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Background: Sporadic amyotrophic lateral sclerosis (sALS) is a severe neurodegenerative disease characterized by continuous diminution of motor neurons in the brain and spinal cord. Earlier studies indicated that the DPP6 gene variant has a role in the development of sALS. This meta-analysis was designed to uncover the role of rs10260404 polymorphism of the DPP6 gene and its association with sALS. Methods: All case–control articles published prior to October 2022 on the association between DPP6 (rs10260404) polymorphism and sALS risk were systematically extracted from different databases which include PubMed, PubMed Central, and Google Scholar. Overall odds ratios (ORs) and "95% confidence intervals (CIs)" were summarized for various genetic models. Subgroup and heterogeneity assessments were performed. Egger's and "Begg's tests were applied to evaluate publication bias. Trial sequential analysis (TSA) and false-positive report probability (FPRP) were performed. Results: Nine case–control studies containing 4202 sALS cases and 4444 healthy controls were included in the meta-analysis. A significant association of the DPP6 (rs10260404) variant with an increased sALS risk in overall pooled subjects under allelic model [C allele vs. T allele, OR = 1.149, 95% CI (1.010–1.307), p-value = 0.035], dominant model [CC + CT vs. TT, OR = 1.165, 95% CI (1.067–1.273), p-value = 0.001], and homozygote comparison [CC vs. TT, OR = 1.421, 95% CI (1.003–2.011), p-value = 0.048] were observed. Moreover, in subgroup analysis by nationality, remarkable associations were detected in Dutch, Irish, American, and Swedish under allelic, dominant, and homozygote models. Additionally, stratification analysis by ethnicity exhibited an association with sALS risk among Caucasians and Americans under different genetic models. Interestingly, none of the models found any significant association with Asians. Conclusion: The present meta-analysis indicates that DPP6 (rs10260404) polymorphism could be a candidate risk factor for sALS predisposition. [ABSTRACT FROM AUTHOR]

Purpose of Review: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing weakness, respiratory failure, and death within 3 to 5 years. Approximately, 10% of ALS cases have a genetic etiology (familial/fALS). The etiology of the remaining 90% of sporadic ALS (sALS) cases remains unknown. In this review, we provide an overview of approved and investigational therapies for fALS, as well as genetically informed therapeutic advances aimed at the larger sALS population. Recent Findings: Antisense oligonucleotides (ASOs) are a promising strategy to treat toxic gain-of-function mutations underlying most forms of fALS. We discuss the recent approval of tofersen for ALS caused by mutation in SOD1. We also discuss progress in the development of therapies for fALS associated with C9orf72 hexanucleotide repeat expansions (C9orf72) and fused in sarcoma (FUS) mutations. Finally, we will discuss the rationale and status of molecular therapies for sALS targeting mediators of TDP-43 pathogenesis: ataxin-2 (ATXN2) and stathmin-2 (STMN2). Summary: Advances in understanding the genetics of ALS have propelled the development of promising gene therapies. Lessons learned from tofersen continue to inform clinical trial design for a growing pipeline of therapies directed towards other fALS subtypes and sALS. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease of motor neurons. Most ALS cases are considered sporadic due to the presence of a combination of environmental and complex genetic risk factors, while approximately 10% of cases have a family history. Pathogenic variants in the SOD1 gene are the second most frequent causative factor of genetics-based ALS worldwide, after C9ORF72 hexanucleotide repeat expansion. The De novo occurrence of pathogenic mutations in ALS-associated genes and its effect on disease progression have been studied previously, especially in the FUS gene. Recent studies have shown that a very small portion of SOD1 cases occurred de novo. Here, we present the first de novo case of the SOD1 His47Arg mutation in a young female patient with mild symptoms and, currently, a slow progression for 7 years.

Amyotrophic lateral sclerosis (ALS) is a clinically highly heterogeneous disease with a survival rate ranging from months to decades. Evidence suggests that a systemic deregulation of immune response may play a role and affect disease progression. Here, we measured 62 different immune/metabolic mediators in plasma of sporadic ALS (sALS) patients. We show that, at the protein level, the majority of immune mediators including a metabolic sensor, leptin, were significantly decreased in the plasma of sALS patients and in two animal models of the disease. Next, we found that a subset of patients with rapidly progressing ALS develop a distinct plasma assess immune–metabolic molecular signature characterized by a differential increase in soluble tumor necrosis factor receptor II (sTNF-RII) and chemokine (C-C motif) ligand 16 (CCL16) and further decrease in the levels of leptin, mostly dysregulated in male patients. Consistent with in vivo findings, exposure of human adipocytes to sALS plasma and/or sTNF-RII alone, induced a significant deregulation in leptin production/homeostasis and was associated with a robust increase in AMP-activated protein kinase (AMPK) phosphorylation. Conversely, treatment with an AMPK inhibitor restored leptin production in human adipocytes. Together, this study provides evidence of a distinct plasma immune profile in sALS which affects adipocyte function and leptin signaling. Furthermore, our results suggest that targeting the sTNF-RII/AMPK/leptin pathway in adipocytes may help restore assess immune–metabolic homeostasis in ALS. [ABSTRACT FROM AUTHOR]

Microbial metabolites affect the neuron system and muscle cell functions. Amyotrophic lateral sclerosis (ALS) is a multifactorial neuromuscular disease. Our previous study has demonstrated elevated intestinal inflammation and dysfunction of the microbiome in patients with ALS and an ALS mouse model (human-SOD1G93A transgenic mice). However, the metabolites in ALS progression are unknown. Using an unbiased global metabolomic measurement and targeted measurement, we investigated the longitudinal changes of fecal metabolites in SOD1G93A mice over the course of 13 weeks. We further compared the changes of metabolites and inflammatory response in age-matched wild-type (WT) and SOD1G93A mice treated with the bacterial product butyrate. We found changes in carbohydrate levels, amino acid metabolism, and the formation of gamma-glutamyl amino acids. Shifts in several microbially contributed catabolites of aromatic amino acids agree with butyrate-induced changes in the composition of the gut microbiome. Declines in gamma-glutamyl amino acids in feces may stem from differential expression of gamma-glutamyltransferase (GGT) in response to butyrate administration. Due to the signaling nature of amino acid-derived metabolites, these changes indicate changes in inflammation, e.g., histamine, and contribute to differences in systemic levels of neurotransmitters, e.g., γ-Aminobutyric acid (GABA) and glutamate. Butyrate treatment was able to restore some of the healthy metabolites in ALS mice. Moreover, microglia in the spinal cord were measured by IBA1 staining. Butyrate treatment significantly suppressed the IBA1 level in the SOD1G93A mice. Serum IL-17 and LPS were significantly reduced in the butyrate-treated SOD1G93A mice. We have demonstrated an inter-organ communications link among microbial metabolites, neuroactive metabolites from the gut, and inflammation in ALS progression. The study supports the potential to use metabolites as ALS hallmarks and for treatment. [ABSTRACT FROM AUTHOR]

In this study, the contributions of light scattering and extra-loss mechanisms to the total losses and to the differential mode attenuation of the guided modes are quantified for three different few-mode fibers. The tested fibers have the same modal content but different refractive index profiles, namely step, trapezoidal and parabolic. It is demonstrated that a trapezoidal index profile is a good compromise between low attenuation, low differential mode attenuation while maintaining large effective index differences between modes so as to reduce mode coupling. [ABSTRACT FROM AUTHOR]

Rutting resistance is an important consideration for paving asphalt mixes. The cause of rutting is a shear strain in the asphalt pavement structure. Here, the rutting behavior of asphalt pavements was evaluated through laboratory simulations using the Hamburg Wheel-Tracking Test (HWTT), UK Wheel-Tracking Test (UKWTT), and Scaled Accelerated Load Simulator (SALS) test. The correlation between the three simulation tests was analyzed to determine the conversion factor (CF). Two parameters of temperature and speed of simulation testing were evaluated in this study. Subsequently, the representative frequency and dynamic modulus were calculated with consideration of viscoelasticity and time-temperature superposition. Using logical analysis, CF between the three simulation tests was validated. The results showed that the full-scale test yielded the highest stiffness modulus of 4,015 MPa, and the UKWTT yielded the lowest stiffness modulus of 1,857 MPa at 60 °C. From the HWTT results, it was found that the impact of moisture damage at 40 °C is not substantial compared to that at 50 °C. The conversion factor of HWTT at 40 °C, HWTT at 50 °C and UKWTT at 60 °C to SALS were 0.92, 0.74, and 0.63, respectively. Furthermore, the similar rutting performance among SALS, HWTT at 40 °C in dry and wet conditions, and HWTT at 50 °C in dry condition can be observed when the CF is applied. Lastly, the effectiveness of the conversion factor is diminished with increasing rutting damage. [ABSTRACT FROM AUTHOR]

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by the neurodegeneration of motoneurons. About 10% of ALS is hereditary and involves mutation in 25 different genes, while 90% of the cases are sporadic forms of ALS (sALS). The diagnosis of ALS includes the detection of early symptoms and, as disease progresses, muscle twitching and then atrophy spreads from hands to other parts of the body. The disease causes high disability and has a high mortality rate; moreover, the therapeutic approaches for the pathology are not effective. miRNAs are small non-coding RNAs, whose activity has a major impact on the expression levels of coding mRNA. The literature identifies several miRNAs with diagnostic abilities on sALS, but a unique diagnostic profile is not defined. As miRNAs could be secreted, the identification of specific blood miRNAs with diagnostic ability for sALS could be helpful in the identification of the patients. In the view of personalized medicine, we performed a meta-analysis of the literature in order to select specific circulating miRNAs with diagnostic properties and, by bioinformatics approaches, we identified a panel of 10 miRNAs (miR-193b, miR-3911, miR-139-5p, miR-193b-1, miR-338-5p, miR-3911-1, miR-455-3p, miR-4687-5p, miR-4745-5p, and miR-4763-3p) able to classify sALS patients by blood analysis. Among them, the analysis of expression levels of the couple of blood miR-193b/miR-4745-5p could be translated in clinical practice for the diagnosis of sALS.

Amyotrophic Lateral Sclerosis is a neuromuscular disease characterized by the progressive death of motor neurons and muscle atrophy. The gastrointestinal symptoms in ALS patients were largely ignored or underestimated. The relationship between the enteric neuromuscular system and microbiome in ALS progression is unknown. We performed longitudinal studies on the enteric neuron system (ENS) and microbiome in the ALS human-SOD1G93A (Superoxide Dismutase 1) transgenic mice. We treated age-matched wild-type and ALS mice with butyrate or antibiotics to investigate the microbiome and neuromuscular functions. We examined intestinal mobility, microbiome, an ENS marker GFAP (Glial Fibrillary Acidic Protein), a smooth muscle marker (SMMHC, Smooth Muscle Myosin Heavy Chain), and human colonoids. The distribution of human-G93A-SOD1 protein was tested as an indicator of ALS progression. At 2-month-old before ALS onset, SOD1G93A mice had significantly lower intestinal mobility, decreased grip strength, and reduced time in the rotarod. We observed increased GFAP and decreased SMMHC expression. These changes correlated with consistent increased aggregation of mutated SOD1G93A in the colon, small intestine, and spinal cord. Butyrate or antibiotics treated SOD1G93A mice had a significantly longer latency to fall in the rotarod test, reduced SOD1G93A aggregation, and enhanced enteric neuromuscular function. Feces from 2-month-old SOD1G93A mice significantly enhanced SOD1G93A aggregation in human colonoids transfected with a SOD1G93A-GFP plasmid. Longitudinal studies of microbiome data further showed the altered bacterial community related to autoimmunity (e.g., Clostridium sp. ASF502, Lachnospiraceae bacterium A4), inflammation (e.g., Enterohabdus Muris,), and metabolism (e.g., Desulfovibrio fairfieldensis) at 1- and 2-month-old SOD1G93A mice, suggesting the early microbial contribution to the pathological changes. We have demonstrated a novel link between the microbiome, hSOD1G93A aggregation, and intestinal mobility. Dysbiosis occurred at the early stage of the ALS mice before observed mutated-SOD1 aggregation and dysfunction of ENS. Manipulating the microbiome improves the muscle performance of SOD1G93A mice. We provide insights into the fundamentals of intestinal neuromuscular function and microbiome in ALS.

The cerebral meninges, made up of the dura, arachnoid, and pia mater, is a tri-layer membrane that surrounds the brain and the spinal cord and has an important function in protecting the brain from injury. Understanding its mechanical behavior is important to ensure the accuracy of finite element (FE) head model simulations which are commonly used in the study of traumatic brain injury (TBI). Mechanical characterization of freshly excised porcine dura-arachnoid mater (DAM) was achieved using uniaxial tensile testing and bulge inflation testing, highlighting the dependency of the identified parameters on the testing method. Experimental data was fit to the Ogden hyperelastic material model with best fit material parameters of μ = 450 ± 190 kPa and α = 16.55 ± 3.16 for uniaxial testing, and μ = 234 ± 193 kPa and α = 8.19 ± 3.29 for bulge inflation testing. The average ultimate tensile strength of the DAM was 6.91 ± 2.00 MPa (uniaxial), and the rupture stress at burst was 2.08 ± 0.41 MPa (inflation). A structural analysis using small angle light scattering (SALS) revealed that while local regions of highly aligned fibers exist, globally, there is no preferred orientation of fibers and the cerebral DAM can be considered to be structurally isotropic. This confirms the results of the uniaxial mechanical testing which found that there was no statistical difference between samples tested in the longitudinal and transversal direction (p = 0.13 for μ, p = 0.87 for α). A finite element simulation of a craniotomy procedure following brain swelling revealed that the mechanical properties of the meninges are important for predicting accurate stress and strain fields in the brain and meninges. Indeed, a simulation using a common linear elastic representation of the meninges was compared to the present material properties (Ogden model) and the intracranial pressure was found to differ by a factor of 3. The current study has provided researchers with primary experimental data on the mechanical behavior of the meninges which will further improve the accuracy of FE head models used in TBI.

• A novel experimental setup integrating biaxial traction and microstructure is proposed. • Experimental data were used for structurally-motivated constitutive modelling. • Successful fitting with fiber-based models was obtained. • The setup feasibility demonstrated the analysis at macro and microstructure level. Mechanical properties and microstructural modifications of vessel tissues are strongly linked, as established in the state of the art of cardiovascular diseases. Techniques to obtain both mechanical and structural information are reported, but the possibility to obtain real-time microstructural and macrostructural data correlated is still lacking. An experimental approach to characterize the aortic tissue is presented. A setup integrating biaxial traction and Small Angle Light Scattering (SALS) analysis is described. The system was adopted to test ex-vivo aorta specimens from healthy and aneusymatic (aTAA) cases. A significant variation of the fiber dispersion with respect to the unloaded state was encountered during the material traction. The corresponding microstructural and mechanical data were successfully used to fit a given anisotropic constitutive model, with satisfactory R 2 values (0.97 ± 0.11 and 0.96 ± 0.17, for aTAA and healthy population, respectively) and fiber dispersion parameters variations between the aTAA and healthy populations (0.39 ± 0.23 and 0.15 ± 0.10). The method integrating the biaxial/SALS technique was validated, allowing for real-time synchronization between mechanical and microstructural analysis of anisotropic biological tissues. [ABSTRACT FROM AUTHOR]

Small angle light scattering (SALS) and differential scanning calorimetry DSC have been applied to investigate the melting of spherulites isothermally crystallized polylactide. At an isothermal crystallization temperature high enough, pure α‐phase crystals are formed. Exposed to a temperature gradient, the crystals first melt and then recrystallize before they finally melt. With decreasing crystallization temperature, an increasing fraction of polylactide is crystallizing in the less stable α′‐phase. α′‐crystals also melt upon increasing the temperature but recrystallize to the more stable α‐phase. A constant spherulite size is revealed by SALS for both processes, the α/α and α′/α melt‐recrystallization, until completion of the final melting, thereby supporting integrity of the spherulites throughout the entire processes. Joint DSC and SALS experiments demonstrate that the depolarized scattering invariant correlates with the heat flow recorded by DSC and thus offer an alternative measure for the degree of crystallinity. The following mechanism is identified for both processes: initial melting and recrystallization overlay each other. Crystallinity is not fully recovered upon recrystallization because only part of the original lamellae survives the melt‐recrystallization, though with an increased thickness. While lamellae are melting and reforming or simply transforming their phase, the spherulites survive the process until final melting. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2019, 57, 1483–1495 [ABSTRACT FROM AUTHOR]

Recent advances in ALS gene discovery have both empowered and challenged clinicians providing evaluation and care for persons with ALS, many of whom seek an answer as to the cause of their condition. In order to study clinician practices and attitudes towards genetic testing, we surveyed members of the Northeast ALS Consortium, an international group of specialist ALS clinicians; responses were received from 80 of 255 (response rate = 31.4%). While 92.3% indicated they offered genetic testing to patients with familial ALS, 57.0% offered testing to patients with ALS and a family history of dementia, and 36.9% offered testing to patients with sporadic ALS, revealing a lack of consensus with respect to the approach to the typical ALS patient encountered in clinical practice. In addition, comparison of clinician and patient attitudes towards genetic testing revealed that clinicians valued the scientific potential of testing, but were less likely to say they would have testing themselves, or to see the value in testing for family members. People with ALS were more likely to see value of testing for themselves and for family members, and less likely to strongly value the scientific potential of testing. [ABSTRACT FROM AUTHOR]

Introduction: Spinal muscular atrophy (SMA) and sporadic amyotrophic lateral sclerosis (SALS) are both motor neuron disorders. SMA results from the deletion of the survival motor neuron (SMN) 1 gene. High or low SMN1 copy number and the absence of SMN2 have been reported as risk factors for the development or severity of SALS. Objective: To investigate the role of SMN gene copy number in the onset and severity of SALS in Malians. Material and Methods: We determined the SMN1 and SMN2 copy number in genomic DNA samples from 391 Malian adult volunteers, 120 Yoruba from Nigeria, 120 Luyha from Kenya and 74 U.S. Caucasians using a Taqman quantitative PCR assay. We evaluated the SALS risk based on the estimated SMA protein level using the Veldink formula (SMN1 copy number + 0.2∗SMN2 copy number). We also characterized the disease natural history in 15 ALS patients at the teaching hospital of Point G, Bamako, Mali. Results: We found that 131 of 391 (33.5%) had an estimated SMN protein expression of ≤2.2; 60 out of 391 (15.3%) had an estimated SMN protein expression

Background Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease characterized by the degeneration and death of upper (UMN) and lower (LMN) motor neurons. In the last decade, it has been shown that Chitinases are an important prognostic indicator of neuro-inflammatory damage induced by microglia and astrocytes. Materials and methods We analyzed microarray datasets obtained from the Array Express in order to verify the expression levels of CHI3L1 and CHI3L2 in motor cortex biopsies of sALS patients with different survival times. We also divided the sALS patients into smokers and non-smokers. In order to extend our analysis, we explored two additional microarray datasets, GSE833 and GSE26927, of post-mortem spinal cord biopsies from sALS patients. Results The analysis showed that CHI3L1 and CHI3L2 expression levels were significantly upregulated in the motor cortex of sALS patients, compared to the healthy controls. Moreover, their expression levels were negatively correlated with survival time. Interesting results were obtained when we compared the expression levels of Chitinases among smokers. We showed that CHI3L1 and CHI3L2 were significantly upregulated in sALS smokers compared to non-smokers. Furthermore, we found that four genes belonging to the Chitinases network ( SERPINA3 , C1s , RRAD , HLA-DQA1 ) were significantly upregulated in the motor cortex of sALS patients and positively correlated with Chitinases expression levels. Similar results were obtained during the exploration of the two-microarray dataset. Conclusions This study suggests that CHI3L1 and CHI3L2 are associated with the progression of neurodegeneration in motor cortex and spinal cord of sALS patients. [ABSTRACT FROM AUTHOR]

Evidence of misfolded wild-type superoxide dismutase 1 (SOD1) has been detected in spinal cords of sporadic ALS (sALS) patients, suggesting an etiological relationship to SOD1-associated familial ALS (fALS). Given that there are currently a number of promising therapies under development that target SOD1, it is of critical importance to better understand the role of misfolded SOD1 in sALS. We previously demonstrated the permissiveness of the G85R-SOD1:YFP mouse model for MND induction following injection with tissue homogenates from paralyzed transgenic mice expressing SOD1 mutations. This prompted us to examine whether WT SOD1 can self-propagate misfolding of the G85R-SOD1:YFP protein akin to what has been observed with mutant SOD1. Using the G85R-SOD1:YFP mice, we demonstrate that misfolded conformers of recombinant WT SOD1, produced in vitro, induce MND with a distinct inclusion pathology. Furthermore, the distinct pathology remains upon successive passages in the G85R-SOD1:YFP mice, strongly supporting the notion for conformation-dependent templated propagation and SOD1 strains. To determine the presence of a similar misfolded WT SOD1 conformer in sALS tissue, we screened homogenates from patients diagnosed with sALS, fALS, and non-ALS disease in an organotypic spinal cord slice culture assay. Slice cultures from G85R-SOD1:YFP mice exposed to spinal homogenates from patients diagnosed with ALS caused by the A4V mutation in SOD1 developed robust inclusion pathology, whereas spinal homogenates from more than 30 sALS cases and various controls failed. These findings suggest that mutant SOD1 has prion-like attributes that do not extend to SOD1 in sALS tissues. [ABSTRACT FROM AUTHOR]

ABSTRACT Genetic discoveries in amyotrophic lateral sclerosis (ALS) have a significant impact on deciphering molecular mechanisms of motor neuron degeneration but, despite recent advances, the etiology of most sporadic cases remains elusive. Several cellular mechanisms contribute to the motor neuron degeneration in ALS, including RNA metabolism, cellular interactions between neurons and nonneuronal cells, and seeding of misfolded protein with prion-like propagation. In this scenario, the importance of protein turnover and degradation in motor neuron homeostasis gained increased recognition. In this study, we evaluated the role of the candidate gene HSPB1, a molecular chaperone involved in several proteome-maintenance functions. In a cohort of 247 unrelated Italian ALS patients, we identified two variants (c.570G>C, p.Gln190His and c.610dupG, p.Ala204Glyfs*6). Functional characterization of the p.Ala204Glyfs*6 demonstrated that the mutant protein alters HSPB1 dynamic equilibrium, sequestering the wild-type protein in a stable dimer and resulting in a loss of chaperone-like activity. Our results underline the relevance of identifying rare but pathogenic variations in sporadic neurodegenerative diseases, suggesting a possible correlation between specific pathomechanisms linked to HSPB1 mutations and the associated neurological phenotype. Our study provides additional lines of evidence to support the involvement of HSPB1 in the pathogenesis of sporadic ALS. [ABSTRACT FROM AUTHOR]

ABSTRACT The mechanism of reducing light scattering in isotactic polypropylene ( i-PP), through the addition of so-called clarifying agents, is studied with small-angle light scattering (SALS) and scanning electron microscopy (SEM). The clarifying agents used in this study depict monotectic phase behavior with i-PP, crystallizing in a relatively narrow concentration range in a nanofibrillar network, providing an ultrahigh nucleation density in the i-PP melt. It is found that the clarifying effect, a dramatically increased transparency and reduced haze, that occurs within the aforementioned additive concentration range, coincides with a change in morphology from strongly scattering spherulites to shish-kebab-like crystalline structures, as evidenced by in situ SALS measurements and confirmed by SEM images. A simple scaling law, relating the diameter of the shish-kebab structures to the fibril diameter and volume fraction of the clarifying agent is proposed, suggesting that the performance of a (fibril-forming) clarifying agent will improve by reducing the fibril diameter and/or increasing the volume concentration of the clarifying agent. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016, 54, 865-874 [ABSTRACT FROM AUTHOR]

The fractal behavior in q space of polypropylene with polydecamethylene sebacamide (Nylon1010, PA1010) (90/10 vol%) blends during melt mixing is investigated, where q is the scattering wave vector. The relation between the small-angle laser scattering image and the power spectrum of the binarized scanning electron microscopy image is discussed. Two fractal dimensions, i.e. D1 and D2, are deduced in q space. The results show that the fractal dimensions are effective parameters to characterize the dynamics of the phase dispersion during melt mixing. D1 can be used to characterize the spatial fluctuation of the phase structure. With the increasing D1, the spatial fluctuation of the phase structure becomes bigger. And D2 can directly characterize the dispersion degree of the dispersed phase. Higher phase dispersion degree corresponds to bigger D2. The results indicate that these two fractal dimensions in q space have almost the same changing rule with the increasing mixing time. Both of them change considerably at the initial stage but, are almost unchanged after 2 min, demonstrating that the phase structure mainly forms at the initial stage during melt mixing. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a progressive and seriously disabling adult-onset neurological disease. Ninety percent of ALS patients are sporadic cases (sALS) with no clear genetic linkage. Accumulating evidence indicates that various microRNAs (miRNAs), expressed in a spatially and temporally controlled manner in the brain, play a key role in neuronal development. In addition, microRNA dysregulation contributes to some mental disorders and neurodegeneration diseases. In our research, the expression of one selected miRNA, miR-338-3p, which previously we have found over-expressed in blood leukocytes, was studied in several different tissues from sALS patients. For the first time, we detected a specific microRNA disease-related upregulation, miR-338-3p, in blood leukocytes as well in cerebrospinal fluid, serum, and spinal cord from sALS patients. Besides, staining of in situ hybridization showed that the signals of miR-338-3p were localized in the grey matter of spinal cord tissues from sALS autopsied patients. We propose that miRNA profiles found in tissue samples from sALS patients can be relevant to understand sALS pathogenesis and lead to set up effective biomarkers for sALS early diagnosis. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate the association between SMN1 and SMN2 copy number variations (CNVs) and sporadic amyotrophic lateral sclerosis (SALS) by a meta-analysis. Methods: Through searching PubMed and EMBASE database (or manual searching) up to November 2013 using the following keywords: “survival motor neuron gene”, “SMN”, and “amyotrophic lateral sclerosis”, “ALS” or “motor neuron disease”. Nine studies were identified as eligible for this meta-analysis. The association between SMN genes and the SALS risk was investigated based on SMN1 and SMN2 CNVs. The heterogeneity across the studies was tested, as was publication bias. Results: The analysis showed significant association for SMN1 duplications in SALS risk: the risk estimates were OR=1.76, 95%CI=1.33–2.32, p<0.0001 (still significant when the p value was Bonferroni adjusted to 0.01). However, there was no significant association between SMN1 deletions and SALS risk after Bonferroni correction (OR=1.78, 95%CI=1.02–3.11, p=0.04). In addition, SMN2 copy number statuses were not associated with SALS in our pooled study. No evidence of publication bias was observed. Conclusion: Our meta-analysis suggested that SMN1 duplications are a genetic risk factor in SALS, while there was no modulator effect of the SMN2 gene. In addition, it was possible that SMN1 deletions in predisposition to SALS vary across different countries. More studies were required to warrant the findings of this study. [Copyright &y& Elsevier]

Cu/Zn superoxide dismutase ( SOD1) gene mutations are the most frequently reported genetic causes of amyotrophic lateral sclerosis (ALS). The objective of the study was to describe a clinical phenotype and haplotype background of Polish and Japanese ALS patients harbouring the K3E SOD1 mutation. The K3E mutation was identified by direct sequencing, high resolution melting analysis or high-throughput microarray-based resequencing system. Microsatellite polymorphic markers flanking SOD1 were genotyped in members of six kindreds and two SALS patients. Results demonstrated that the K3E mutation was responsible for classic ALS. The median age of onset was 54 years. The clinical phenotype did not substantially differ between SALS and FALS cases of either ethnic origin, with some intrafamiliar variabilities. There was a limb onset in 92% of patients. In patients with bulbar syndrome, dysphagia predominated over dysarthria. Respiratory insufficiency was found in 61.1% of patients (19-84 months after the first symptoms onset). Median survival was 101 months with age of death ranging from 45 to 77 years. K3E was the most frequent SOD1 mutation among Polish FALS patients. It originated independently, on different haplotype background in the Polish and Japanese populations. In conclusion, recurrent K3E mutation results in a relatively slowly progressing limb onset ALS with classic phenotype. [ABSTRACT FROM AUTHOR]

Abstract: Amyotrophic lateral sclerosis (ALS) is a progressive and seriously disabling adult-onset neurological disease. Accumulating evidence indicates that various miRNAs, expressed in a spatially and temporally controlled manner in the brain, play a key role in neuronal development. In addition, misregulation of microRNAs contributes to some mental disorders and neurodegeneration diseases. Here, we analyzed the expression profiles of 911 human miRNAs using microarray technology in leukocytes, the most readily available human tissue cells, obtained from 8 patients affected by sporadic amyotrophic lateral sclerosis (sALS) and 12 healthy controls. An independent group of 14 sALS patients and 14 controls was used for validation by TaqMan real-time polymerase chain reaction assay. We identified 8 miRNAs that were significantly up- or downregulated in sALS patients as compared to healthy controls. The significant variations in miRNAs profiles detected in leukocytes have been related to miRNAs predominantly expressed in the nervous system. One of these miRNAs, miR-338-3p, has previously been shown to be de-regulated in ALS brains. This study, for the first time, detected specific microRNAs disease-related changes at an earlier stage of sALS. We suggest that miRNAs profiles found in the peripheral blood leukocytes from sALS patients can be relevant to understand the pathogenesis of sALS and/or used as biomarkers of the disease. [Copyright &y& Elsevier]

Abstract: Amyotrophic lateral sclerosis (ALS; Lou Gehrig''s disease) is a progressive debilitating neurodegenerative disease with no cure. We propose a novel molecular model for the pathogenesis of ALS that involves an adenosine triphosphate (ATP)-dependent muscle neuronal lactate shuttle (MNLS) at the neuromuscular junction (NMJ) to regulate the flow of lactate from muscle to neurons and vice versa. Failure of the MNLS due to respiratory chain dysfunction is proposed to result in lactate toxicity and degeneration of nerve endings at the NMJ leading to nerve terminus dysjunction from the muscle cell. At a critical threshold where denervation outpaces reinnervation, a vicious cycle is established where the remaining innervated muscle fibers are required to work harder to compensate for normal function, and in so doing produce toxic lactate concentrations which induces further denervation and neuronal death. This mechanism explains the exponential progression of ALS leading to paralysis. The molecular events leading to the dysregulation of the MNLS and the dismantling of NMJ are explained in the context of known ALS familial mutations and age-related endocrine dyscrasia. Combination drug therapies that inhibit lactate accumulation at the NMJ, enhance respiratory chain function, and/or promote reinnervation are predicted to be effective therapeutic strategies for ALS. [Copyright &y& Elsevier]

Copyright of Arquivos de Neuro-Psiquiatria is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Over the last couple of decades, there has been a growing body of clinical, genetic, and histopathological evidence that similar pathological processes underlie amyotrophic lateral sclerosis (ALS) and some types of frontotemporal lobe dementia (FTD). Even though there is great diversity in the genetic causes of these disorders, there is a high degree of overlap in their histopathology. Genes linked to rare cases of familial ALS and/or FTD, like FUS, TARDBP, OPTN, and UBQLN2 may converge onto a unifying pathogenic pathway and thereby provide novel therapeutic targets common to a spectrum of etiologically diverse forms of ALS and ALS-FTD. Additionally, there are major loci for ALS-FTD on chromosomes 9p and 15q. Identification of causative genetic alterations at those loci will be an important step in understanding the pathogenesis of juvenile- and adult-onset ALS and ALS-FTD. Interactions between TDP-43, FUS, optineurin, and ubiquilin 2 need to be studied to understand their common molecular pathways. Future efforts should also be directed towards generation and characterization of in vivo models to dissect the pathogenic mechanisms of these diseases. Such efforts will rapidly accelerate the discovery of new drugs that regulate accumulation of pathogenic proteins and their downstream consequences. [ABSTRACT FROM AUTHOR]

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While it is known that the aorta stiffens with location and age, little is known about the underlying mechanisms that govern these alterations. The purpose of this study was to investigate the relationship between the anisotropic biomechanical behavior and extracellular matrix microstructure of the human aorta and quantify how each changes with location and age. A total of 207 specimens were harvested from 5 locations (ascending n = 33, arch n = 38, descending n = 54, suprarenal n = 52, and abdominal n = 30) of 31 autopsy donor aortas (aged 3 days to 93 years). Each specimen underwent planar biaxial testing in order to derive quantitative biomechanical endpoints of anisotropic stiffness and compliance. Quantitative measures of fiber alignment and degree of fiber alignment were also generated on the same samples using a small-angle light scattering (SALS) technique. Circumferential and axial stiffening occurred with age and increased from the proximal to distal aorta, and the abdominal region was found to be more stiff than all others ( p ≤ 0.006). Specimens from donors aged 61 and above were drastically more stiff than younger specimens ( p < 0.001) and demonstrated greater circumferential compliance and axial stiffening ( p < 0.001). Fiber direction for all ages and locations was predominantly circumferential ( p < 0.001), and the degree of fiber alignment was found to increase with age ( p < 0.001). Our results demonstrate that the aorta becomes more biomechanically and structurally anisotropic after age 60; with significant changes occurring preferentially in the abdominal aorta, these changes may play an important role in the predisposition of disease formation (e.g., aneurysm) in this region with age. [ABSTRACT FROM AUTHOR]

The blends of poly(butylene terephthalate) (PBT) with thermoplastic elastomer (TPE) at a blending composition of 10-30 wt.% TPE were prepared with an objective to enhance impact toughness of PBT. Two different grades of PBT were selected based on carboxyl end group and viscosity. Melting behavior, mechanical properties, morphology, and rheology of the blends were studied. At all levels of TPE, PBT showed negligible changes in its melting and crystallization temperature; however, percentage crystallinity decreased with an increase in the amount of thermoplastic elastomer. The notched as well as unnotched Izod impact strength of PBT increased with the incorporation of TPE, the increase being about 47% (unnotched) and 54% (notched) with low molecular weight PBT and 18% (unnotched) and 70% (notched) with high molecular weight PBT at 10% TPE level. The tensile strength and tensile modulus of the blends decreased steadily as the weight percent of TPE increased. Analysis of the tensile data using predicted theories indicated that at TPE levels of 30 wt.%, the blends cannot take excessive stress because the interfacial adhesion is lowered. Small angle light scattering (SALS) studies of the samples indicated the decreased rate of crystallization and, hence, an increase in spherulitic radius in the presence of TPE. The increasing incorporation of TPE in PBT/TPE blends increased the shear thinning behavior and hence eased processability. [ABSTRACT FROM AUTHOR]

The effect of nanoCaCO3 on crystallisation behaviour of linear low density polyethylene (LLDPE) was investigated through time resolved small angle light scattering (SALS). The results indicate that the spherulite size of LLDPE is influenced in the presence of nanoCaCO3. In case the LLDPE and composites were crystallised at room temperature, the spherulite size of LLDPE composites is smaller than that of LLDPE. Also, the contents of the nanoCaCO3 (20·0–30·0 wt-%) could influence the structure of spherulite. The spherulite size of LLDPE is also influenced by the crystallisation temperature. When the crystallisation temperature is increased to 85°C, the spherulite size of LLDPE is remarkably affected by the contents of nanoCaCO3. At isothermal crystallisation temperature of 85°C, the crystallisation induction time of LLDPE is greatly shortened in the presence of nanoCaCO3. Furthermore, there is an orientation fluctuation emerging in the early stage of crystallisation in LLDPE containing 2·0 wt-% nanoCaCO3. [ABSTRACT FROM AUTHOR]

Abstract: We report a novel missense mutation (Asp109Tyr) in exon 4 of the Cu/Zn superoxide dismutase (sod1) gene in a woman with apparently sporadic amyotrophic lateral sclerosis (SALS). Signs of motor deficit appeared at the age of 51 years which progressed over the next 6 years to upper and lower motor neuron disease and death occurred by the age of 57 years. In this mutation, the base change of guanine to thymine at codon 109 of sod1 gene leads to the replacement of aspartic by tyrosine in the protein. This amino acid change in the protein however, did not alter the catalytic activity of the SOD1 enzyme as there was no change in the enzymatic activity of purified SOD1 from the patient''s erythrocytes compared to control. [Copyright &y& Elsevier]

An equimolar mixture of a cationic surfactant, cetylperidinium chloride (CPyCl) and the salt sodium salicylate (NaSal) forms wormlike micelles in aqueous solutions. Under shear, the solution shows a pronounced shear-thickening behavior, which is coupled with oscillations in shear rate and the apparent viscosity. In this shear-thickening regime the formation of shear-bands is observed, which also oscillate in position and intensity. Fast Fourier Transformations (FFT) of the oscillating shear rate and intensity signals show a single dominating frequency in the power spectrum analysis. This characteristic frequency as well as the amplitude of shear rate oscillation is found to increase with stress. Experiments performed in transparent parallel-plate geometry show dampening of the shear rate oscillations and increase in the characteristic frequency with decrease in the gap. Rheo-small angle light scattering and rheo-optical techniques confirm the formation of different kinds of structures at smaller gaps. [ABSTRACT FROM AUTHOR]

Abstract: Diseases affecting motor neurons, such as amyotrophic lateral sclerosis (Lou Gerhig''s disease), hereditary spastic paraplegia and spinal bulbar muscular atrophy (Kennedy''s disease) are a heterogeneous group of chronic progressive diseases and are among the most puzzling yet untreatable illnesses. Over the last decade, identification of mutations in genes predisposing to these disorders has provided the means to better understand their pathogenesis. The discovery 13 years ago of SOD1 mutations linked to ALS, which account for less than 2% of total cases, had a major impact in the field. However, despite intensive research effort, the pathways leading to the specific motor neurons degeneration in the presence of SOD1 mutations have not been fully identified. This review provides an overview of the genetics of both familial and sporadic forms of ALS. [Copyright &y& Elsevier]

Abstract: The tensile strength and stiffness of load-bearing soft tissues are dominated by their collagen fiber orientation. While microgrooved substrates have demonstrated a capacity to orient cells and collagen in monolayer tissue culture, tissue engineering (TE) scaffolds are structurally distinct in that they consist of a three-dimensional (3-D) open pore network. It is thus unclear how the geometry of these open pores might influence cell and collagen orientation. In the current study we developed an in vitro model system for quantifying the capacity of large scale (∼200μm), geometrically well-defined open pores to guide cell and collagen orientation in engineered tissues. Non-degradable scaffolds exhibiting a grid of 200μm wide rectangular pores (1:1, 2:1, 5:1, and 10:1 aspect ratios) were fabricated from a transparent epoxy resin via high-resolution stereolithography. The scaffolds ( per aspect ratio) were surface modified to support cell adhesion by covalently grafting GRGDS peptides, sterilized, and seeded with neonatal rat skin fibroblasts. Following 4 weeks of static incubation, the resultant collagen orientation was assessed quantitatively by small angle light scattering (SALS), and cell orientation was evaluated by laser confocal and scanning electron microscopy. Cells adhered to the struts of the pores and proceeded to span the pores in a generally circumferential pattern. While the cell and collagen orientations within 1:1 aspect ratio pores were effectively random, higher aspect ratio rectangular pores exhibited a significant capacity to guide global cell and collagen orientation. Preferential alignment parallel to the long strut axis and decreased spatial variability were observed to occur with increasing pore aspect ratio. Intra-pore variability depended in part on the spatial uniformity of cell attachment around the perimeter of each pore achieved during seeding. Evaluation of diamond-shaped pores [Sacks, M.S. et al., 1997. J. Biomech. Eng. 119(1), 124–127] suggests that they are less sensitive to initial conditions of cell attachment than rectangular pores, and thus more effective in guiding engineered tissue cell and collagen orientation. [Copyright &y& Elsevier]

Abstract: Background: SOD1 gene mutations are the most common identified cause of ALS, accounting for approximately 20% of familial ALS cases and around 4% of sporadic ALS cases. However, the prevalence of SOD1 varies in different ethnic groups. No previous epidemiological studies have been carried out in Catalonia. Objective: To determine the prevalence of SOD1 gene mutations in a Catalan ALS population, and to analyze the genotype-phenotype relationship. Materials and methods: 30 different FALS pedigrees and 94 sporadic ALS patients were screened for SOD1 mutations using direct sequence analysis. Results: Five of the 30 FALS pedigrees (16.6%) carried a SOD1 mutant. The mutations identified in this group were G37R, D76V, S105L, I112M and N139H. Four SOD1 mutants (4.25%) were found in the sporadic ALS group (SALS). The overall frequency (FALS plus SALS) of SOD1 mutations in our series was 6.45%. In the SALS group, D90A was identified in a patient presenting the typical Scandinavian phenotype. A 53-year-old woman with no family history of ALS carried the N139H mutation. Two unrelated sporadic ALS cases carried the A140A SOD1 mutant. Conclusions: The prevalence of the SOD1 mutation in FALS in Catalonia is similar to levels in other Mediterranean countries, but lower than those in reports studying the Belgian, Japanese, and Scottish populations. The prevalence of the SOD1 mutation was 4.25% in patients with no family history of ALS. These results may have significant repercussions on genetic counseling, and screening for the SOD1 mutation in sporadic ALS cases must therefore be considered. [Copyright &y& Elsevier]