantia nigra Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Selective D1 and D2 dopamine agonists differentially alter basal ganglia glucose utilization in rats with unilateral 6-hydroxydopamine substantia nigra lesions Pubmed Abstract | Pubmed Full Text Presynaptic dopaminergic compartment determines the susceptibility to L-DOPA-induced dyskinesia in rats Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties Pubmed Abstract | Pubmed Full Text Dopamine D3 receptor stimulation underlies the development of L-DOPA-induced dyskinesia in animal models of Parkinson’s disease Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Chronic dopaminergic stimulation in Parkinson’s disease: from dyskinesias to impulse control disorders Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Dopaminergic control of corticostriatal long-term synaptic depression in medium spiny neurons is mediated by cholinergic interneurons Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Endothelial proliferation and increased blood-brain barrier permeability in the basal ganglia in a rat model of 3,4-dihydroxyphenyl-L-alanine-induced dyskinesia Pubmed Abstract | Pubmed Full Text | CrossRef Full Text Spatiotemporal pattern of striatal ERK1/2 phosphorylation in a rat model of L-DOPA-induced dyskinesia and the role of dopamine D1 receptors Pubmed Abstract | Pubmed Full Text | CrossRef Full Text L-DOPA-induced dyskinesia in the intrastriatal 6-hydroxydopamine model of Parkinson’s disease: relation to motor and cellular parameters of nigrostriatal function Pubmed Abstract | Pubmed Full Text | CrossRef Full Text for many years a leading owner in France best known in Britain for her success with Francois Doumen-trained jumpers including 1994 Gold Cup winner The Fellow rode Garde Toi to finish third in the 1950 Cheltenham Gold Cup the Marquesa became a prominent owner in France in the 1970s – the vast majority of her horses would be trained in France She recorded her first Group 1 win in 1982 courtesy of The Wonder in the Prix Jacques Le Marois She also enjoyed Classic success on the Flat in France with Hours After winning the Prix du Jockey Club under Pat Eddery in 1988 and Tin Horse the Prix d'Essai des Poulains some 23 years later It was as a jumps owner that her most memorable successes came her colours were carried to success in four out of five renewals of the Grand Steeple-Chase de Paris with three different horses: The Fellow The Fellow went on to twice land the King George eventually won the 1994 Cheltenham Gold Cup under Adam Kondrat another Grand Steeple-Chase de Paris winner brought a third King George in 2000 and was subsequently sold to JP McManus christened Soledad and known as Sol to her friends who included commentator Sir Peter O'Sullevan Full name Maria de la Soledad Cabeza de Vaca y Leighton Mother Olga Leighton Mackey (daughter of Edward Leighton Cheltenham Gold Cup winner The Fellow (1994) Grand Steeple-Chase de Paris winners The Fellow (1991) Grande Course de Haies d'Auteuil winner Ubu (1992 Prix du Jockey Club winner Hours After (1988) Poule d'Essai des Poulains winner Tin Horse (2011) King George VI Chase winners The Fellow (1991 Prix La Haye Jousselin winner The Fellow (1990) Prix du President de la Republique winners Blacklock (1965) Anniversary Hurdle & Tingle Creek Chase winner Sybillin (1990 Prix Jacques le Marois winner The Wonder (1982) Prix Morny winner Charge D'Affaires (1997) King's Stand Stakes winner Chineur (2005) Cesarewitch & Coral Cup winner Trainglot (1990 Members can read the latest exclusive interviews news analysis and comment available from 6pm daily on racingpost.com Published on 6 December 2017inNews Copyright © 2025 Spotlight Sports Group Limited or its licensors The TimesProsecutors have ordered an inquiry into the death of a wealthy Anglo-Spanish aristocrat in France after her son claimed that she was murdered whose mother was British and father Spanish died aged 87 at her home in southwest France on Wednesday in the midst of a battle over her fortune The owner of one of Europe’s finest horse-racing stables Kempton and other courses in Britain and France opened an investigation to determine the cause of her death after Forester Labrouche The preliminary findings of an autopsy into the death of leading racehorse owner Marquesa de Moratalla have found no evidence of foul play The Marquesa died last week aged 87, but there was subsequent controversy when her son Forester Labrouche claimed she was murdered, although he did not specify how or why his mother was killed. The autopsy, conducted by the prosecutor's office in Bayonne, France, did not substantiate such allegations. The initial findings await toxicological analyses, but the marquesa was found to have a major pulmonary infection and the results "excluded the intervention of a third party" in her death. Labrouche is contesting the family fortune, which is reportedly worth more than £1 billion, with the marquesa's adopted son, German de la Cruz. Labrouche claims he was prevented from seeing his mother by De La Cruz in the final years of her life, and earlier last month, while the marquesa was still alive, he went to court to contest a mandate she had signed handing the management of her fortune to De La Cruz. The marquesa enjoyed Classic success on the Flat but gained her most memorable triumphs over jumps. Her colours were carried to victory in the 1990s in four out of five runnings of the Grand Steeple-Chase de Paris with three different horses: The Fellow, dual winner Ucello and Ubu. The Fellow went on to land the King George twice, in 1991 and 1992, and, after two short-head defeats and a fourth, landed the Cheltenham Gold Cup in 1994. or call 01933 304858 ReporterPublished on 6 December 2017inNews Please enable JS and disable any ad blocker Mission Statement: to assist the integration of foreign residents living in Spain and this is never more accurate than when you establish yourself as a foreign resident in a new country Being able to quickly familiarise yourself with the culture and customs can help ease the transition during a challenging time This is why Euro Weekly News makes it our mission to provide you with a free news resource in English that covers both regional and national Spanish news – anything that we feel you will benefit from knowing as you integrate into your new community and live your best life in Spain you can forget about translating articles from Spanish into awkward English that probably don’t make much sense Let us be your convenient and essential guide to all things that will likely affect you as a foreign resident living in Spain the scorching heat and relentless heat waves during the summer months can be quite challenging to endure the thermometers in some parts of the Region of Murcia reached an astonishing 44 degrees Celsius or even higher there’s a perfect way to find respite from the sweltering temperatures – a refreshing dip in natural pools and water spots While beaches and swimming pools are the first choices that come to mind the interior of the Region of Murcia also boasts an array of natural swimming pools and river beaches that offer a rejuvenating experience Let’s explore ten such hidden gems where you can spend a day of leisure and escape the summer heat specifically in the Barranco del Arroyo Hondares ravine near Benizar Poza de las Tortugas enchants visitors with its exotic appearance This enchanting enclave features a picturesque waterfall surrounded by lush vegetation making it a perfect destination for nature enthusiasts and hikers alike Also situated in the Barranco del Arroyo Hondares ravine Poza termal de Somogil is a well-kept secret crystal-clear thermal waters that offer the ideal remedy for scorching summer days this area holds high ecological value and is located near Camping La Puerta Located just 10 kilometres from Mula and a little over 40 minutes from the capital Fuente Caputa awaits to provide a refreshing retreat This natural pool covers an impressive 500 square meters where you can immerse yourself in the cool waters The unique way in which the water springs up among reeds and flows in a stream gives it a touch of magic it has been recognised as a Site of Community Interest and of Geological Interest A part of the Red Natura 2000, Estrecho de Bolvonegro is a stunning landscape where the rivers Alhárebe and Benamor converge with the Moratalla River. Over time, water erosion has shaped canyons, pools, and waterfalls, making it a remarkable destination for cooling off while enjoying captivating natural formations A true marvel, Salto de Usero became the fifth Natural Monument in the Region of Murcia last December Its captivating pool is encompassed by a vault where the water falls from a height of approximately four meters this natural pool is perfect for a refreshing escape this river beach along the banks of the Segura River provides the perfect setting for a tranquil morning cooling off you can find the river beach El Arenal in the same locality offering even more options to enjoy the water Situated between Cieza and Calasparra, Fuente del Gorgotón boasts a landscape of limestone rock formations that create a small pool of clear Flowing from a small spring in the middle of the Segura River this enchanting spot offers a unique and refreshing experience Surrounded by diverse varieties of pine trees provides a serene natural space to unwind and cool off in the pure waters of the Quípar River Río Alhárabe’s crystal-clear waters originate in the Moratell district of El Sabinar The perfect destination for a shady picnic under the pine trees this spot offers a serene landscape to enjoy Abanilla is home to several natural spots of great beauty, including the Badlands. Among its tourist attractions The river’s pools offer an ideal place to spend quality time with family and enjoy the refreshing waters When the summer heat becomes too much to bear escape to these 10 natural pools and water spots in the Region of Murcia Subscribe to our Euro Weekly News alerts to get the latest stories into your inbox Euro Weekly News is the leading English language newspaper in Spain by delivering news with a social conscience we are proud to be the voice for the expat communities who now call Spain home With around half a million print readers a week and over 1.5 million web views per month EWN has the biggest readership of any English language newspaper in Spain The paper prints over 150 news stories a week with many hundreds more on the web – no one else even comes close Our publication has won numerous awards over the last 25 years including Best Free Newspaper of the Year (Premios AEEPP) Company of the Year (Costa del Sol Business Awards) and Collaboration with Foreigners honours (Mijas Town Hall) All of this comes at ZERO cost to our readers All our print and online content always has been and always will be FREE OF CHARGE Download our media pack in either English or Spanish (ANS - San Salvador) - A new church was designed in San Salvador by a Valencian engineering firm as a replica of the famous Güell Park in Barcelona the work of the Catalan architect Antonio Gaudí The large church will have the possibility of welcoming up to 1,000 faithful and will be destined for the first beneficiaries of the Salesian mission as it is located in a peripheral and humble area of ​​the capital of El Salvador is that of the "Don Bosco Industrial Polygon" thanks to the commitment of the Salesian priest Fr José Moratalla was transformed from a landfill that it was 35 years ago to a place of social inclusion for the most disadvantaged The vast center of the Don Bosco Industrial Park shall also accompany all the new structures to be built to help the area's inhabitants one is immediately struck by the architectural beauty of the temple: the church recovers the stylistic features of Gaudí which makes it an out of the ordinary building better known in El Salvador as "Father Pepe" confessed to being in love with Gaudí's work and from the very beginning of the project he wanted the church to be a replica of Güell Park in Barcelona ANS - “Agenzia iNfo Salesiana” is a on-line almost daily publication the communication agency of the Salesian Congregation enrolled in the Press Register of the Tibunal of Rome as n 153/2007 This site also uses third-party cookies to improve user experience and for statistical purposes By scrolling through this page or by clicking on any of its elements Heavy rains result in submerged rice fields in Barangay Calzada in Oas Submerged rice fields mean income losses for farmers Days before Kristine (international name: Trami) developed into a severe tropical storm the typhoon-prone Bicol Region is more vulnerable with decimated forests Both Camarines Sur and Albay saw a net loss of tree cover from 2000 to 2020 Albay — A day after severe tropical storm Kristine flooded the Bicol Region with record-breaking rainfall councilor Leonido Moratalla took pictures of submerged rice fields in Barangay Calzada Moratalla said that more than 10 hectares of rice fields have been affected resulting in losses of approximately P1.5 million (USD 25,710) but they are already stale or of low quality.” This is nothing new for farmers like him during the typhoon season especially since Oas town in the northern province is located in the flood-prone Bicol River Basin where the region’s main river system flows to San Miguel Bay in Camarines Sur (CamSur) paid local workers cleared away the thick mud that had been left behind by the severe flooding where mud flooded the neighborhoods for the first time where boats became a mode of transportation post-Kristine forcing the Bicol Region to confront its flooding vulnerabilities on a long-term basis an atmospheric physicist and professor at the University of the Philippines told Bulatlat that data from Japan Meteorological Agency showed that the surface temperature of the ocean surrounding the Philippines was 1°C above average — a deviation that made Kristine mostly rainy because warmer seas fueled extreme weather events Bagtasa said that it was not really that intense because of wind shearing the same reason that brought rainfall to Bicol though Kristine was still over 300 kilometers away or the opposing wind speed and direction between surface and upper-level winds pushed most of Kristine’s rain clouds to [its] southwest where Bicol is located,” Bagtasa said adding that shearing occurs naturally in the Pacific as part of large-scale weather systems and is only one factor that may influence tropical storm intensity the warming climate contributed to Kristine’s heavy rain but determining how much of it was caused by climate change will be difficult for now A screenshot of the land cover map of Bicol River Basin from the flood hazard mapping study of the UP Training Center for Applied Geodesy and Photogrammetry (TCAGP) Kristine’s onslaught overwhelmed the Bicol River Basin after it spared none of the high-risk areas of central CamSur and its closest Albay neighbors including Oas and Libon from the life-threatening flooding and landslides Iraya Sur along the Cabilogan River exposes its poor quality the Cabilogan River not only overflowed but also destroyed several sections of the dike which the town mayor blamed on the “silted” Bato Lake in CamSur The Cabilogan River and other small rivers that flow into Bato Lake can deposit soil particles and organic materials reducing water depth and increasing flood risk Moratalla said that tenant-farmers like him cannot skip planting during typhoon season because they rent the land and would have to pay their regular dues Their location at the end of the irrigation system made them more vulnerable “They can only wish to be able to plant earlier so that they can harvest earlier.” He refused to return to his submerged rice field because “it was disheartening to see.” Calzada dike trail was completed in the first quarter of the year Albay incurred about P403 million ($ 6.9 million) agricultural damage second to CamSur with P1.027 billion ($ 17.6 million) according to the Department of Agriculture Bicol Kristine’s disastrous impact on infrastructure and irrigation significantly increased the total damage to almost P9 billion ($ 154.26 million) A vendor fixes the tarpaulin roof of her stall in downtown Oas According to the Office of Civil Defense (OCD) Bicol Kristine disrupted the lives of 742,395 families forcing thousands to evacuate and isolating others due to landslides told Bulatlat that the unprecedented flooding forced neighbors without second-floor houses to sleep in makeshift tents along the high elevation road The subsequent power outages and poor internet signal heightened their anxieties as they were unable to contact relatives who were trapped in their flooded homes and could not be rescued Patients who needed emergency care were left unattended because of impassable roads Google Earth shows quarried/mined areas in Palanog where Carlito Aparri and Ibalong Resources Development Corp are permitted to get limestone and limestone/shale clay UP Los Baños forestry professor Rogelio Andrada II said that Kristine’s abnormal rainfall would catch any region off-guard But since most of the Philippine forests have been decimated (hence the government’s regreening program) he said that “these areas are vulnerable to the impact of rainfall According to Global Forest Watch (GFW) satellite data both CamSur and Albay provinces experienced a net loss of tree cover between 2000 to 2020 The GFW defined tree cover loss [as] “dry and non-tropical primary forests as well as humid primary forest loss.” It detected tree cover loss within 30-meter resolution pixels “Albay experienced a net change of -1.50 kilohectare (kha) in tree cover,” while “Camarines Sur experienced a net change of -4.53 kha in tree cover.” CamSur and Albay used to have natural forests that covered more than half of their land area in 2010 CamSur lost 156 hectares of natural forest Andrada suggested that CamSur and Albay would benefit the most from forest regreening due to the Bicol River Basin’s relatively flat plains as engineering measures such as matting are best suited to sloped areas He said that before issuing permits to cut trees authorities should keep in mind that vegetation takes time to establish an effective protective soil cover and costly engineering measures should be used as backup He stressed how infrastructure could be easily overwhelmed by poor quality He urged government leaders to use data with historical context and current events for inter-local applications as physical environments are not bound by political boundaries Mining and quarrying are two of the region’s main causes of deforestation these drivers of environmental degradation put Bicol to greater dangers given its environmental features and its location in the Western Pacific typhoon corridor Bicol is one of the five regions with the lowest wages making it even worse for informal workers in agriculture (its biggest economy) since they do not have the safety net to withstand the effects of typhoons The National Economic and Development Authority (NEDA) Bicol reported in 2023 that mitigating vulnerabilities “extend[s] beyond mere income levels” for “many families may exceed the poverty threshold but still struggle with necessities,” as “rising costs for [redacted] food housing and healthcare further strain their budgets.” The people’s organization Kilusang Magbubukid ng Pilipinas (KMP)-Bicol in multiple Facebook posts demanded accountability from “the Marcos-allied Villafuertes” “The late Goa Mayor Marcel Pan implicated his predecessor as well as specific political figures and task forces in shielding certain quarry operators from penalties He also accused the Villafuertes of accepting protection money from unauthorized quarry operations,” according to KMP-Bicol’s statement “[Pan] further revealed that despite extensive earthfill extraction for high-profile infrastructure projects while riverbanks and hillsides in towns like Siruma and San Fernando suffered significant unaddressed damage.” KMP-Bicol stressed that the President’s call for a “safer and disaster-resilient future” at the Asia-Pacific Ministerial Conference on Disaster Risk Reduction which the country hosted a few days before Kristine must result in holding concerned government officials accountable it claimed that “LGUs and DENR permits contribute to environmental degradation [causing] preventable losses of life and livelihood.” Certain social media users echoed the call through memes volcanic debris from previous eruptions of the active Mayon Volcano exacerbated flooding hazards there were 149 quarry sites for small-scale operations across the province for 136 operators: 40 companies and the rest individuals Forty-eight of the permits will expire between 2024 and 2028 Corporation was issued permits in areas highly-prone to lahar The fourth permit was for Buyoan in Legazpi (project based) & Dev’t Corporation obtained three permits in lahar-prone areas: Budiao in Daraga (expiring this December) Mabinit in Legazpi City (expiring in 2028) and Tumpa in Camalig (project-based) and individuals Emilito Pascual and Jose Garcia all got two permits for two quarry sites Fifty-two permits were issued in lahar-prone areas within six and seven-kilometer danger zones Budiao and Busay in Daraga and Anoling in Camalig Some of the operators included 3 Diamonds Construction & Supply In terms of large-scale operations in the province Rapu-Rapu’s total of 4,539 hectares for four mining sites made up 30 percent of its land area Camalig’s 674 hectares accounted for 5.14 percent Albay-based volcanologist Chris Newhall said that there are two points of interest in the province: the quarries themselves (mostly located in pre-existing river channels) and stockpiling areas “which doesn’t add to the hectare count of land without tree cover.” the general rule is that quarrying of materials from river channels is good as it will deepen them he warned that excessive extraction could increase bank collapse which should be prohibited particularly in the lower sections to mitigate the increased chances of overflow He added that “placing any obstacles in a channel will increase the chances of overflow and this can include sabo dams and highway crossings if using culverts rather than bridges.” Even if Moratalla has been a farmer for 34 years he received P5,000 in cash aid only once in 2023 they are unable to replant because hybrid seeds do not produce the same yield “We frequently receive treated seeds and fertilizer from the Department of Agriculture There are other high-yield seeds available in stores He said that farmers are forced to sell salvaged harvests at lower prices because buyers would insist that they had been flooded said that he was going to harvest in two weeks both of his rice fields with a combined size of 1.3 hectares were submerged in floodwaters They might take out loans to cover their losses for the following planting season farmers who are members of Damayan nin Paraoma (DAMPA) in Camarines Sur told KMP-Bicol that “from the beginning of his presidency he did not prioritize the interests of the farmers.” (JJE A community of readers and supporters that help us sustain our operations through microdonations for as low as $1 Albay-based Mavic Conde reports on the link between the environment and agricultural livelihoods Her desire for solution-focused data reporting is as strong as her dream to become a digital nomad even though she still gets confused with left and right  | May 6  | May 6  | May 6  | May 6  | May 5  | May 4  | May 4 About us  |  Community  |  Contact us  |  Syndication Policy  |  Privacy Policy  |  Subscribe begins at 11.00 on Friday June 9 (a regional hloiday in Murcia) at the main entrance to the Town Hall Admission to the castle is included in the 5-euro price of joining the tour (free for children under 10), which lasts approximately two hours. Reservations should be made online here.  The heavy rains in the Region of Murcia have caused the closure of ten roads in Cartagena, Cehegín, Moratalla, Lorca, Totana, and Mazarrón. | Europa Press NEWS Alert in Murcia Due to Rain: Roads Flooded and Chaos in Several CitiesIn Lorca the authorities have asked residents to stay in their homes due to adverse weather conditions.06/03/2025 18:35:00h by Rafael Alejandro Escalona The Intense Rains in the Region of Murcia Have Led to the Closure of Ten Roads in Cartagena The Ministry of Development and Infrastructure has reported these incidents the Authorities Have Asked Residents to Stay in Their Homes Due to Adverse Weather Conditions the Firefighters of the Firefighting and Rescue Consortium have rescued a woman trapped between two ravines in Lorca The incident occurred near a scrapyard on the Caravaca de la Cruz road The driver was taken to a meeting point where she received medical attention for symptoms of hypothermia Precipitation of up to 30 mm in an hour and associated storms are expected several people have been trapped in a campsite due to flooding The Emergency Coordination Center 112 has managed 331 calls related to wind and rain since Wednesday These calls correspond to 326 issues in various areas of the Community The State Meteorological Agency (AEMET) has raised the alert to orange level in Lorca and the Guadalentín Valley (30 mm) in an hour and associated storms are expected The Lorca City Council has activated the Inunlor Plan in the emergency phase and has suspended events and closed municipal facilities It is recommended to avoid travel in the affected areas the rains have forced the closure of schools in La Aljorra and the closure of several roads due to water accumulation following recommendations from emergency services and Firefighters are working to ensure public safety Drivers are advised to exercise extreme caution and avoid flooded areas although drivers in distress have been assisted The Emergency Coordination Center 112 Has Activated the Inunmur Plan in the Pre-Emergency Phase Throughout the Region This measure is due to the overflow of sections of the Mula The pre-emergency phase alerts authorities and services and informs the population about possible problems due to water accumulation AEMET's weather forecasts indicate intense rains until 6:00 a.m 112 has managed 28 calls related to obstacles on the roads and water pumping Mumbai: Well known Spanish football club FC Barcelona announced on Wednesday the launch of its FCBEscola Football Schools here The FCBEscola Football Schools will start in mid-September at the Don Bosco High School in Matunga and St Dominic Savio High School in suburban Andheri The schools will cater to over 1,000 budding footballers The club had held its first five-day camp here in 2013 in which over 200 young footballers had participated The schools will be under the supervision of FCBEscola Project Director Albert Moratalla the son of FCBarcelona legend Josep Moratalla who was involved in the initial stages of the FCBEscola India project educating and mentoring local coaches in inculcating the FCB methodology and values "It is a year-long programme and not a camp as such We give a lot of value to our partners and are very selective about it Barca and our values coincided so did Don Bosco's values they have good footballers produced by them and the main thing was numbers," Anupama Jain "So the capacity is about 500 in each centre We keep around 10 per cent of scholarships all across depending on the players we get and we are focusing on the age category 6-18 years," she added "We have shared the infrastructure (with Don Bosco) and they are helping us with the facilities," said Jain.