Dysprosium-based complexes with a flat pentadentate donor: a magnetic and ab initio study

The reactivity of the well-known pentadentate N3O2 Schiff base H2L (2,6-bis(2-hydroxyphenyliminomethyl)pyridine) towards a lanthanoid metal, in this case DyIII, has been investigated for the first time. This reactivity markedly depends on the pH of the medium and, accordingly, two different complexes, [Dy(HL)(NO3)2]·H2O (1·H2O) and [Dy(L)(NO3)(EtOH)(H2O)]·2H2O (2·2H2O), could be isolated from dysprosium(III) nitrate and H2L. In addition, reaction of H2L with dysprosium(III) chloride in methanol yields [Dy(HL′)2][Dy(L)(Cl2)] (3), where H2L′ ((6-(2-hydroxyphenyliminomethyl)-2-methoxyhydroxymethyl)pyridine) is an N2O2 hemiacetal donor derived from the partial hydrolysis of the H2L ligand, and subsequent addition of the methanol solvent to the carbonyl group. This latter reaction has been firstly observed for a lanthanoid metal. Single crystal X-ray diffraction studies of 1·1.15Py·0.3CH3C6H5, 2·2H2O and 3 show that the Schiff base is acting as a nearly flat pentadentate donor in all the cases, this behaviour being independent of the deprotonation degree of the phenolic oxygen atoms, both mono- or bisdeprotonated. Complexes 1·1.15Py·0.3CH3C6H5 and 2·2H2O show DyN3O6 cores, with distorted geometries closer to spherical tricapped trigonal prism or spherical capped square antiprism for 1·1.15Py·0.3CH3C6H5 and 2·2H2O, respectively. In the case of 3, the [Dy(HL′)2]+ cation shows a dysprosium ion in an N4O4 triangular dodecahedron environment, while the [Dy(L)(Cl2)]− anion displays a DyN3O2Cl2 core with distorted pentagonal bipyramidal geometry. Moreover, attempts to dilute 1·H2O with yttrium yielded single crystals of (Et3NH)[Dy0.09Y0.91(L)(NO3)2] (4), where the Schiff base shows a similar pentadentate coordination mode. Dynamic magnetic studies of 1·H2O, 2·2H2O and 3 show that 2·2H2O and 3 present field-induced slow relaxation of the magnetisation, with Ueff barriers of 46.1(9) and 31.0(7) K for 2·2H2O and 3, respectively, while 1·H2O does not exhibit frequency-dependent peaks of the out of phase susceptibility, even in the presence of an external dc magnetic field. By contrast, the dilute sample 4 behaves as a SIM at zero dc field, with an energy barrier of ca. 49 K. Ab initio calculations using CASSCF methods including spin–orbit effects qualitatively support the obtained magnetic results, indicating that axiality is not the only factor that should be taken into account in order to increase effective energy barriers.Authors thank the Spanish Ministerio de Innovación, Ciencia y Universidades (PGC2018-102052-B-C21, PGC2018-093863-B-C21 and MDM-2017-0767) for financial support. J. C. V thanks Xunta de Galicia for his Ph.D. fellowship. E. R. thanks Generalitat de Catalunya for an ICREA Academia award and for the SGR2017-1289 grant, and S. G. C. for a Beatriu de Pinòs grant. The authors acknowledge computer resources, technical expertise and assistance provided by the CSUC.S

Anticonvulsant and Antioxidant Effects of Tilia americana

Tilia genus is commonly used around the world for its central nervous system properties; it is prepared as tea and used as tranquilizing, anticonvulsant, and analgesic. In this study, anticonvulsant activity of the Tilia americana var. mexicana inflorescences and leaves was investigated by evaluating organic and aqueous extracts (100, 300, and 600 mg/kg, i.p.) and some flavonoids in the pentylenetetrazole-induced seizures in mice. Moreover, antioxidant effect of these extracts and flavonoids was examined in an in vitro study by using spectrophotometric technique. Significant activity was observed in the methanol extract from inflorescences. An HPLC analysis of the methanol extract from inflorescences and leaves of Tilia allowed demonstrating the respective presence of some partial responsible flavonoid constituents: quercetin (20.09 ± 1.20 μg/mg and 3.39 ± 0.10 μg/mg), rutin (3.52 ± 0.21 μg/mg and 8.94 ± 0.45 μg/mg), and isoquercitrin (1.74 ± 0.01 μg/mg and 1.24 ± 0.13 μg/mg). In addition, significant but different antioxidant properties were obtained among the flavonoids and the extracts investigated. Our results provide evidence of the anticonvulsant activity of Tilia reinforcing its utility for central nervous system diseases whose mechanism of action might involve partial antioxidant effects due to the presence of flavonoids

Dinuclear fluoride single-bridged lanthanoid complexes as molecule magnets: unprecedented coupling constant in a fluoride-bridged gadolinium compound

A new synthetic method allows isolating fluoride-bridged complexes Bu4N{[M(3NO2,5Br-H3L1,1,4)]2(μ-F)} (M = Dy, 1; M = Ho, 2; M = Gd, 3) and Bu4N{[Dy(3Br,5Cl-H3L1,2,4)]2(μ-F)}·2H2O, 4·2H2O. The crystal structures of 1·5CH3C6H5,·2·2H2O·0.75THF, 3, and 4·2H2O·2THF show that all of them are dinuclear compounds with linear single fluoride bridges and octacoordinated metal centers. Magnetic susceptibility measurements in the temperature range of 2–300 K reveal that the GdIII ions in 3 are weakly antiferromagnetically coupled, and this constitutes the first crystallographically and magnetically analyzed gadolinium complex with a fluoride bridge. Variable-temperature magnetization demonstrates a poor magnetocaloric effect for 3. Alternating current magnetic measurements for 1, 2, and 4·2H2O bring to light that 4·2H2O is an SMM, 1 shows an SMM-like behavior under a magnetic field of 600 Oe, while 2 does not show relaxation of the magnetization even under an applied magnetic field. In spite of this, 2 is the first fluoride-bridged holmium complex magnetically analyzed. DFT and ab initio calculations support the experimental magnetic results and show that apparently small structural differences between 1 and 4·2H2O introduce important changes in the dipolar interactions, from antiferromagnetic in 1 to ferromagnetic in 4·2H2OThe authors thank the Spanish Ministerio de Ciencia e Innovación projects (PGC2018-102052-B-C21, PGC2018-093863-B-C21, MCIN/AEI/10.13039/501100011033/FEDER “Una manera de hacer Europa”) for financial support. E.C. acknowledges Junta de Andalucía for the FEDER Andalucía project A-FQM-172-UGR18. J.C.-V. also thanks Xunta de Galicia for his Ph.D. fellowship (ED481A-2018/136)S

Nonmotor Symptoms in LRRK2 G2019S Associated Parkinson's Disease

BACKGROUND: Idiopathic Parkinson's disease (IPD) and LRRK2-associated PD (LRRK2-PD) might be expected to differ clinically since the neuropathological substrate of LRRK2-PD is heterogeneous. The range and severity of extra-nigral nonmotor features associated with LRRK2 mutations is also not well-defined. OBJECTIVE: To evaluate the prevalence and time of onset of nonmotor symptoms (NMS) in LRRK2-PD patients. METHODS: The presence of hyposmia and of neuropsychiatric, dysautonomic and sleep disturbances was assessed in 33 LRRK2-G2019S-PD patients by standardized questionnaires and validated scales. Thirty-three IPD patients, matched for age, gender, duration of parkinsonism and disease severity and 33 healthy subjects were also evaluated. RESULTS: University of Pennsylvania Smell Identification Test (UPSIT) scores in LRRK2-G2019S-PD were higher than those in IPD (23.5±6.8 vs 18.4±6.0; p = 0.002), and hyposmia was less frequent in G2019S carriers than in IPD (39.4% vs 75.8%; p = 0.01). UPSIT scores were significantly higher in females than in males in LRRK2-PD patients (26.9±4.7 vs 19.4±6.8; p<0.01). The frequency of sleep and neuropsychiatric disturbances and of dysautonomic symptoms in LRRK2-G2019S-PD was not significantly different from that in IPD. Hyposmia, depression, constipation and excessive daytime sleepiness, were reported to occur before the onset of classical motor symptoms in more than 40% of LRRK2-PD patients in whom these symptoms were present at the time of examination. CONCLUSION: Neuropsychiatric, dysautonomic and sleep disturbances occur as frequently in patients with LRRK2-G2019S-PD as in IPD but smell loss was less frequent in LRRK2-PD. Like in IPD, disturbances such as hyposmia, depression, constipation and excessive daytime sleepiness may antedate the onset of classical motor symptoms in LRRK2-G2019S-PD

Copernicus Ocean State Report, issue 6

The 6th issue of the Copernicus OSR incorporates a large range of topics for the blue, white and green ocean for all European regional seas, and the global ocean over 1993–2020 with a special focus on 2020

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Predominance of Dystrophinopathy Genotypes in Mexican Male Patients Presenting as Muscular Dystrophy with A Normal Multiplex Polymerase Chain Reaction DMD Gene Result: A Study Including Targeted Next-Generation Sequencing

The complete mutational spectrum of dystrophinopathies and limb-girdle muscular dystrophy (LGMD) remains unknown in Mexican population. Seventy-two unrelated Mexican male patients (73% of pediatric age) with clinical suspicion of muscular dystrophy and no evidence of DMD gene deletion on multiplex polymerase chain reaction (mPCR) analysis were analyzed by multiplex ligation-dependent probe amplification (MLPA). Those with a normal result were subjected to Sanger sequencing or to next-generation sequencing for DMD plus 10 selected LGMD-related genes. We achieved a diagnostic genotype in 80.5% (n = 58/72) of patients with predominance of dystrophinopathy-linked genotypes (68%, n = 49/72), followed by autosomal recessive LGMD-related genotypes (types 2A-R1, 2C-R5, 2E-R4, 2D-R3 and 2I-R9; 12.5%, n = 9/72). MLPA showed 4.2% of false-negatives for DMD deletions assessed by mPCR. Among the small DMD variants, 96.5% (n = 28/29) corresponded to null-alleles, most of which (72%) were inherited through a carrier mother. The FKRP p.[Leu276Ile]; [Asn463Asp] genotype is reported for the first time in Mexican patients as being associated with dilated cardiomyopathy. Absence of dysferlinopathies could be related to the small sample size and/or the predominantly pediatric age of patients. The employed strategy seems to be an affordable diagnosis approach for Mexican muscular dystrophy male patients and their families

Development of a multiplex PCR assay to detect gastroenteric pathogens in the feces of mexican children

Abstract Acute gastroenteritis (AGE) is a major cause of childhood morbidity and mortality worldwide; the etiology ofAGEincludes viruses, bacteria, and parasites.Amultiplex PCR assay to simultaneously identify human Astrovirus (HAstV), Calicivirus (HuCVs), Entamoeba histolytica (E. histolytica), and enteroinvasive Escherichia coli (EIEC) in stool samples is described. A total of 103 samples were individually analyzed by ELISA (enzyme-linked immunosorbent assays) and RT-PCR/PCR. HAstV and HuCVs were detected in four out of 103 samples (3.8 %) by RT-PCR, but ELISAs found only one sample as positive for HuCVs (2.5 %). E. histolytica was identified in two out of 19 samples (10.5 %) and EIEC in 13 out of 20 samples (70 %) by PCR, and all PCR products were sequenced to verify their identities. Our multiplex PCR results demonstrate the simultaneous amplification of different pathogens such as HAstV, EIEC, and E. histolytica in the same reaction, though the HuCVs signal was weak in every replicate. Regardless, this multiplex PCR protocol represents a novel tool for the identification of distinct pathogens and may provide support for the diagnosis of AGE in children

Analysis of Adverse Drug Reactions in Pediatric Patients with Epilepsy: An Intensive Pharmacovigilance Study

Epilepsy is a chronic neurological disease characterized by the presence of spontaneous seizures, with a higher incidence in the pediatric population. Anti-seizure medication (ASM) may produce adverse drug reactions (ADRs) with an elevated frequency and a high severity. Thus, the objective of the present study was to analyze, through intensive pharmacovigilance over 112 months, the ADRs produced by valproic acid (VPA), oxcarbazepine (OXC), phenytoin (PHT), and levetiracetam (LEV), among others, administered to monotherapy or polytherapy for Mexican hospitalized pediatric epilepsy patients. A total of 1034 patients were interviewed; 315 met the inclusion criteria, 211 patients presented ADRs, and 104 did not. A total of 548 ASM-ADRs were identified, and VPA, LEV, and PHT were the main culprit drugs. The most frequent ADRs were drowsiness, irritability, and thrombocytopenia, and the main systems affected were hematologic, nervous, and dermatologic. LEV and OXC caused more nonsevere ADRs, and PHT caused more severe ADRs. The risk analysis showed an association between belonging to the younger groups and polytherapy with ADR presence and between polytherapy and malnutrition with severe ADRs. In addition, most of the severe ADRs were preventable, and most of the nonsevere ADRs were nonpreventable