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Accumulating evidence has suggested that neurotrophins participate in the pathophysiology of mood disorders. We have developed transgenic mice overexpressing the full-length neurotrophin-3 receptor TrkC (TgNTRK3) in the central nervous system. TgNTRK3 mice show increased anxiety-like behavior and enhancement of panic reaction in the mouse defense test battery, along with an increase in the number and density of catecholaminergic (tyrosine hydroxylase positive) neurons in locus coeruleus and substantia nigra. Furthermore, treatment of TgNTRK3 mice with diazepam significantly attenuated the anxiety-like behaviors in the plus maze. These results provide evidence for the involvement of TrkC in the development of noradrenergic neurons in the central nervous system with consequences on anxiety-like behavior and panic reaction. Thus, changes in TrkC expression levels could contribute to the phenotypic expression of panic disorder through a trophic effect on noradrenergic neurons in the locus coeruleus. Our results demonstrate that the elevated NT3-TrkC tone via overexpression of TrkC in the brain may constitute a molecular mechanism for the expression of anxiety and anxiety.

DYRK1A, dual-specificity tyrosine-regulated kinase 1A, maps to human chromosome 21 within the Down syndrome (DS) critical region. Dyrk1 phosphorylates the human microtubule-associated protein tau at Thr212 in vitro, a residue that is phosphorylated in fetal tau and hyper-phosphorylated in Alzheimer disease (AD) and tauopathies, including Pick disease (PiD). Furthermore, phosphorylation of Thr212 primes tau for phosphorylation by glycogen synthase kinase 3 (GSK-3). The present study examines Dyrk1A in the cerebral cortex of sporadic AD, adult DS with associated AD, and PiD. Increased Dyrk1A immunoreactivity has been found in the cytoplasm and nuclei of scattered neurons of the neocortex, entorhinal cortex, and hippocampus in AD, DS, and PiD. Dyrk1A is found in sarkosyl-insoluble fractions which are enriched in phosphorylated tau in AD brains, thus suggesting a possible association of Dyrk1A with neurofibrillary tangle pathology. Yet, no clear relationship has been observed between tau phosphorylation at Thr212, and GSK-3 and Dyrk1A expression in diseased brains. Transgenic mice bearing a triple tau mutation (G272V, P301L, and R406W) and expressing hyper-phosphoyrylated tau in neurons of the entorhinal cortex, hippocampus, and cerebral neocortex show increased expression of Dyrk1A in individual neurons in the same regions. However, transgenic mice over-expressing Dyrk1A do not show increased phosphorylation of tau at Thr212, thus suggesting that Dyrk1A over-expression does not trigger per se hyper-phosphorylation of tau at Thr212 in vivo. The present observations indicate modifications in the expression of constitutive Dyrk1A in the cytoplasm and nuclei of neurons in various neurodegenerative diseases associated with tau phosphorylation.

Abstract Despite the advances in the understanding of Huntington's disease (HD), there is a need for molecular biomarkers to categorize mutation carriers during the preclinical stage of the disease preceding functional decline. Small RNAs (sRNAs) are a promising source of biomarkers since their expression levels are highly sensitive to pathobiological processes. Here, using an optimized method for plasma extracellular vesicles (EVs) purification and an exhaustive analysis pipeline of sRNA sequencing data, we show that EV‐sRNAs are downregulated early in mutation carriers and that this deregulation is associated with premanifest cognitive performance. Seven candidate sRNAs (tRF‐Glu‐CTC, tRF‐Gly‐GCC, miR‐451a, miR‐21‐5p, miR‐26a‐5p, miR‐27a‐3p and let7a‐5p) were validated in additional subjects, showing a significant diagnostic accuracy at premanifest stages. Of these, miR‐21‐5p was significantly decreased over time in a longitudinal study; and miR‐21‐5p and miR‐26a‐5p levels correlated with cognitive changes in the premanifest cohort. In summary, the present results suggest that deregulated plasma EV‐sRNAs define an early biosignature in mutation carriers with specific species highlighting the progression and cognitive changes occurring at the premanifest stage.

In this paper, we address a key issue in Numerical Functional Analysis: to perform the local convergence analysis of a fourth order of convergence iterative method in Banach spaces, examining conditions on the operator and its derivatives near the solution to ensure convergence. Moreover, this approach provides a local convergence ball, within which initial estimates lead to guaranteed convergence with details about the radii of domain of convergence and estimates on error bounds. Next, we perform a comparative study of the Computational Efficiency Index (CEI) between the analyzed scheme and some known iterative methods of fourth order of convergence. Our ultimate goal is to use these theoretical findings to address practical problems in engineering and technology.

In this paper, we present a new fixed-point result to draw conclusions about the existence and uniqueness of the solution for a nonlinear Fredholm integral equation of the second kind with non-differentiable Nemytskii operator. To do this, we will transform the problem of locating a fixed point for an integral operator into the problem of locating a solution of an integral equation. Thus, assuming conditions on the Nemytskii operator, we will obtain a global convergence domain for the solution of the considered integral equation, taking for this a uniparametric family of derivativefree iterative processes with quadratic convergence. This result provides us a new fixed-point result for the integral operator considered.

Abstract Extracellular vesicles (EVs) play an important role in intercellular communication as carriers of signalling molecules such as bioactive miRNAs, proteins and lipids. EVs are key players in the functioning of the central nervous system (CNS) by influencing synaptic events and modulating recipient neurons. However, the specific role of neuron‐to‐neuron communication via EVs is still not well understood. Here, we provide evidence that primary neurons uptake neuron‐derived EVs in the soma, dendrites, and even in the dendritic spines, and carry synaptic proteins. Neuron‐derived EVs increased spine density and promoted the phosphorylation of Akt and ribosomal protein S6 (RPS6), via TrkB‐signalling, without impairing the neuronal network activity. Strikingly, EVs exerted a trophic effect on challenged nutrient‐deprived neurons. Altogether, our results place EVs in the spotlight for synaptic plasticity modulation as well as a possible therapeutic tool to fight neurodegeneration.

Abstract Background The adverse health effects of early life exposure to tobacco smoking have been widely reported. In spite of this, the underlying molecular mechanisms of in utero and postnatal exposure to tobacco smoke are only partially understood. Here, we aimed to identify multi-layer molecular signatures associated with exposure to tobacco smoke in these two exposure windows. Methods We investigated the associations of maternal smoking during pregnancy and childhood secondhand smoke (SHS) exposure with molecular features measured in 1203 European children (mean age 8.1 years) from the Human Early Life Exposome (HELIX) project. Molecular features, covering 4 layers, included blood DNA methylation and gene and miRNA transcription, plasma proteins, and sera and urinary metabolites. Results Maternal smoking during pregnancy was associated with DNA methylation changes at 18 loci in child blood. DNA methylation at 5 of these loci was related to expression of the nearby genes. However, the expression of these genes themselves was only weakly associated with maternal smoking. Conversely, childhood SHS was not associated with blood DNA methylation or transcription patterns, but with reduced levels of several serum metabolites and with increased plasma PAI1 (plasminogen activator inhibitor-1), a protein that inhibits fibrinolysis. Some of the in utero and childhood smoking-related molecular marks showed dose-response trends, with stronger effects with higher dose or longer duration of the exposure. Conclusion In this first study covering multi-layer molecular features, pregnancy and childhood exposure to tobacco smoke were associated with distinct molecular phenotypes in children. The persistent and dose-dependent changes in the methylome make CpGs good candidates to develop biomarkers of past exposure. Moreover, compared to methylation, the weak association of maternal smoking in pregnancy with gene expression suggests different reversal rates and a methylation-based memory to past exposures. Finally, certain metabolites and protein markers evidenced potential early biological effects of postnatal SHS, such as fibrinolysis.

Background: The identification of expression quantitative trait methylation (eQTMs), defined as associations between DNA methylation levels and gene expression, might help the biological interpretation of epigenome-wide association studies (EWAS). We aimed to identify autosomal cis eQTMs in children’s blood, using data from 832 children of the Human Early Life Exposome (HELIX) project. Methods: Blood DNA methylation and gene expression were measured with the Illumina 450K and the Affymetrix HTA v2 arrays, respectively. The relationship between methylation levels and expression of nearby genes (1 Mb window centered at the transcription start site, TSS) was assessed by fitting 13.6 M linear regressions adjusting for sex, age, cohort, and blood cell composition. Results: We identified 39,749 blood autosomal cis eQTMs, representing 21,966 unique CpGs (eCpGs, 5.7% of total CpGs) and 8,886 unique transcript clusters (eGenes, 15.3% of total transcript clusters, equivalent to genes). In 87.9% of these cis eQTMs, the eCpG was located at

In this study, we suggest a new iterative family of iterative methods for approximating the roots with multiplicity in nonlinear equations. We found a lack in the approximation of multiple roots in the case that the nonlinear operator be non-differentiable. So, we present, in this paper, iterative methods that do not use the derivative of the non-linear operator in their iterative expression. With our new iterative technique, we find better numerical results of Planck’s radiation, Van Der Waals, Beam designing, and Isothermal continuous stirred tank reactor problems. Divided difference and weight function approaches are adopted for the construction of our schemes. The convergence order is studied thoroughly in the Theorems 1 and 2, for the case when multiplicity p≥2. The obtained numerical results illustrate the preferable outcomes as compared to the existing ones in terms of absolute residual errors, number of iterations, computational order of convergence (COC), and absolute error difference between two consecutive iterations.

Small non-coding RNAs (sncRNAs), including microRNAs (miRNAs) are important post-transcriptional gene expression regulators relevant in physiological and pathological processes. Here, we combined a high-throughput functional screening (HTFS) platform with a library of antisense oligonucleotides (ASOs) to systematically identify sncRNAs that affect neuronal cell survival in basal conditions and in response to oxidative stress (OS), a major hallmark in neurodegenerative diseases. We considered hits commonly detected by two statistical methods in three biological replicates. Forty-seven ASOs targeting miRNAs (miRNA-ASOs) consistently decreased cell viability under basal conditions. A total of 60 miRNA-ASOs worsened cell viability impairment mediated by OS, with 36.6% commonly affecting cell viability under basal conditions. In addition, 40 miRNA-ASOs significantly protected neuronal cells from OS. In agreement with cell viability impairment, damaging miRNA-ASOs specifically induced increased free radical biogenesis. miRNAs targeted by the detrimental ASOs are enriched in the fraction of miRNAs downregulated by OS, suggesting that the miRNA expression pattern after OS contributes to neuronal damage. The present HTFS highlighted potentially druggable sncRNAs. However, future studies are needed to define the pathways by which the identified ASOs regulate cell survival and OS response and to explore the potential of translating the current findings into clinical applications. Keywords: miRNAs, non-coding RNAs, neurodegeneration, high-throughput screening, oxidative stress, mitochondrial function, expression profiles, small RNA sequencing

Extracellular RNAs (exRNAs) including abundant full length tRNAs and tRNA fragments (tRFs) have recently garnered attention as a promising source of biomarkers and a novel mediator in cell-to-cell communication in eukaryotes. Depending on the physiological state of cells, tRNAs/tRFs are released to the extracellular space either contained in extracellular vesicles (EVs) or free, through a mechanism that is largely unknown. In this perspective article, we propose that extracellular tRNAs (ex-tRNAs) and/or extracellular tRFs (ex-tRFs) are relevant paracrine signaling molecules whose activity depends on the mechanisms of release by source cells and capture by recipient cells. We speculate on how ex-tRNA/ex-tRFs orchestrate the effects in target cells, depending on the type of sequence and the mechanisms of uptake. We further propose that tRNA modifications may be playing important roles in ex-tRNA biology.

In this paper, we want to construct a new high-order and efficient iterative technique for solving a system of nonlinear equations. For this purpose, we extend the earlier scalar scheme [16] to a system of nonlinear equations preserving the same convergence order. Moreover, by adding one more additional step, we obtain minimum 5th-order convergence for every value of a free parameter, θ∈ℝ, and for θ=−1, the method reaches maximum 6-order convergence. We present an extensive convergence analysis of our scheme. The analytical discussion of the work is upheld by performing numerical experiments on some applied science problems and a large system of nonlinear equations. Furthermore, numerical results demonstrate the validity and reliability of the suggested methods.

In this work, we use the technique of recurrence relations to prove the semilocal convergence in Banach spaces of the multidimensional extension of Chun’s iterative method. This is an iterative method of fourth order, that can be transferred to the multivariable case by using the divided difference operator. We obtain the domain of existence and uniqueness by taking a suitable starting point and imposing a Lipschitz condition to the first Fréchet derivative in the whole domain. Moreover, we apply the theoretical results obtained to a nonlinear integral equation of Hammerstein type, showing the applicability of our results.

There is no doubt that the fourth-order King’s family is one of the important ones among its counterparts. However, it has two major problems: the first one is the calculation of the first-order derivative; secondly, it has a linear order of convergence in the case of multiple roots. In order to improve these complications, we suggested a new King’s family of iterative methods. The main features of our scheme are the optimal convergence order, being free from derivatives, and working for multiple roots (m≥2). In addition, we proposed a main theorem that illustrated the fourth order of convergence. It also satisfied the optimal Kung–Traub conjecture of iterative methods without memory. We compared our scheme with the latest iterative methods of the same order of convergence on several real-life problems. In accordance with the computational results, we concluded that our method showed superior behavior compared to the existing methods.

The benefits and properties of iterative splitting methods, which are based on serial versions, have been studied in recent years, this work, we extend the iterative splitting methods to novel classes of parallel versions to solve nonlinear fractional convection-diffusion equations. For such interesting partial differential examples with higher dimensional, fractional, and nonlinear terms, we could apply the parallel iterative splitting methods, which allow for accelerating the solver methods and reduce the computational time. Here, we could apply the benefits of the higher accuracy of the iterative splitting methods. We present a novel parallel iterative splitting method, which is based on the multi-splitting methods, The flexibilisation with multisplitting methods allows for decomposing large scale operator equations. In combination with iterative splitting methods, which use characteristics of waveform-relaxation (WR) methods, we could embed the relaxation behavior and deal better with the nonlinearities of the operators. We consider the convergence results of the parallel iterative splitting methods, reformulating the underlying methods with a summation of the individual convergence results of the WR methods. We discuss the numerical convergence of the serial and parallel iterative splitting methods with respect to the synchronous and asynchronous treatments. Furthermore, we present different numerical applications of fluid and phase field problems in order to validate the benefit of the parallel versions.

Oxidative stress (OS) results from an imbalance between the production of reactive oxygen species and the cellular antioxidant capacity. OS plays a central role in neurodegenerative diseases, where the progressive accumulation of reactive oxygen species induces mitochondrial dysfunction, protein aggregation and inflammation. Regulatory non-protein-coding RNAs (ncRNAs) are essential transcriptional and post-transcriptional gene expression controllers, showing a highly regulated expression in space (cell types), time (developmental and ageing processes) and response to specific stimuli. These dynamic changes shape signaling pathways that are critical for the developmental processes of the nervous system and brain cell homeostasis. Diverse classes of ncRNAs have been involved in the cell response to OS and have been targeted in therapeutic designs. The perturbed expression of ncRNAs has been shown in human neurodegenerative diseases, with these changes contributing to pathogenic mechanisms, including OS and associated toxicity. In the present review, we summarize existing literature linking OS, neurodegeneration and ncRNA function. We provide evidences for the central role of OS in age-related neurodegenerative conditions, recapitulating the main types of regulatory ncRNAs with roles in the normal function of the nervous system and summarizing up-to-date information on ncRNA deregulation with a direct impact on OS associated with major neurodegenerative conditions.

This work is devoted to Fredholm integral equations of second kind with non-separable kernels. Our strategy is to approximate the non-separable kernel by using an adequate Taylor’s development. Then, we adapt an already known technique used for separable kernels to our case. First, we study the local convergence of the proposed iterative scheme, so we obtain a ball of starting points around the solution. Then, we complete the theoretical study with the semilocal convergence analysis, that allow us to obtain the domain of existence for the solution in terms of the starting point. In this case, the existence of a solution is deduced. Finally, we illustrate this study with some numerical experiments.

In this work, we performed an study about the domain of existence and uniqueness for an efficient fifth order iterative method for solving nonlinear problems treated in their infinite dimensional form. The hypotheses for the operator and starting guess are weaker than in the previous studies. We assume omega continuity condition on second order Fréchet derivative. This fact it is motivated by showing different problems where the nonlinear operators that define the equation do not verify Lipschitz and Hölder condition; however, these operators verify the omega condition established. Then, the semilocal convergence balls are obtained and the R-order of convergence and error bounds can be obtained by following thee main theorem. Finally, we perform a numerical experience by solving a nonlinear Hammerstein integral equations in order to show the applicability of the theoretical results by obtaining the existence and uniqueness balls.

Increasing evidence indicates that microRNAs (miRNAs) are contributing factors to neurodegeneration. Alterations in miRNA signatures have been reported in several neurodegenerative dementias, but data in prion diseases are restricted to ex vivo and animal models. The present study identified significant miRNA expression pattern alterations in the frontal cortex and cerebellum of sporadic Creutzfeldt-Jakob disease (sCJD) patients. These changes display a highly regional and disease subtype-dependent regulation that correlates with brain pathology. We demonstrate that selected miRNAs are enriched in sCJD isolated Argonaute(Ago)-binding complexes in disease, indicating their incorporation into RNA-induced silencing complexes, and further suggesting their contribution to disease-associated gene expression changes. Alterations in the miRNA-mRNA regulatory machinery and perturbed levels of miRNA biogenesis key components in sCJD brain samples reported here further implicate miRNAs in sCJD gene expression (de)regulation. We also show that a subset of sCJD-altered miRNAs are commonly changed in Alzheimer's disease, dementia with Lewy bodies and fatal familial insomnia, suggesting potential common mechanisms underlying these neurodegenerative processes. Additionally, we report no correlation between brain and cerebrospinal fluid (CSF) miRNA-profiles in sCJD, indicating that CSF-miRNA profiles do not faithfully mirror miRNA alterations detected in brain tissue of human prion diseases. Finally, utilizing a sCJD MM1 mouse model, we analyzed the miRNA deregulation patterns observed in sCJD in a temporal manner. While fourteen sCJD-related miRNAs were validated at clinical stages, only two of those were changed at early symptomatic phase, suggesting that the miRNAs altered in sCJD may contribute to later pathogenic processes. Altogether, the present work identifies alterations in the miRNA network, biogenesis and miRNA-mRNA silencing machinery in sCJD, whereby contributions to disease mechanisms deserve further investigation.

The semilocal and local convergence analyses of a two-step iterative method for nonlinear nondifferentiable operators are described in Banach spaces. The recurrence relations are derived under weaker conditions on the operator. For semilocal convergence, the domain of the parameters is obtained to ensure guaranteed convergence under suitable initial approximations. The applicability of local convergence is extended as the differentiability condition on the involved operator is avoided. The region of accessibility and a way to enlarge the convergence domain are provided. Theorems are given for the existence-uniqueness balls enclosing the unique solution. Finally, some numerical examples including nonlinear Hammerstein type integral equations are worked out to validate the theoretical results.

This article proposes adaptive iterative splitting methods to solve Multiphysics problems, which are related to convection−diffusion−reaction equations. The splitting techniques are based on iterative splitting approaches with adaptive ideas. Based on shifting the time-steps with additional adaptive time-ranges, we could embedded the adaptive techniques into the splitting approach. The numerical analysis of the adapted iterative splitting schemes is considered and we develop the underlying error estimates for the application of the adaptive schemes. The performance of the method with respect to the accuracy and the acceleration is evaluated in different numerical experiments. We test the benefits of the adaptive splitting approach on highly nonlinear Burgers’ and Maxwell−Stefan diffusion equations.

Male premutation carriers presenting between 55 and 200 CGG repeats in the Fragile-X-associated (FMR1) gene are at risk of developing Fragile X Tremor/Ataxia Syndrome (FXTAS), and females undergo Premature Ovarian Failure (POF1). Here, we have evaluated gene expression profiles from blood in male FMR1 premutation carriers and detected a strong deregulation of genes enriched in FXTAS relevant biological pathways, including inflammation, neuronal homeostasis and viability. Gene expression profiling distinguished between control individuals, carriers with FXTAS and carriers without FXTAS, with levels of expanded FMR1 mRNA being increased in FXTAS patients. In vitro studies in a neuronal cell model indicate that expression levels of expanded FMR1 5′-UTR are relevant in modulating the transcriptome. Thus, perturbations of the transcriptome may be an interplay between the CGG expansion size and FMR1 expression levels. Several deregulated genes (DFFA, BCL2L11, BCL2L1, APP, SOD1, RNF10, HDAC5, KCNC3, ATXN7, ATXN3 and EAP1) were validated in brain samples of a FXTAS mouse model. Downregulation of EAP1, a gene involved in the female reproductive system physiology, was confirmed in female carriers. Decreased levels were detected in female carriers with POF1 compared to those without POF1, suggesting that EAP1 levels contribute to ovarian insufficiency. In summary, gene expression profiling in blood has uncovered mechanisms that may underlie different pathological aspects of the premutation. A better understanding of the transcriptome dynamics in relation with expanded FMR1 mRNA expression levels and CGG expansion size may provide mechanistic insights into the disease process and a more accurate FXTAS diagnosis to the myriad of phenotypes associated with the premutation.

The aim of this paper is to introduce new high order iterative methods for multiple roots of the nonlinear scalar equation; this is a demanding task in the area of computational mathematics and numerical analysis. Specifically, we present a new Chebyshev–Halley-type iteration function having at least sixth-order convergence and eighth-order convergence for a particular value in the case of multiple roots. With regard to computational cost, each member of our scheme needs four functional evaluations each step. Therefore, the maximum efficiency index of our scheme is 1.6818 for α = 2 , which corresponds to an optimal method in the sense of Kung and Traub’s conjecture. We obtain the theoretical convergence order by using Taylor developments. Finally, we consider some real-life situations for establishing some numerical experiments to corroborate the theoretical results.

In this article, I show a descriptive analysis about Teaching Free Institution Bulletin in its two periods, such periods are delimited by our Civil War Events. The first period is the most important due to its duration, is extended to sixty years of continued publication from 1877 to the middle of 1936. The second period of this Bulletin, is relatively recent, reappears in 1987 and it is edited by Francisco Giner de los Ríos Foundation. Revising the aim of this magazine, its beginnings, evolution and structure will contribute to the convinction that this Bulletin is considered a very important and imprescindible source for the study of Teaching Free Institution and in the same way, for people who wants to deepen in the evolution of Spanish Education history from the ending of 19th century to the beginning of 20th century. It is specially a necessary source to know our incorporation to New School Pedagogy Movement,educational guidelines, which were followed by Teaching Free Institution and whose principles and realizations had placed the pages of this Bulletin on record.

We present new high-order optimal iterative methods for solving a nonlinear equation, f(x)=0, by using Padé-like approximants. We compose optimal methods of order 4 with Newton’s step and substitute the derivative by using an appropriate rational approximant, getting optimal methods of order 8. In the same way, increasing the degree of the approximant, we obtain optimal methods of order 16. We also perform different numerical tests that confirm the theoretical results.

Experimental evidence suggests that the massive release of glutamate during experimental brain ischemia both directly and indirectly regulates downstream mechanisms of cell suicide. Cerebral ischemia was produced by distal, permanent occlusion of the middle cerebral artery (MCAO) in the rat. Sets of three animals and one sham-operated for each time-point were kept alive for 0–30 min, 1, 4, 12, 24, and 48 h, and 4 days. Additional animals were treated by local administration of a 10 μM (in 10 μl) cocktail of caspase inhibitors (YVAD-cmk, DEVD-fmk, IETD). Immunohistochemistry was performed on free-floating tissue sections with goat polyclonal antibodies to procaspase-1, -2, -3, -6, and -8. Some sections were processed for double-labeling procaspase immunohistochemistry and in situ end-labeling of nuclear DNA fragmentation (TUNEL method). Both immunohistochemistry and double-labeling procaspase immunohistochemistry and TUNEL method were carried out on formalin-fixed sections. For gel electrophoresis and Western blotting, we used antibodies to poly (ADP-ribose) polymerase (PARP), lamin B, and PKC-δ, as specific cleavage substrates of caspases. There was increased immunoreactivity ipsilaterally in the areas corresponding to the infarct and surrounding penumbra with the peak of immunoreactivity between 12 and 24 h for most of the procaspases. Procaspases were present early in the infarcted tissue neurones and their dendrites and axons. Additional procaspase expression occurred in astrocytes and microglial cells at different times following ischemia. Cells with positive in situ end-labeling of nuclear DNA fragmentation appeared in high number predominantly in the infarcted areas and at the edge of the infarction and colocalized with enhanced procaspase expression. These findings suggest increased procaspase expression in dying cells at the edge of the infarction. A major product of PARP degradation of about 89 kDa was found in the samples taken from the infarcted and penumbra areas. There was no difference in the intensity of the bands corresponding to lamin B or PKC-δ. Injection of procaspase inhibitors reduced the levels of major PARP products of 89 kDa and decreased the number of TUNEL-positive cells at 12 h post-MCAO. In conclusion, these results give support to further research on the use of caspase inhibitors as add-on therapeutic agents for the treatment of ischemia.

Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches.

A family of derivative-free methods of seventh-order convergence for solving nonlinear equations is suggested. In the proposed methods, several linear combinations of divided differences are used in order to get a good estimation of the derivative of the given function at the different steps of the iteration. The efficiency indices of the members of this family are equal to 1.6266. Also, numerical examples are used to show the performance of the presented methods, on smooth and nonsmooth equations, and to compare with other derivative-free methods, including some optimal fourth-order ones, in the sense of Kung-Traub’s conjecture.