On the possibility of magneto-structural correlations: detailed studies of di-nickel carboxylate complexes

A series of water-bridged dinickel complexes of the general formula [Ni<sub>2</sub>(μ<sub>2</sub>-OH<sub>2</sub>)(μ2- O<sub>2</sub>C<sup>t</sup>Bu)<sub>2</sub>(O<sub>2</sub>C<sup>t</sup>Bu)2(L)(L0)] (L = HO<sub>2</sub>C<sup>t</sup>Bu, L0 = HO<sub>2</sub>C<sup>t</sup>Bu (1), pyridine (2), 3-methylpyridine (4); L = L0 = pyridine (3), 3-methylpyridine (5)) has been synthesized and structurally characterized by X-ray crystallography. The magnetic properties have been probed by magnetometry and EPR spectroscopy, and detailed measurements show that the axial zero-field splitting, D, of the nickel(ii) ions is on the same order as the isotropic exchange interaction, J, between the nickel sites. The isotropic exchange interaction can be related to the angle between the nickel centers and the bridging water molecule, while the magnitude of D can be related to the coordination sphere at the nickel sites

Pittsburgh compound B imaging and cerebrospinal fluid amyloid-β in a multicentre European memory clinic study

The aim of this study was to assess the agreement between data on cerebral amyloidosis, derived using Pittsburgh compound B positron emission tomography and (i) multi-laboratory INNOTEST enzyme linked immunosorbent assay derived cerebrospinal fluid concentrations of amyloid-β 42 ; (ii) centrally measured cerebrospinal fluid amyloid-β 42 using a Meso Scale Discovery enzyme linked immunosorbent assay; and (iii) cerebrospinal fluid amyloid-β 42 centrally measured using an antibody-independent mass spectrometry-based reference method. Moreover, we examined the hypothesis that discordance between amyloid biomarker measurements may be due to interindividual differences in total amyloid-β production, by using the ratio of amyloid-β 42 to amyloid-β 40 . Our study population consisted of 243 subjects from seven centres belonging to the Biomarkers for Alzheimer’s and Parkinson’s Disease Initiative, and included subjects with normal cognition and patients with mild cognitive impairment, Alzheimer’s disease dementia, frontotemporal dementia, and vascular dementia. All had Pittsburgh compound B positron emission tomography data, cerebrospinal fluid INNOTEST amyloid-β 42 values, and cerebrospinal fluid samples available for reanalysis. Cerebrospinal fluid samples were reanalysed (amyloid-β 42 and amyloid-β 40 ) using Meso Scale Discovery electrochemiluminescence enzyme linked immunosorbent assay technology, and a novel, antibody-independent, mass spectrometry reference method. Pittsburgh compound B standardized uptake value ratio results were scaled using the Centiloid method. Concordance between Meso Scale Discovery/mass spectrometry reference measurement procedure findings and Pittsburgh compound B was high in subjects with mild cognitive impairment and Alzheimer’s disease, while more variable results were observed for cognitively normal and non-Alzheimer’s disease groups. Agreement between Pittsburgh compound B classification and Meso Scale Discovery/mass spectrometry reference measurement procedure findings was further improved when using amyloid-β 42/40 . Agreement between Pittsburgh compound B visual ratings and Centiloids was near complete. Despite improved agreement between Pittsburgh compound B and centrally analysed cerebrospinal fluid, a minority of subjects showed discordant findings. While future studies are needed, our results suggest that amyloid biomarker results may not be interchangeable in some individuals

II Jornadas de la Sociedad Española para la Conservación y Estudio de Los Mamíferos (SECEM) Soria 7-9 diciembre 1995

Seguimiento de una reintroducción de corzo (Capreolus capreolus) en ambiente mediterráneo. Dispersión y área de campeoModelos de distribución de los insectívoros ern la Península IbéricaDieta anual del zorro, Vulpes vulpes, en dos hábitats del Parque Nacional de DoñanaDesarrollo juvenil del cráneo en las poblaciones ibéricas de gato montés, Felis silvestris Schreber, 1777Presencia y expansión del visón americano (Mustela vison) en las provincias de Teruel y Castellón (Este de España).Preferencias de hábitat invernal de la musaraña común (Crocidura russula) en un encinar fragmentado de la submeseta norteUso de cámaras automáticas para la recogida de información faunística.Dieta del lobo en dos zonas de Asturias (España) que difieren en carga ganadera.Consumo de frutos y dispersión de semillas de serbal (Sorbus aucuparia L.) por zorros y martas en la cordillera Cantábrica occidentalEvaluación de espermatozoides obtenidos postmorten en el ciervo.Frecuencia de aparición de diferentes restos de conejo en excrementos de lince y zorroAtlas preliminar de los mamíferos de Soria (España)Censo y distribución de la marmota alpina (Marmota marmota) en Navarra.Trampeo fotográfico del género Martes en el Parque Nacional de Aigüestortes i Estany de Sant Maurici (Lleida)Peer reviewe

Sfrp3 modulates stromal-epithelial crosstalk during mammary gland development by regulating Wnt levels

Mammary stroma is essential for epithelial morphogenesis and development. Indeed, postnatal mammary gland (MG) development is controlled locally by the repetitive and bi-directional cross-talk between the epithelial and the stromal compartment. However, the signalling pathways involved in stromal–epithelial communication are not entirely understood. Here, we identify Sfrp3 as a mediator of the stromal–epithelial communication that is required for normal mouse MG development. Using Drosophila wing imaginal disc, we demonstrate that Sfrp3 functions as an extracellular transporter of Wnts that facilitates their diffusion, and thus, their levels in the boundaries of different compartments. Indeed, loss of Sfrp3 in mice leads to an increase of ductal invasion and branching mirroring an early pregnancy state. Finally, we observe that loss of Sfrp3 predisposes for invasive breast cancer. Altogether, our study shows that Sfrp3 controls MG morphogenesis by modulating the stromal-epithelial cross-talk during pubertal development

SARS-CoV-2 infection of human cortical cells is influenced by the interaction between aneuploidy and biological sex: insights from a Down syndrome in vitro model

Individuals with Down Syndrome (DS) represent one of the most susceptible populations for developing severe COVID-19, and a unique human genetic condition for investigating molecular mechanisms underlying susceptibility of neurologically vulnerable individuals to SARS-CoV-2 infection. Human Chromosome-21 (HSA21) triplication in DS causes global transcriptional deregulation, affecting multiple genes that may directly (e.g., TMPRSS2) or indirectly influence the SARS-CoV-2 entry into central nervous system (CNS) cells. The anti-viral immune response may also be altered in cells with trisomy-21 (T21) due to triplication of genes encoding for several interferon receptor subunits and interferon-stimulated genes (ISGs). Here, we demonstrate that human cells derived from fetal cortical specimens and maintained in primary cultures are susceptible to infection with a molecular clone of vesicular stomatitis virus engineered to express the Spike protein of SARS-CoV-2 (VSV-eGFP-SARS-CoV-2) and to authentic SARS-CoV-2. The level of SARS-CoV-2 infectivity in cultures originated from different cortical specimens varied, seemingly depending on ploidy and chromosomal sex of the cells. We confirmed the presence of ACE2 and TMPRSS2 in cultures and found that XY T21 group had the highest TMPRSS2 mRNA levels, which was associated with increased infectivity in XY-compared to XX T21 cultures. The XX T21 cultures exhibited elevated expression of several ISGs (MX1, STAT1, and STAT2) which was associated with lower infectivity. The comparisons of postmortem aged brain specimens revealed reduced ACE2, TMPRSS2, but elevated STAT2 protein levels in individuals with DS and Alzheimer's disease (DS-AD) compared to control and Alzheimer's disease (AD) group. Collectively, these results suggest multifactorial regulation of SARS-CoV-2 infectivity in cortical cells that involves ploidy, chromosomal sex, and the expression of genes implicated in regulation of virus entry and anti-viral response as contributing factors

Regional grey matter microstructural changes and volume loss according to disease duration in multiple sclerosis patients

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER, "Otra manera de hacer Europa", "Investing in your future"); Red Española de Esclerosis Múltiple (REEM - RD16/0015/0002, RD16/0015/0003, RD12/0032/0002, RD12/0060/01-02); TEVA Spain; Fundación Merck Salud (Ayudas Merck de Investigación 2017); Proyecto Societat Catalana Neurologia 2017; CIBERNED program (Program 1, Alzheimer Disease and SIGNAL study); National Institutes of Health (NIA grants 1R01AG056850-01A1, R21AG056974, R01AG061566;, Fundació La Marató de TV3 (20142030, 20141210); Fundació Catalana Síndrome de Down; Fundació Víctor Grífols i Lucas; Generalitat de Catalunya (SLT006/17/00119); Universitat de Barcelona (APIF Pre-doctoral grant); Hospital Clinic Emili Letang).The spatio-temporal characteristics of grey matter (GM) impairment in multiple sclerosis (MS) are poorly understood. We used a new surface-based diffusion MRI processing tool to investigate regional modifications of microstructure, and we quantified volume loss in GM in a cohort of patients with MS classified into three groups according to disease duration. Additionally, we investigated the relationship between GM changes with disease severity. We studied 54 healthy controls and 247 MS patients classified regarding disease duration: MS1 (less than 5 years, n = 67); MS2 (5-15 years, n = 107); and MS3 (more than15 years, n = 73). We compared GM mean diffusivity (MD), fractional anisotropy (FA) and volume between groups, and estimated their clinical associations. Regional modifications in diffusion measures (MD and FA) and volume did not overlap early in the disease, and became widespread in later phases. We found higher MD in MS1 group, mainly in the temporal cortex, and volume reduction in deep GM and left precuneus. Additional MD changes were evident in cingulate and occipital cortices in the MS2 group, coupled to volume reductions in deep GM and parietal and frontal poles. Changes in MD and volume extended to more than 80% of regions in MS3 group. Conversely, increments in FA, with very low effect size, were observed in the parietal cortex and thalamus in MS1 and MS2 groups, and extended to the frontal lobe in the later group. MD and GM changes were associated with white matter lesion load and with physical and cognitive disability. Microstructural integrity loss and atrophy present differential spatial predominance early in MS and accrual over time, probably due to distinct pathogenic mechanisms that underlie tissue damage

Basal forebrain atrophy along the Alzheimer's disease continuum in adults with Down syndrome

Background: Basal forebrain (BF) degeneration occurs in Down syndrome (DS)-associated Alzheimer's disease (AD). However, the dynamics of BF atrophy with age and disease progression, its impact on cognition, and its relationship with AD biomarkers have not been studied in DS. Methods: We included 234 adults with DS (150 asymptomatic, 38 prodromal AD, and 46 AD dementia) and 147 euploid controls. BF volumes were extracted from T-weighted magnetic resonance images using a stereotactic atlas in SPM12. We assessed BF volume changes with age and along the clinical AD continuum and their relationship to cognitive performance, cerebrospinal fluid (CSF) and plasma amyloid/tau/neurodegeneration biomarkers, and hippocampal volume. Results: In DS, BF volumes decreased with age and along the clinical AD continuum and significantly correlated with amyloid, tau, and neurofilament light chain changes in CSF and plasma, hippocampal volume, and cognitive performance. Discussion: BF atrophy is a potentially valuable neuroimaging biomarker of AD-related cholinergic neurodegeneration in DS

Clinical value of plasma pTau181 to predict Alzheimer's disease pathology in a large real-world cohort of a memory clinic

The identification of patients with an elevated risk of developing Alzheimer's disease (AD) dementia and eligible for the disease-modifying treatments (DMTs) in the earliest stages is one of the greatest challenges in the clinical practice. Plasma biomarkers has the potential to predict these issues, but further research is still needed to translate them to clinical practice. Here we evaluated the clinical applicability of plasma pTau181 as a predictive marker of AD pathology in a large real-world cohort of a memory clinic. Methods: Three independent cohorts (modelling [n = 991, 59.7% female], testing [n = 642, 56.2% female] and validation [n = 441, 55.1% female]) of real-world patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), AD dementia, and other dementias were included. Paired cerebrospinal fluid (CSF) and plasma samples were used to measure AT(N) CSF biomarkers and plasma pTau181. CSF and plasma pTau181 showed correlation in all phenotypes except in SCD and other dementias. Age significantly influenced the biomarker's performance. The general Aβ(+) vs Aβ(−) ROC curve showed an AUC = 0.77 [0.74-0.80], whereas the specific ROC curve of MCI due to AD vs non-AD MCI showed an AUC = 0.89 [0.85-0.93]. A cut-off value of 1.30 pg/ml of plasma pTau181 exhibited a sensitivity of 93.57% [88.72-96.52], specificity of 72.38% [62.51-79.01], VPP of 77.85% [70.61-83.54], and 8.30% false negatives in the subjects with MCI of the testing cohort. The HR of cox regression showed that patients with MCI up to this cut-off value exhibited a HR = 1.84 [1.05-3.22] higher risk to convert to AD dementia than patients with MCI below the cut-off value. Plasma pTau181 has the potential to be used in the memory clinics as a screening biomarker of AD pathology in subjects with MCI, presenting a valuable prognostic utility in predicting the MCI conversion to AD dementia. In the context of a real-world population, a confirmatory test employing gold-standard procedures is still advisable. This study has been mainly funded by Ace Alzheimer Center Barcelona, Instituto de Salud Carlos III (ISCIII), Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Spanish Ministry of Science and Innovation, Fundación ADEY, Fundación Echevarne and Grífols S.A

Neuroanatomical heterogeneity and homogeneity in individuals at clinical high risk for psychosis

Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the 'normativeness' of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5?SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.© 2022. The Author(s)

Plasma and cerebrospinal fluid glial fibrillary acidic protein levels in adults with Down syndrome: a longitudinal cohort study

Background: The diagnosis of symptomatic Alzheimer's disease is a clinical challenge in adults with Down syndrome. Blood biomarkers would be of particular clinical importance in this population. The astrocytic Glial Fibrillary Acidic Protein (GFAP) is a marker of astrogliosis associated with amyloid pathology, but its longitudinal changes, association with other biomarkers and cognitive performance have not been studied in individuals with Down syndrome. Methods: We performed a three-centre study of adults with Down syndrome, autosomal dominant Alzheimer's disease and euploid individuals enrolled in Hospital Sant Pau, Barcelona (Spain), Hospital Clinic, Barcelona (Spain) and Ludwig-Maximilians-Universität, Munich (Germany). Cerebrospinal fluid (CSF) and plasma GFAP concentrations were quantified using Simoa. A subset of participants had PET 18F-fluorodeoxyglucose, amyloid tracers and MRI measurements. Findings: This study included 997 individuals, 585 participants with Down syndrome, 61 Familial Alzheimer's disease mutation carriers and 351 euploid individuals along the Alzheimer's disease continuum, recruited between November 2008 and May 2022. Participants with Down syndrome were clinically classified at baseline as asymptomatic, prodromal Alzheimer's disease and Alzheimer's disease dementia. Plasma GFAP levels were significantly increased in prodromal and Alzheimer's disease dementia compared to asymptomatic individuals and increased in parallel to CSF Aβ changes, ten years prior to amyloid PET positivity. Plasma GFAP presented the highest diagnostic performance to discriminate symptomatic from asymptomatic groups (AUC = 0.93, 95% CI 0.9−0.95) and its concentrations were significantly higher in progressors vs non-progressors (p < 0.001), showing an increase of 19.8% (11.8–33.0) per year in participants with dementia. Finally, plasma GFAP levels were highly correlated with cortical thinning and brain amyloid pathology. Interpretation: Our findings support the utility of plasma GFAP as a biomarker of Alzheimer's disease in adults with Down syndrome, with possible applications in clinical practice and clinical trials. Funding: AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, Alzheimer's Association, National Institute for Health Research, EU Joint Programme–Neurodegenerative Disease Research, Alzheimer's Society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens, Fundación Tatiana Pérez de Guzmán el Bueno & European Union's Horizon 2020 und Umwelteinflüssen auf die menschliche Gesundheit