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PubMed2005

The effects of executive and behavioral dysfunction on the course of ALS.

OBJECTIVE: To determine whether patients with ALS-frontotemporal lobar dementia (FTLD) have a shorter survival and are less compliant with recommended treatments than those with ALS who have normal executive and behavioral function (classic ALS). METHODS: Survival analysis from ALS symptom onset to death included 81 of 100 consecutive patients who could be classified definitely as ALS with abnormal executive or behavioral function or as classic ALS. Criteria were defined for compliance with noninvasive positive-pressure ventilation (NPPV) and percutaneous endoscopic gastrostomy (PEG). RESULTS: Median survival was 2 years 4 months for the 28 patients with FTLD and 3 years 3 months for the 53 patients with classic ALS (relative hazard for death 1.93, CI 1.09 to 3.43; p = 0.024). However, the relative hazard associated with FTLD (1.49) in the multivariate model was diminished by the association of FTLD with bulbar onset and older age and was not significant in this sample size. With bulbar onset, median survival was 2 years 0 months for the 14 with ALS-FTLD and 2 years 10 months for the 10 with classic ALS (relative hazard for death 2.78, CI 1.02 to 7.55; p = 0.045), and older age was not a significant risk. Noncompliance with NPPV and PEG were 75% and 72% in ALS-FTLD, respectively, vs 38% and 31% in classic ALS (relative risks 2.00 and 2.34; p = 0.013 and 0.022). CONCLUSIONS: Survival is significantly shorter among patients with ALS-FTLD than with classic ALS. Furthermore, patients with ALS-FTLD are twice as likely to be noncompliant.

Age of Onset↗
PubMed2006

[Distribution characters and affecting factors of Al(i)/(Ca + Mg) molar ratio in acid forest soils].

By using principle component analysis (PCA) and partial least square (PLS) regression, this paper studied the distribution characters and their affecting factors of Al(i)/(Ca + Mg) molar ratio in acid forest soils in southern and southwestern China. The monitoring data from 2000 to 2002 showed that in most cases, the Al(i)/(Ca + Mg) molar ratio in soil moisture was lower than assumed critical value 1.0, indicating that significant aluminum toxicity to vegetation was not occurred in the study regions. PLS regression suggested that soil aluminum saturation (AlS) was the dominant factor affecting the Al(i)/(Ca + Mg) molar ratio in soil A horizon. Higher AlS led to a higher Al(i)/ (Ca + Mg) molar ratio in soil moisture. Despite of its lower acid deposition, Liuxihe basin had a higher Al(i)/(Ca + Mg) molar ratio in soil A horizon than other catchments, mainly due to its higher AIS. In deeper soil horizons (B1, B2 and BC), the inorganic aluminum (Al(i)) in soil moisture was the main factor affecting Al(i)/(Ca + Mg) molar ratio. Higher inorganic aluminum concentration resulted in higher Al(i)/(Ca + Mg) molar ratio. In each of study catchments, the vertical distribution of Al(i)/(Ca + Mg) molar ratio was basically identical with the distribution of inorganic aluminum (Al(i)) through soil profile. It was concluded that soil aluminum saturation was the main factor controlling the regional variation of Al(i)/(Ca + Mg) molar ratio in soil moisture, and the vertical distribution of soil Al(i)/(Ca + Mg) molar ratio in each site was mainly due to the vertical change of inorganic aluminum in soil moisture.

Acids↗
PubMed2004

The adsorption of palmytic acid on rice husk ash chemically modified with Al(III) ion using the sol-gel technique.

Silica-incorporated aluminum (RHA-Al) was synthesized from rice husk ash (RHA) using the sol-gel technique. RHA-Al was calcined at 500 degrees C for 5 h to yield RHA-Al(C). The ratio of silica to alumina was found to be 4:1. The BET analysis of RHA-Al(C) showed an increase in total pore volume and specific surface area compared to RHA-Al. SEM and XRD showed that RHA-Al and RHA-Al(C) were composed of microcrystals and the surface of both samples had a porous structure. Adsorption studies of palmytic acid on RHA-Al and RHA-Al(C) at 30, 40, and 50 degrees C conformed to the Langmuir isotherm. The equilibrium parameter, R, revealed that both are good adsorbents for palmytic acid. The Gibbs free energy of adsorption, DeltaG(ads)(0), was determined to be between -21.0 and -26.0 kJ mol(-1). DeltaH(ads)(0) and DeltaS(ads)(0) for RHA-Al were found to be 26.2 kJ mol(-1) and 158 J mol(-1), respectively. Corresponding values for RHA-Al(C) were 31.7 kJ mol(-1) and 178 J mol(-1). The adsorption of fatty acid on RHA-Al and RHA-Al(C) was an endothermic process, which occurred spontaneously. An FTIR study on the adsorbed material was used to determine the possible adsorbed complex on the surface of the adsorbent.

Journal Article↗
PubMed2001

Monoclonal anti-acid-labile subunit oligopeptide antibodies and their use in a two-site immunoassay for ALS measurement in humans.

Quantification of the acid-labile subunit (ALS) has to date been restricted to immunoassays utilizing polyclonal antibodies. By immunization with N-terminal and C-terminal specific ALS oligopeptides, we generated monoclonal antibodies (mAbs) that target ALS-specific sequences outside the nonspecific leucine-rich repeats in the ALS molecule. For mAb selection, a special screening method was developed. Monoclonal antibody 5C9, which targets the N-terminus of ALS, is immobilized and the anti-ALS mAb 7H3, directed against the C-terminus, is biotinylated and used as tracer Ab. Due to the extreme pH-lability of ALS, changes in immunorecognition of ALS were investigated after acidification for protein unfolding in different pH ranges and in a time-dependent manner. It was determined that acidification of the serum samples to pH 2.7 for 30 min, followed by neutralization and dilution to 1:100 was the optimal acid-neutralization method. For standardization purposes, a serum pool derived from healthy volunteers was assigned the value 1 U/ml ALS. The sandwich assay has a working range with a linear dose-response curve in a log/log system between 0.005 and 10 U/ml. ALS levels in seven acromegalic patients ranged from 2.0 to 4.2 U/ml, and in 12 untreated growth hormone deficient patients from 0.036 to 0.986 U/ml (mean=0.45 U/ml). After 12 months of growth hormone therapy, ALS levels increased significantly to 1.18+/-0.45 U/ml (mean+/-SD; p<0.0006). The increase ranged from 0.48 to 1.4 U/ml. The change in ALS with growth hormone (GH) therapy correlated closer with the change in IGF-I (r=0.798, p=0.0057; Spearman rank correlation) than with the change in insulin-like growth factor binding protein (IGFBP3; r=0.549, p=0.057). This specific sandwich assay for the measurement of ALS provides a potentially valuable indicator of growth hormone secretory status. With this mAb-based immunofluorometric assay, the nonspecific detection of other proteins containing leucine-rich repeat sequences can be excluded.

Acromegaly↗
PubMed2002

Potentiometric and (1)H NMR studies of complexation of Al(3+) with (-)-epigallocatechin gallate, a major active constituent of green tea.

The acid dissociation of (-)-epigallocatechin gallate (abbreviated as egcg) and its complexation with Al(3+) were studied by potentiometric titrations, and were compared with those of (-)-epicatechin (ec) and (-)-epigallocatechin (egc). In Al(3+)-ec and Al(3+)-egc reaction systems, [Al(LH(-2))](+), [Al(LH(-2))(OH)](0), and [Al(LH(-2))(2)](-) are formed, as reported for Al(3+)-catechin (c). Reactions between Al(3+) and egcg at pH <4.1 yield AlLH(-2) and AlLH(-3) species. The 1H NMR studies have shown that two hydroxyl groups of the gallate (D) ring are deprotonated and coordinated to an Al(3+) ion in [Al(egcgH(-2))](+). The AlLH(-3) species of egcg is supposed to be formulated as [Al(egcgH(-3))](0) in which one hydroxyl group of the pyrogallol (B) ring and two hydroxyl groups of the D ring are deprotonated; an Al(3+) ion is coordinated to two oxygen atoms of the D ring and one oxygen atom from the B ring of the neighboring chelate molecule, resulting in the formation of a polymeric structure. In the Al(3+) complex of egcg, the gallate group forms major coordinate bonds and results in solution properties that are different from those of ec, egc and c which have no gallate group.

Aluminum↗
PubMed1996

Analysis of prehospital ALS cases in a rural community.

BACKGROUND: An Emergency Medical Services (EMS) system containing the advanced life support (ALS) and manned with paramedics, is developing in many countries in view of the importance of prehospital ALS skills on ALS eligible patients, although previous studies have only revealed that a meager need for ALS in urban community. The purpose of this study is to understand the real demand of ALS in a rural community, so that a well organized and cost-effective EMS system can be developed in this country. METHODS: An EMS system with a single tiered response configuration, using firefighters to give basic prehospital care, stored in computer with some necessary informations was established in Ilan County. Cases with ALS from January 1993 through December 1994 were retrieved from the computer. The ones truely eligible for ALS were reconfirmed and analized in terms of neurological outcome while discharging from hospital, sex, age, response time, time spent on scene, transportation time, as well as whether the cases were trauma or medically induced. RESULTS: Of 11352 cases collected during 731 study days, 594(5.28%) ALS eligible cases (including 211 DOA and 383 nonDOA) were studied. Of 211 DOA, 103(48%) were caused by trauma. The response time, time spent on scene and transportation time in ALS and DOA cases were 5.5min., 4.7min., 13.6min., and 5.6min., 5.6min., and 15.7min., respectively. Of 211 cases of trauma (55% of total ALS cases), traffic accident accounted for 46%. Altered mental status and chest pain or tightness made of 90% of medical induced ALS cases. Five percent of patients felt worsening of condition during transit. One third of patients seemed to experience a bad outcome. CONCLUSIONS: Based on the characteristics of low demand for ALS services, more than half trauma-induced ALS cases, acceptable response time, short transportation time, extremely few medically-induced DOA cases, and quite a poor outcome in the setting of limited prehospital care, a unique EMS system different from that in the United States or in the urban area is needed in the rural area.

Adult↗
PubMed2001

Physiological basis of reduced AL tolerance in ditelosomic lines of Chinese Spring wheat.

Aluminum tolerance was assessed in the moderately Al-tolerant wheat (Triticum aestivum L.) cultivar Chinese Spring and a set of ditelosomic lines derived from Chinese Spring. Three ditelosomic lines lacking chromosome arms 4DL, 5AS and 7AS, respectively, exhibited decreased Al tolerance relative to the euploid parent Chinese Spring based on reduced root growth in Al-containing solutions. The physiological basis of the reduced Al tolerance was investigated. Measurements by inductively coupled argon plasma mass spectroscopy of root apical Al accumulation demonstrated that two of these three lines had a decreased ability to exclude Al from the root apex, the site of Al phytotoxicity. As Al-induced malate exudation has been suggested to be an important physiological mechanism of Al tolerance in wheat, this parameter was quantified and malate exudation was shown to be smaller in all three deletion lines compared with Chinese Spring. These results suggest that the decreased Al tolerance in at least two of the three ditelosomic lines is due to the loss of different genes independently influencing a single Al-tolerance mechanism, rather than to the loss of genes encoding alternative Al-tolerance mechanisms.

Adaptation, Physiological↗
PubMed2006

Distribution of Al-, Fe- and Mn-pools and their correlation in soils from two acid deposition small catchments in Hunan, China.

Distribution of Al-, Fe- and Mn-pools was investigated in five forest soil profiles (consisting of four horizons) in each of two Hunan catchments (BLT and LKS) where acid deposition has been considered critical. Al- and Fe-pools were higher in BLT than those in LKS, but Mn-pools much lower in BLT. Mn-pools vary from topsoils to bottom soils, but there are different trends for different Mn speciation. Al- and Fe-pools, except amorphous Fe(ox), were positively correlated to contents of soil organic matter (OM) showed by the loss on ignition in the two catchments. Accumulation of Al- and Fe-pools may occur in the area where soil organic matter was enriched (e.g. in top soil and rhizosphere soil). However, no direct correlation is observed between Mn and OM. Acidic atmospheric deposition may affect transforming among speciations of Al-, Fe- and Mn-pools and leaching of soil Al, Fe and Mn through formation of soluble organo-metal dissolved Al which was potentially toxic, increased. There were significant correlations between Al-pools complexes or change of oxidation-reduction conditions. Mn(ex) (exchangeable Mn) and Mn(ox) (amorphous and organic Mn) were highly linearly correlation with soil pH values at LKS but at BLT. Under acid deposition, the availability of the nutrient Fe increased with the amount of dissolved Al, which was potentially toxic, in the two catchments. There are no significant correlations between Al(ex) (exchangeable Al) and Mn(ex), Fe(ex) (exchangeable Fe) and Mn(ex) in this work, indicating potentially toxic Mn increase seldom accompanying with Al increase in the two catchments.

Aluminum↗
PubMed2001

Theoretical study of icosahedral closo-borane, -alane, and -gallane dianions (A(12)H(12)(2-); A = B, Al, Ga) with endohedral noble gas atoms (Ng = He, Ne, Ar, and Kr) and their lithium salts (Li[Ng@A(12)H(12)](-) and Li(2)[Ng@A(12)H(12)]).

Geometries, energies, vibrational frequencies, and magnetic properties have been computed at the B3LYP level with the 6-31G and 6-311+G basis sets for a family of endohedral closo-boranes, -alanes, and -gallanes Ng@A(12)H(12)(2-) with noble gas atoms (Ng) located in the centers of icosahedral [B(12)], [Al(12)], and [Ga(12)] clusters. The endohedral structures of most of the systems are minima lying above separated Ng + A(12)H(12)(2-) by 166 (He@B(12)H(12)(2-)) and 403 (Ne@B(12)H(12)(2-)) kcal/mol for boranes; 29 (He@Al(12)H(12)(2-)), 63 (Ne@Al(12)H(12)(2-)), 154 (Ar@Al(12)H(12)(2-)), and 189 (Kr@Al(12)H(12)(2-)) kcal/mol for alanes; and 39 (He@Ga(12)H(12)(2-)), 71 (Ne@Ga(12)H(12)(2-)), and 213 (Ar@Ga(12)H(12)(2-)) kcal/mol for gallanes. Three types of transition states are found for the exit of Ng from a cage: via an edge (TS-1), through a face (TS-2), and via a more extensive deformation through a pentagonal cage "neck" (TS-3). The most favorable exit path depends on the rigidity of the cage, the exothermicity of the dissociation, and the relationship between the size of the internal cavity of the cage and the Ng atomic radius. Ng exit via TS-3 is preferred for He@Al(12)H(12)(2-), Ne@Al(12)H(12)(2-), He@Ga(12)H(12)(2-), Ne@Ga(12)H(12)(2-), Ar@Al(12)H(12)(2), and Kr@Al(12)H(12)(2-). Helium exits via a cage edge (TS-1) for He@B(12)H(12)(2-), while for Ne@B(12)H(12)(2-) the neon exits via a triangular face (TS-2). Exit barriers (H(exit)(double dagger)) are high enough (30-60 kcal/mol) for all helium clusters and for Ne@Al(12)H(12)(2-) and Ne@Ga(12)H(12)(2-) to ensure the kinetic stability of these systems. The barriers for Ar@Al(12)H(12)(2-) and Kr@Al(12)H(12)(2-) decrease to 10-15 kcal/mol, while Ne@B(12)H(12)(2-) has a very low exit barrier and is not expected to be stable kinetically. There is a linear dependence of Ng@A(12)H(12)(2-) cage size on the Ng atomic radii; that is, the heavier Ng atoms "bulge" the cages. Nucleus independent chemical shifts (NICS) indicate that all three A(12)H(12)(2-) anions are aromatic but the alanes are the least so. A face- or edge-coordinated external Li(+) cation has a moderate effect on the structure and vibrational and magnetic properties of the helium-containing clusters, i.e., Li[He@A(12)H(12)](-). In contrast, for systems with very large exothermicities of Ng exit, Li(+) complexation promotes their dissociation. Thus, the internal atom Ne exits from the cage of Li[Ne@B(12)H(12)](-) and the salt dissociates into Ne + LiB(12)H(12)(-) without barrier. Systems with two Li(+) ions located initially above opposite cage faces (Li(2)[Ng@A(12)H(12)]) undergo complex intramolecular rearrangements leading to destruction of the icosahedral closo structures.

Journal Article↗
PubMed2003

Inhibition of growth and development of root border cells in wheat by Al.

The production and development of border cells vary with genotype, and they are released in wheat at an earlier stage of root development than other species studied so far. No significant difference was observed in the maximum number of border cells between Al-tolerant (Atlas 66) and Al-sensitive (Scout 66) cultivars in the absence of Al treatment. Al seriously inhibited the production and release of border cells, resulting in clumping of border cells in Scout 66, but less clustering in Atlas 66. The number of border cells released from roots treated with Al is significantly less than that from roots grown without Al treatment. Al treatment induced the death of detached border cells in vitro and they were killed by a 20-h treatment with 25 micro m Al. No significant difference in survival percentage of detached border cells was observed between Atlas 66 and Scout 66, regardless of the presence or absence of Al. The removal of border cells from root tips of both Atlas 66 and Scout 66 enhanced the Al-induced inhibition of root elongation concomitant with increased Al accumulation in the root. These results suggest that border cells adhered to the root tips play a potential role in the protection of root from Al injury in wheat.

Journal Article↗
PubMed2004

Molecular pharmacology of the DP/EP2 class prostaglandin AL-6598 and quantitative autoradiographic visualization of DP and EP2 receptor sites in human eyes.

DP-class prostaglandins and prostaglandin analogs (collectively, prostaglandins or PGs) such as PGD2, BW245C, ZK110841, and ZK118182, lower intraocular pressure (IOP) in animal models of ocular hypertension. A new analog of ZK118182 (AL-6556; 13,14-dihydro-ZK118182) was synthesized, and the isopropyl ester of AL-6556 (AL-6598) was shown recently to lower IOP in the ocular hypertensive cynomolgus monkey model of glaucoma and in human subjects. AL-6556 and AL-6598 had an affinity (Ki) of 2.66-4.43 microM for DP receptors but a much lower affinity (K(i)s = 38-103 microM) for EP3, FP, IP, and TP receptors (n = 3-5). In addition, AL-6556 and AL-6598 exhibited K(i)s > 100 microM for 19 nonprostanoid receptors. Both PGs stimulated cAMP production (EC50 = 1.07 +/- 0.1 microM and EC50 = 2.64 +/- 0.84 microM; n = 3) by way of DP receptors in embryonic bovine tracheal fibroblasts. While AL-6556 and AL-6598 were partial agonists (EC(50)s = 0.47-0.69 microM; E(max) = 35%-46%) at EP2 receptors in human nonpigmented epithelial cells, neither had any agonist activity at EP4, IP, or FP receptors. The DP antagonist, BWA868C, effectively antagonized the effects of AL-6556 with a high potency (IC50 = 22.8 +/- 3.9 nM; n = 3). DP receptors radiolabeled with [3H]BWA868C on human eye sections by quantitative autoradiography were highly concentrated in the ciliary process (CP), longitudinal (LCM) and circular (CCM) ciliary muscles, and iris with much lower specific binding in the cornea (CN), lens (LNS), and retina (RET). EP2 receptors labeled with [3H]PGE2 were concentrated in the LCM, CM, RET, and iris. In conclusion, AL-6598 and AL-6556 are relatively DP-receptor-selective PGs with full agonist activity at the DP and partial agonist activity at the EP2 receptor. The IOP-lowering activities of these compounds may involve both the inflow and outflow mechanisms, as DP and EP2 receptors were visualized in human ocular tissues involved in such aqueous humor dynamics.

Adult↗
PubMed2006

Preclinical pharmacology of AL-12182, a new ocular hypotensive 11-oxa prostaglandin analog.

PURPOSE: The aim of this study was to determine selected in vivo ocular properties of AL-12182 (5,6-dihydro-4,5-didehydro-11-deoxy-11-oxa-16-(3-chlorophenoxy)-omega-tetranor-PGF(2alpha) isopropyl ester) and the in vitro profile of its free acid, AL-12180. METHODS: Previously documented radioligand binding and functional assays involving human ciliary muscle cells (h-CM), human trabecular meshwork (h-TM) and other cells, and porcine ocular arteries were utilized. For in vivo procedures, we utilized rabbits, cats, and nonhuman primates to measure hyperemia, pupil diameter, and intraocular pressure (IOP), respectively. RESULTS: AL-12180 exhibited the highest affinity for the FP-receptor (K(i) = 143 +/- 36 nM) and much lower affinity for DP-, EP(3)-, IP-, and TP-receptors, and for several nonprostanoid receptors, enzymes, neurotransmitter uptake sites, ion channels, and other regulatory sites. AL-12180 activated phospholipase C-mediated phosphoinositide hydrolysis (potency, EC(50) = 13.7-42.7 nM) through the FP-receptor in a variety of cells, such as h-CM, h-TM cells, human embryonic kidney cells expressing the cloned human ciliary body FP-receptor (HEK-FP), mouse 3T3 cells, and rat vascular smooth muscle cells. AL-8810, an FP-antagonist, blocked the effects of AL-12180 in h-CM cells (IC(50) = 8.7 microM). AL-12180 also stimulated the mobilization of intracellular Ca(2+) ([Ca(2+)](i)) in h-TM cells (EC(50) = 111 +/- 36 nM), h-CM cells (EC(50) = 11 nM), and in host cells expressing the cloned human ciliary body FP-receptor (EC(50) = 5.9 +/- 3.1 nM). AL-12180 lacked significant agonist activity at DP-, EP(2)-, EP(4)-, IP-, and TP-receptors in cell-based assays. However, AL-12180 contracted porcine central retinal and short posterior ciliary arteries in vitro with micromolar potencies that appeared to involve TP-receptor activation. in vivo, AL-12182 elicited dose-related hyperemia in the rabbit eye, miosis in the cat eye, and ocular hypotension in the nonhuman primate eye. CONCLUSIONS: AL-12180 is a relatively potent and selective FP-receptor agonist whose isopropyl ester prodrug (AL-12182) lowers IOP by as much as 40% following topical ocular dosing in a laser-induced nonhuman primate model of ocular hypertension.

Animals↗
PubMed2005

Isolation and characterization of a rice mutant hypersensitive to Al.

Rice (Oryza sativa L.) is a highly Al-resistant species among small grain crops, but the mechanism responsible for the high Al resistance has not been elucidated. In this study, rice mutants sensitive to Al were isolated from M(3) lines derived from an Al-resistant cultivar, Koshihikari, irradiated with gamma-rays. Relative root elongation was used as a parameter for evaluating Al resistance. After initial screening plus two rounds of confirmatory testing, a mutant (als1) was isolated from a total of 560 lines. This mutant showed a phenotype similar to the wild-type plant in the absence of Al. However, in the presence of 10 microM Al, root elongation was inhibited 70% in the mutant, but only 8% in the wild-type plant. The mutant also showed poorer root growth in acid soil. The Al content of root apices (0-1 cm) was much lower in the wild-type plant. The sensitivity to other metals including Cd and La did not differ between the mutant and the wild-type plants. A small amount of citrate was secreted from the roots of the mutant in response to Al stress, but there was no difference from that secreted by the wild-type plant. Genetic analysis of F(2) populations between als1 and wild-type plants showed that the Al-resistant seedlings and Al-sensitive seedlings segregated at a 3 : 1 ratio, indicating that the high sensitivity to Al in als1 is controlled by a single recessive gene. The gene was mapped to the long arm of chromosome 6, flanked by InDel markers MaOs0619 and MaOs0615.

Aluminum↗
PubMed2025

Redefining ALS: Large-scale proteomic profiling reveals a prolonged pre-diagnostic phase with immune, muscular, metabolic, and brain involvement.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form. METHODS: We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM). FINDINGS: Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson's and Alzheimer's disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance. INTERPRETATION: Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention. FUNDING: Clinical Research in ALS and Related Disorders for Therapeutic Development (CreATe) Consortium, Cure Alzheimer's Fund, Michael J Fox Foundation, Interdisciplinary Centre for Clinical Research, University M&#xfc;nster.

Journal Article↗
PubMed1990

Competitive Al Inhibition of Net Mg Uptake by Intact Lolium multiflorum Roots : II. Plant Age Effects.

Rhizotoxicity of Al is more pronounced in younger plants. Effects of Al on nutrient uptake by plants of different age are poorly understood. The depletion technique was used to monitor net Mg(2+) uptake from nutrient solutions by intact 15- and 35-day-old plants of two ryegrass (Lolium multiflorum Lam.) cultivars. Lowering the pH from 6.0 to 4.2 decreased the maximum net ion influx without affecting K(m). Aluminum at 6.6 micromolar Al(3+) activity increased K(m) indicating competitive inhibition. The effects of pH and 6.6 micromolar Al(3+) on net Mg(2+) uptake were much larger in 15- than in 35-day-old plants. Aluminum at 26 micromolar Al(3+) activity competitively inhibited net Mg(2+) uptake by 35-day-old plants, while causing time- and external Mg(2+) activity-dependent net Mg(2+) efflux from 15-day-old plants. The equilibrium constant (K(i)) of a reversible combination of postulated plasmalemma Mg(2+) transporter and Al(3+) was calculated to be 2 and 5 micromolar Al(3+) activity for 15-day-old plants of Wilo and Gulf ryegrass, respectively, and 21 micromolar Al(3+) activity for 35-day-old plants of both cultivars. The Al(3+)-mediated increase in K(m) was larger for 15-day-old plants of the Al-sensitive cultivar ;Wilo' than of the more Al-tolerant cultivar ;Gulf,' while Al(3+) affected 35-day-old plants of both cultivars to the same extent.

Journal Article↗
PubMed1992

Interactive effects of Al, h, and other cations on root elongation considered in terms of cell-surface electrical potential.

The rhizotoxicities of Al(3+) and of La(3+) to wheat (Triticum aestivum L.) were similarly ameliorated by cations in the following order of effectiveness: H(+) approximately C(3+) > C(2+) > C(1+). Among tested cations of a given charge, ameliorative effectiveness was similar except that Ca(2+) was slightly more effective than other divalent cations and H(+) was much more effective than other monovalent cations. H(+) rhizotoxicity was also ameliorated by cations in the order C(3+) > C(2+) > C(1+). These results suggest a role for cell-surface electrical potential in the rhizotoxicity of Al(3+), La(3+), H(+), and other toxic cations: negatively charged cell surfaces of the root accumulate the toxic cations, and amelioration is effected by treatments that reduce the negativity of the cell-surface electrical potential by charge screening or cation binding. Membrane-surface activities of free Al(3+) or La(3+) computed according to a Gouy-Chapman-Stern model correlated well with growth inhibition, which correlated only poorly with Al(3+) or La(3+) activities in the external medium. The similar responses of Al-intoxicated and La-intoxicated roots to ameliorative treatments provide evidence that Al(3+), rather than AlOH(2+) or Al(OH)(2) (+), is the principal toxic species of mononuclear Al. Comparisons of the responses of Al-sensitive and Al-tolerant wheats to Al(3+) and to La(3+) did not support the hypothesis that varietal sensitivity to Al(3+) is based upon differences in cell-surface electrical potential.

Journal Article↗
PubMed2005

The beneficial effect of aluminium and the role of citrate in Al accumulation in Melastoma malabathricum.

* Here we investigated the beneficial effect of aluminium (Al) on the development of the Al accumulating plant Melastoma malabathricum. * Seedlings of M. malabathricum were cultivated in a nutrient solution containing 0.5 mM Al and compared with barley (Hordeum vulgare). In addition, roots of M. malabathricum were divided into one part growing in a nutrient solution, and the other part growing in a calcium solution. Al (0.5 mM) was applied to either solution. * Al-induced improvements of the root activity contributed to a growth enhancement in M. malabathricum. Al exposure without nutrients did not increase root growth and Al accumulation in the leaves. The beneficial effect, however, was induced by the combination of Al and nutrients. * We suggest that without nutrients roots are not able to synthesize an adequate amount of citrate that is required for transporting Al to the leaves. High Al levels in the plant tissues and/or an interaction of Al with particular nutrient elements in the apoplast of root cells appear to be essential to exert the beneficial effect of Al.

Aluminum↗
PubMed2000

Glutamate transporter EAAT2 splice variants occur not only in ALS, but also in AD and controls.

OBJECTIVE: To ascertain the specificity of alternatively spliced mRNA variants of the astroglial glutamate transporter EAAT2 for ALS. BACKGROUND: An important hypothesis for ALS pathogenesis is that motor neuron injury may result from chronically elevated glutamate levels in the CNS. Supporting this idea are reports of decreased glutamate transport in ALS. This in turn has recently been suggested to be due to the presence of aberrant mRNA splice variants for EAAT2 in ALS. METHODS: Postmortem human brain tissue was obtained from different brain regions of patients with ALS, normal controls (NC), and patients with AD and Lewy body dementia (LB)-neurodegenerative diseases in which motor neurons are unaffected. Brain RNA was analyzed for EAAT2 isoforms using reverse transcription PCR and cDNA cloning/sequencing methods. RESULTS: Splice variants lacking exons 7 or 9 were present in ALS brain, as previously reported, but were also present in brains from NC, AD, and LB patients. PCR product sequence analyses from non-ALS brain show variant splicing identical to that reported for ALS. Quantitative PCR analysis shows that these isoforms may be somewhat more abundant in ALS than AD, LB, and NC brains. CONCLUSIONS: EAAT2 mRNA splice variants are found in the brains of NC and AD patients, as in ALS. The authors cannot exclude the possibility that quantitative changes in variant EAAT2 isoforms might relate directly, or indirectly, to ALS pathology. However, the qualitative presence of these "abnormal" EAAT2 splice variants does not appear to be sufficient to explain motor neuron degeneration in ALS.

Alternative Splicing↗