Neuronal pentraxin 1: A synaptic-derived plasma biomarker in Alzheimer's disease

Synaptic neurodegeneration is thought to be an early event initiated by soluble β-amyloid (Aβ) aggregates that closely correlates with cognitive decline in Alzheimer disease (AD). Apolipoprotein ε4 (APOE4) is the most common genetic risk factor for both familial AD (FAD) and sporadic AD; it accelerates Aβ aggregation and selectively impairs glutamate receptor function and synaptic plasticity. However, its molecular mechanisms remain elusive and these synaptic deficits are difficult to monitor. AD- and APOE4-dependent plasma biomarkers have been proposed, but synapse-related plasma biomarkers are lacking. We evaluated neuronal pentraxin 1 (NP1), a potential CNS-derived plasma biomarker of excitatory synaptic pathology. NP1 is preferentially expressed in brain and involved in glutamate receptor internalization. NP1 is secreted presynaptically induced by Aβ oligomers, and implicated in excitatory synaptic and mitochondrial deficits. Levels of NP1 and its fragments were increased in a correlated fashion in both brain and plasma of 7–8 month-old E4FAD mice relative to E3FAD mice. NP1 was also found in exosome preparations and reduced by dietary DHA supplementation. Plasma NP1 was higher in E4FAD+ (APOE4+/+/FAD+/−) relative to E4FAD- (non-carrier; APOE4+/+/FAD−/−) mice, suggesting NP1 is modulated by Aβ expression. Finally, relative to normal elderly, plasma NP1 was also elevated in patients with mild cognitive impairment (MCI) and elevated further in the subset who progressed to early-stage AD. In those patients, there was a trend towards increased NP1 levels in APOE4 carriers relative to non-carriers. These findings indicate that NP1 may represent a potential synapse-derived plasma biomarker relevant to early alterations in excitatory synapses in MCI and early-stage AD

Развитие электрохимических методов измерения скорости коррозии металлов научной школы профессора Л.И. Антропова

Розглянуто розвиток наукових основ електрохімічних методів визначення швидкості корозії металів, робота над якими започаткована під керівництвом видатного електрохіміка Л.І. Антропова та продовжується послідовниками його школи. Опрацьовано аспекти точності визначення швидкості корозії методом поляризаційного опору (Rp). Показано, що використання двохелектродної схеми істотно знижує похибку вимірювань Rp. Уточнені співвідношення для коефіцієнта пропорційності між Rp і швидкістю корозії з урахуванням структури подвійного електрохімічного шару та впливу специфічної адсорбції іонів, які перевірено експериментально. Виведено аналітичну залежність для визначення швидкості корозії за наявності великих поляризаційних ємностей. Розглянуто метод нелінійної подвійної поляризації для визначення кінетичних параметрів корозії за аналітичною формулою в системі з дифузійним або пасиваційним контролем, який не потребує застосування емпіричних коефіцієнтів. Описано новий неруйнівний метод на основі поляризаційного опору з використанням неполяризованих електродів. Показано приклади практичного застосування цього методу в дослідженнях корозійної стійкості зварного з’єднання. За дослідженнями характеру зміни поляризаційного опору в часі в сульфатній кислоті за наявності амінокислот і похідних гуанідину виведено кількісні співвідношення, які визначають зростання фазових плівок на поверхні металів залежно від часу експозиції та концентрації інгібітору.The development of scientific bases of electrochemical methods for the determination of the corrosion rate, which were originated under the guidance of outstanding electrochemists L.I. Antropov and continued by his followers’ school, was investigated. Accuracy aspects of the corrosion rate determination by polarization resistance (Rp) method were discussed. It was shown that application of the two-electrode cell significantly decreases Rp determination error. The relations for the proportionality constant between R p and corrosion rate accounting the electrochemical double layer structure and the influence of specific ion adsorption were improved and experimentally tested. Analytical dependence for corrosion rate determination in the presence of large polarization capacities was derived. A method of non-linear double polarization for the kinetic parameters of corrosion determination was discussed using analytical equation in systems with diffusion or passivation control without application of empirical coefficients. New non-destructive methods based on polarization resistance with application of non-polarizable electrodes were described. The examples of the practical application of this method in corrosion research of welded connection were shown. Quantitative relations for films growth on the metal surface at different exposure time and acid concentration were derived from time dependences of polarization resistance in sulfuric acid in the presence of aminoacids and guanidine derivatives.Рассмотрено развитие научных основ электрохимических методов определения скорости коррозии, работа над которыми была начата под руководством выдающегося электрохимика Л.И. Антропова и продолжается последователями его школы. Рассмотрены аспекты точности определения скорости коррозии методом поляризационного сопротивления (Rp). Показано, что использование двухэлектродной схемы существенно снижает погрешность измерений Rp. Уточнены соотношения для коэффициента пропорциональности между Rp и скоростью коррозии с учетом структуры двойного электрического слоя и влияния специфической адсорбции ионов, которые проверены экспериментально. Выведена аналитическая зависимость для определения скорости коррозии при наличии больших поляризационных емкостей. Представлен метод нелинейной двойной поляризации для определения кинетических параметров коррозии в системе с диффузионным или пассивационным контролем по аналитической формуле, который не требует использования эмпирических коэффициентов. Описан новый неразрушающий метод на основе поляризационного сопротивления с использованием неполяризуемых электродов. Показаны примеры практического применения этого метода в исследованиях коррозионной стойкости сварного шва. По результатам исследований характера изменения поляризационного сопротивления во времени в серной кислоте в присутствии аминокислот и производных гуанидина выведены количественные соотношения, которые определяют рост фазовых пленок на поверхности металла в зависимости от времени экспозиции и концентрации ингибитора

Open-label add-on treatment trial of minocycline in fragile X syndrome

<p>Abstract</p> <p>Background</p> <p>Fragile X syndrome (FXS) is a disorder characterized by a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socio-emotional problems. It is hypothesized that the absence of the fragile X mental retardation protein (FMRP) leads to higher levels of matrix metallo-proteinase-9 activity (MMP-9) in the brain. Minocycline inhibits MMP-9 activity, and alleviates behavioural and synapse abnormalities in <it>fmr1 </it>knockout mice, an established model for FXS. This open-label add-on pilot trial was conducted to evaluate safety and efficacy of minocycline in treating behavioural abnormalities that occur in humans with FXS.</p> <p>Methods</p> <p>Twenty individuals with FXS, ages 13-32, were randomly assigned to receive 100 mg or 200 mg of minocycline daily. Behavioural evaluations were made prior to treatment (baseline) and again 8 weeks after daily minocycline treatment. The primary outcome measure was the Aberrant Behaviour Checklist-Community Edition (ABC-C) Irritability Subscale, and the secondary outcome measures were the other ABC-C subscales, clinical global improvement scale (CGI), and the visual analog scale for behaviour (VAS). Side effects were assessed using an adverse events checklist, a complete blood count (CBC), hepatic and renal function tests, and antinuclear antibody screen (ANA), done at baseline and at 8 weeks.</p> <p>Results</p> <p>The ABC-C Irritability Subscale scores showed significant improvement (p < 0.001), as did the VAS (p = 0.003) and the CGI (p < 0.001). The only significant treatment-related side effects were minor diarrhea (n = 3) and seroconversion to a positive ANA (n = 2).</p> <p>Conclusions</p> <p>Results from this study demonstrate that minocycline provides significant functional benefits to FXS patients and that it is well-tolerated. These findings are consistent with the <it>fmr1 </it>knockout mouse model results, suggesting that minocycline modifies underlying neural defects that account for behavioural abnormalities. A placebo-controlled trial of minocycline in FXS is warranted.</p> <p>Trial registration</p> <p>ClinicalTrials.gov Open-Label Trial NCT00858689.</p

Targeted treatments for fragile X syndrome

Fragile X syndrome (FXS) is the most common identifiable genetic cause of intellectual disability and autistic spectrum disorders (ASD), with up to 50% of males and some females with FXS meeting criteria for ASD. Autistic features are present in a very high percent of individuals with FXS, even those who do not meet full criteria for ASD. Recent major advances have been made in the understanding of the neurobiology and functions of FMRP, the FMR1 (fragile X mental retardation 1) gene product, which is absent or reduced in FXS, largely based on work in the fmr1 knockout mouse model. FXS has emerged as a disorder of synaptic plasticity associated with abnormalities of long-term depression and long-term potentiation and immature dendritic spine architecture, related to the dysregulation of dendritic translation typically activated by group I mGluR and other receptors. This work has led to efforts to develop treatments for FXS with neuroactive molecules targeted to the dysregulated translational pathway. These agents have been shown to rescue molecular, spine, and behavioral phenotypes in the FXS mouse model at multiple stages of development. Clinical trials are underway to translate findings in animal models of FXS to humans, raising complex issues about trial design and outcome measures to assess cognitive change that might be associated with treatment. Genes known to be causes of ASD interact with the translational pathway defective in FXS, and it has been hypothesized that there will be substantial overlap in molecular pathways and mechanisms of synaptic dysfunction between FXS and ASD. Therefore, targeted treatments developed for FXS may also target subgroups of ASD, and clinical trials in FXS may serve as a model for the development of clinical trial strategies for ASD and other cognitive disorders

FMR1 premutation and full mutation molecular mechanisms related to autism

Fragile X syndrome (FXS) is caused by an expanded CGG repeat (>200 repeats) in the 5′ un-translated portion of the fragile X mental retardation 1 gene (FMR1) leading to a deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA-binding protein that regulates the translation of a number of other genes that are important for synaptic development and plasticity. Furthermore, many of these genes, when mutated, have been linked to autism in the general population, which may explain the high comorbidity that exists between FXS and autism spectrum disorders (ASD). Additionally, premutation repeat expansions (55 to 200 CGG repeats) may also give rise to ASD through a different molecular mechanism that involves a direct toxic effect of FMR1 mRNA. It is believed that RNA toxicity underlies much of the premutation-related involvement, including developmental concerns like autism, as well as neurodegenerative issues with aging such as the fragile X-associated tremor ataxia syndrome (FXTAS). RNA toxicity can also lead to mitochondrial dysfunction, which is common in older premutation carriers both with and without FXTAS. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in idiopathic autism. Research regarding dysregulation of neurotransmitter systems caused by the lack of FMRP in FXS, including metabotropic glutamate receptor 1/5 (mGluR1/5) pathway and GABA pathways, has led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism

Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients.

High cancerous inhibitor of PP2A (CIP2A) protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib-treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=<0.0001). 2G TKIs induce more potent suppression of CIP2A and c-Myc than imatinib. The transcription factor E2F1 is elevated in high CIP2A patients and following 1 month of in vivo treatment 2G TKIs suppress E2F1 and reduce CIP2A; these effects are not seen with imatinib. Silencing of CIP2A, c-Myc or E2F1 in K562 cells or CML CD34+ cells reactivates PP2A leading to BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive feedback loop, which imatinib cannot overcome