New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Batch desorption studies and multiple sorption-regeneration cycles in a fixed-bed column for Cd(II) elimination by protonated Sargassum muticum

The protonated alga Sargassum muticum was employed in batch desorption studies to find the most appropriate eluting agent for Cd(II)-laden biomass regeneration. Eleven types of eluting solutions at different concentrations were tested, finding elution efficiencies higher than 90\% for most of the desorbents studied. Total organic carbon and biomass weight loss measurements were made. The reusability of the protonated alga was also studied using a fixed-bed column. Eleven consecutive sorption-regeneration cycles at a flow rate of 10 mL min(-1) were carried out for the removal of 50 mg L-1 Cd(II) solution. A 0.1 M HNO3 solution was employed as desorbing agent. The column was operated during 605 h for sorption and 66 h for desorption, equivalent to a continuous use during 28 days, with no apparent loss of sorption performance. In these cycles, no diminution of the breakthrough time was found; although, a relative loss of sorption capacity, regarding the found in the first cycle, was observed. The slope of the breakthrough curves experiments a gradual increase reaching its maximum value for the last cycle tested (40\% greater than for the first one). The maximum Cd(II) concentration elution peak was achieved in 5 min or less, and the metal effluent concentration was always lower than 0.9 mg L-1 after 1 h of elution. The maximum concentration factor was determined to be between 55 and 109

The use of protonated Sargassum muticum as biosorbent for cadmium removal in a fixed-bed column

The protonated Sargassum muticum seaweed was studied as a possible biosorbent for cadmium removal in a fixed-bed column. The experiments were conducted in order to determine the effect of flow rate (0.42, 5, 10 and 20 mL min(-1)) and bed height (0.6 and 15.3 cm for the lowest flow rate or 7.4, 13 and 16.6 cm for the others) on breakthrough curves behaviour. The determined breakthrough and exhaustion times increased with the diminution in flow rate and with the increase in bed height. The maximum cadmium uptake capacity, obtained from the area below adsorbed cadmium concentration versus time curves, was found to remain practically constant with bed depth and flow rate. The bed depth service time (BDST) model was applied to analyse experimental data, determining the characteristic process parameters. The optimal lowest sorbent usage rate was evaluated at 2 min contact time and the minimum bed height values necessaries to prevent the effluent solution concentration from exceeding 0.02 mg L-1 at zero time were 5.3, 6.9 and 7.5 cm for flow rates of 5, 10 and 20 mL min(-1), respectively. Several empirical models proposed in the literature (Bohart-Adams, Yan, Belter and Chu models) were investigated in order to obtain the best fit of column data, describing in a simple manner the breakthrough curves. A correlation between model parameters and the variables implied in the process was attempted

Electroreduction of diphenyl disulfide on a self-assembled lipid monolayer on mercury

In the present work, a voltammetric study of permeability and redox behavior of diphenyl disulfide (Ph2S2) through a self-assembled monolayer of dioleoylphosphatidylcholine adsorbed on mercury is carried out; the results are compared with those obtained on a bare electrode; in this case, the reduction of Ph2S2 proceeds in a reversible way with the formation of a mercurial compound. The presence of the monolayer of phospholipid provokes an increase in the process irreversibility. Different mechanisms based on Ph2S2 adsorption either directly on a mercury drop or on phospholipids heads are proposed. The charge associated with the adsorbed Ph2S2 electroreduction was employed to calculate its solubility, and the method is compared with semiempirical expressions proposed in the literature for obtaining approximate values of solubility

The marine macroalga Cystoseira baccata as biosorbent for cadmium(II) and lead(II) removal: Kinetic and equilibrium studies

This work reports kinetic and equilibrium studies of cadmium(II) and lead(II) adsorption by the brown seaweed Cystoseira baccata. Kinetic experiments demonstrated rapid metal uptake. Kinetic data were satisfactorily described by a pseudo-second order chemical sorption process. Temperature change from 15 to 45 degrees C showed small variation on kinetic parameters. Langmuir-Freundlich equation was selected to describe the metal isotherms and the proton binding in acid-base titrations. The maximum metal uptake values were around 0.9 mmol g-1 (101 and 186 mg g-1 for cadmium(II) and lead(II), respectively) at pH 4.5 (raw biomass), while the number of weak acid groups were 2.2 mmol g-1 and their proton binding constant, K-H, 10(3.67) (protonated biomass). FTIR analysis confirmed the participation of carboxyl groups in metal uptake. The metal sorption was found to increase with the solution pH reaching a plateau above pH 4. Calcium and sodium nitrate salts in solution were found to affect considerably the metal biosorption

Biosorption of cadmium by biomass of brown marine macroalgae

Five different brown seaweeds, Bifurcaria bifurcata, Saccorhiza polyschides, Ascophyllum nodosum, Laminaria ochroleuca and Pelvetia caniculata were studied for their ability to remove cadmium from aqueous solution. Kinetics of cadmium adsorption by all the algae were relatively fast, with 90% of total adsorption occurring in less than I h. These experiments could be accurately described by a pseudo-second-order rate equation, obtaining values between 1.66 x 10-3 and 9.92 x 10-3 g/Mg min for the sorption rate constant k. Several equilibrium adsorption isotherms were obtained for the quantitative description of cadmium uptake. The use of the Langmuir isotherm led to values between 64 and 95 mg/g for qmax and between 0.036 and 0.094 L/mg for b. The effect of pH on biosorption was also studied. Acid-base properties of algae were studied by potentiometry to determine pK values (from 3.54 to 3.98) and the total number of acid groups. <br/

Biosorption of cadmium by the protonated macroalga Sargassum muticum: Binding analysis with a nonideal, competitive, and thermodynamically consistent adsorption (NICCA) model

Protonated biomass of the seaweed Sargassum muticum was investigated for its ability to remove cadmium(II) from aqueous solutions. In this work, a nonideal, semiempirical, thermodynamically consistent (NICCA) isotherm was proposed to fit the experimental ion binding data obtained in NaNO3 0.05 mol L-1. This model describes the competition between protons and metal ions satisfactorily. Moreover, it reflects the complexity of the macromolecular systems that take part in biosorption considering the heterogeneity of the sorbent. It was demonstrated in this work that the NICCA isotherm constitutes a great improvement with respect to a simpler Langmuir competitive equation, which was not able to describe all the experimental data satisfactorily. Potentiometric acid-base titrations in the absence of cadmium were made to estimate the maximum amount of acid functional groups (2.61 mmol g-1 and the conditional proton binding parameters, log (K) over tilde (H) (3.8) and m(H) (0.54). The values of the binding parameters for the cadmium ion were chosen to provide the best simultaneous description of the isotherm at pH 4.5, as well as the dependence of cadmium adsorption on pH. Values of log (K) over tilde (Cd) (3.1), n(Cd) (1.8), and p (0.19) in the case of the NICCA isotherm or log K-Cd (2.94-3.4) for Langmuir competitive models were obtained. Kinetic experiments were performed at two different pH values (3.0 and 4.5), establishing the time dependence that represents the sorption of cadmium with a pseudo-second-order kinetic model. It was observed that 4 h is enough to ensure that the equilibrium uptake was reached. <br/

Interactions of cadmium(II) and protons with dead biomass of marine algae Fucus sp.

Samples of dead biomass from the marine brown algae Fucus ceranoides, Fucus vesiculosus and Fucus serratus were studied for their ability to remove cadmium from aqueous solutions. The metal sorption process is rapid, with 90\% of the metal uptake completed within the first 25 min of contact. The kinetic data was described successfully by a pseudo second order chemical sorption process with rate constants of ca. 0.6 g mmol(-1) min(-1). At pH 4.5, the raw biomass of the three species exhibited equilibrium uptake capacities for Cd as high as 0.8 mmol g(-1) (90 mg g(-1)), on a dry weight basis, without chemical pretreatment. These sorption capacities are much higher than those reported for activated carbon and chitin. The sorption of Cd was found to increase as pH increases, reaching a plateau at pH 5. Batch sorption experiments and continuous potentiometric titrations of acid-treated biomass samples in 0.05 M NaNO3 were used to derive thermodynamic binding parameters according to the NICCA model. The total amount of acid sites was 2.4-2.9 mmol g(-1), with median values of the affinity distribution for protons and cadmium ions, 109 K-H and log K-Cd, of 3.7 and 2.69, respectively (conditional values). The apparent heterogeneity of the sorbent was successfully taken into account by the empirical NICCA isotherm, which described very well the competition between protons and metal ions, in contrast with a simpler discrete competitive Langmuir model. The experimental results demonstrate that these seaweeds constitute a promising, efficient, cheap and biodegradable sorbent biomaterial for cadmium removal from wastewaters. This use would represent an example of exploitation of a renewable marine resource in water treatment technologies for the prevention of heavy metal pollution in the environment

Voltammetry of L-cysteine and 2-mercaptopyridine on a self-assembled phospholipid monolayer

The redox behaviour of 2-mercaptopyridine and the aminoacid L-cysteine was studied through a self-assembled monolayer of dioleoylphosphatidylcholine adsorbed on mercury by using cyclic voltammetry. 2-Mercaptopyridine penetrates into monolayer in the zone of stability of the phospholipid layer and shows an quasi-reversible behaviour while reversibility is observed in the absence of a monolayer. This fact is reflected in the occurrence of voltammetric peaks in the above mentioned region of potentials. Conversely, cysteine was found not to penetrate in the lipid layer as long as the latter behaves like a half-membrane. Voltammetric signal of cysteine was only obtained when the potential was scanned to values positive to -0.2 V. Beyond this potential the cyclic voltammograms show a series of anodic peaks, due to a rearrangement of the lipid film and to the formation of Hg(RS)2, followed by three cathodic peaks when the scan is reversal. The behaviour of these peaks was analized