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In this study, gelatin/carboxylated cellulose nanocrystal (cCNC) bionanocomposite films were developed as an eco-friendly alternative to non-biodegradable flexible plastic packaging. Cellulose nanocrystals were modified by 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-mediated oxidation (cCNC) to strategically interact with amino groups present in the gelatin macromolecular backbone. Gelatin/cCNC bionanocomposite films (0.5-6.0 wt% cCNC) obtained by solution casting were transparent to visible light while displayed high UV-blocking properties. The chemical compatibility between gelatin and cCNC was deepened by electrostatic COO - /NH 3 + interactions, as detected by FTIR spectroscopy and morphologically indicated by scanning electron microscopy (SEM). Accordingly, Young's modulus and tensile strength of films were largely increased by 80 and 64 %, respectively, specifically near the cCNC percolation threshold (4 wt%), whereas the water vapor permeability (WVP) was reduced by 52 % at the optimum 6.0 wt% cCNC content in relation to the non-reinforced gelatin matrix (0.10 vs. 0.18 g H 2 O mm m -2  h -1  kPa -1 ). The oxygen transmission rates (OTR) of the gelatin/cCNC bionanocomposites were < 0.01 cm 3  m- 2  day -1 , making them technically competitive to most promising biopolymers like polycaprolactone (PCL) and poly(lactic acid) (PLA). This study reveals how TEMPO-oxidized cellulose nanocrystals can broaden the performance of biodegradable gelatin films for use in packaging. The gelatin/cCNC bionanocomposites also represent an effective approach for designing newly sustainability-inspired flexible materials from the surface modification of nanocelluloses targeting specific interactions with protein structures., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and retinal vasculopathy with cerebral leukodystrophy and systemic manifestations (RVCL-S) are the most common forms of rare monogenic early-onset cerebral small vessel disease and share clinical, and, to different extents, neuroradiological and neuropathological features. However, whether CADASIL and RVCL-S overlapping phenotype may be explained by shared genetic risk or causative factors such as TREX1 coding variants remains poorly understood. To investigate this intriguing hypothesis, we used exome sequencing to screen TREX1 protein-coding variability in a large multi-ethnic cohort of 180 early-onset independent familial and apparently sporadic CADASIL-like Caucasian patients from the USA, Portugal, Finland, Serbia and Turkey. We report 2 very rare and likely pathogenic TREX1 mutations: a loss of function mutation (p.Ala129fs) clustering in the catalytic domain, in an apparently sporadic 46-year-old patient from the USA and a missense mutation (p.Tyr305Cys) in the well conserved C-terminal region, in a 57-year-old patient with positive family history from Serbia. In concert with recent findings, our study expands the clinical spectrum of diseases associated with TREX1 mutations., Competing Interests: Disclosure statement All the authors declare no competing financial or personal interests that can influence the presented work. Written informed consent was obtained for each individual and the study was approved by the appropriate institutional review boards., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Synapse loss is an early event in late-onset Alzheimer's disease (LOAD). In this study, we have assessed the capacity of a polygenic risk score (PRS) restricted to synapse-encoding loci to predict LOAD. We used summary statistics from the International Genetics of Alzheimer's Project genome-wide association meta-analysis of 74,046 patients for model construction and tested the "synaptic PRS" in 2 independent data sets of controls and pathologically confirmed LOAD. The mean synaptic PRS was 2.3-fold higher in LOAD than that in controls (p < 0.0001) with a predictive accuracy of 72% in the target data set (n = 439) and 73% in the validation data set (n = 136), a 5%-6% improvement compared with the APOE locus (p < 0.00001). The model comprises 8 variants from 4 previously identified (BIN1, PTK2B, PICALM, APOE) and 2 novel (DLG2, MINK1) LOAD loci involved in glutamate signaling (p = 0.01) or APP catabolism or tau binding (p = 0.005). As the simplest PRS model with good predictive accuracy to predict LOAD, we conclude that synapse-encoding genes are enriched for LOAD risk-modifying loci. The synaptic PRS could be used to identify individuals at risk of LOAD before symptom onset., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We report on gelatin films incorporating rosin-grafted cellulose nanocrystals (r-CNCs), which fulfill the most relevant requirements for antimicrobial packaging applications. Transparent gelatin/r-CNCs bionanocomposite films (0.5-6 wt% r-CNCs) were obtained by solution casting and displayed high UV-barrier properties, which were superior to the most used plastic packaging films. The gelatin/r-CNCs films exhibited a moderate water vapor permeability (0.09 g mm/m 2  h kPa), and high tensile strength (40 MPa) and Young's modulus (1.9 GPa). The r-CNCs were more efficient in improving the optical, water vapor barrier and tensile properties of gelatin films than conventional CNCs. Grafting of rosin on CNCs resulted in an antimicrobial nanocellulose that inhibited the growth of Staphylococcus aureus and Escherichia coli. The antibacterial properties of r-CNCs were sustained in the gelatin films, as demonstrated by agar diffusion tests and proof-of-principle experiments involving cheese storage. Overall, the incorporation of r-CNCs as active fillers in gelatin films is a suitable approach for producing novel eco-friendly, antimicrobial packaging materials., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

MAPT mutations were the first discovered genetic cause of frontotemporal dementia (FTD) in 1998. Since that time, over 60 MAPT mutations have been identified, usually causing behavioral variant FTD and/or parkinsonism clinically. We describe 2 novel MAPT mutations, D252V and G389&#95;I392del, each presenting in a patient with behavioral variant FTD and associated language and cognitive deficits. Neuroimaging revealed asymmetrical left greater than right temporal lobe atrophy in the first case, and bifrontal atrophy in the second case. Disease duration was 8 years and 5 years, respectively. Postmortem examination in both patients revealed a 3-repeat predominant tauopathy, similar in appearance to Pick's disease. These 2 mutations add to the literature on genetic FTD, both presenting with similar clinical and imaging features to previously described cases, and pathologically showing a primary tauopathy similar to a number of other MAPT mutations., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

The role of genetic variability in dementia with Lewy bodies (DLB) is now indisputable; however, data regarding copy number variation (CNV) in this disease has been lacking. Here, we used whole-genome genotyping of 1454 DLB cases and 1525 controls to assess copy number variability. We used 2 algorithms to confidently detect CNVs, performed a case-control association analysis, screened for candidate CNVs previously associated with DLB-related diseases, and performed a candidate gene approach to fully explore the data. We identified 5 CNV regions with a significant genome-wide association to DLB; 2 of these were only present in cases and absent from publicly available databases: one of the regions overlapped LAPTM4B, a known lysosomal protein, whereas the other overlapped the NME1 locus and SPAG9. We also identified DLB cases presenting rare CNVs in genes previously associated with DLB or related neurodegenerative diseases, such as SNCA, APP, and MAPT. To our knowledge, this is the first study reporting genome-wide CNVs in a large DLB cohort. These results provide preliminary evidence for the contribution of CNVs in DLB risk., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, cerebral autosomal dominant and recessive arteriopathy with subcortical infarcts and leukoencephalopathy, cerebroretinal vasculopathy, metachromatic leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids, and vanishing white matter disease present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer's disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis (1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10, and TAU) at 5 different developmental stages (embryo [E15], 2, 4, 8, and 18 months), (2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant-based and single-gene-based (c-alpha test and sequence kernel association test (SKAT)) genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (log2FC > 1, adj. p-value < 0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ dense-core plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H, and p.H703Y) in our discovery and validation cohort, composed of 465 AD and mild cognitive impairment (MCI) Caucasian patients from the United Kingdom. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-value = 0.01). Adult-onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R, and sporadic late-onset AD, which warrants further investigation., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Sporadic early-onset Alzheimer's disease (sEOAD) exhibits the symptoms of late-onset Alzheimer's disease but lacks the familial aspect of the early-onset familial form. The genetics of Alzheimer's disease (AD) identifies APOEε4 to be the greatest risk factor; however, it is a complex disease involving both environmental risk factors and multiple genetic loci. Polygenic risk scores (PRSs) accumulate the total risk of a phenotype in an individual based on variants present in their genome. We determined whether sEOAD cases had a higher PRS compared to controls. A cohort of sEOAD cases was genotyped on the NeuroX array, and PRSs were generated using PRSice. The target data set consisted of 408 sEOAD cases and 436 controls. The base data set was collated by the International Genomics of Alzheimer's Project consortium, with association data from 17,008 late-onset Alzheimer's disease cases and 37,154 controls, which can be used for identifying sEOAD cases due to having shared phenotype. PRSs were generated using all common single nucleotide polymorphisms between the base and target data set, PRS were also generated using only single nucleotide polymorphisms within a 500 kb region surrounding the APOE gene. Sex and number of APOE ε2 or ε4 alleles were used as variables for logistic regression and combined with PRS. The results show that PRS is higher on average in sEOAD cases than controls, although there is still overlap among the whole cohort. Predictive ability of identifying cases and controls using PRSice was calculated with 72.9% accuracy, greater than the APOE locus alone (65.2%). Predictive ability was further improved with logistic regression, identifying cases and controls with 75.5% accuracy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low-cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases., (Published by Elsevier Inc.)

Recent focus on the preparation of antimicrobial surfaces using cellulose nanofibers (CNF) has gained considerable attention. In this work, functionalization of CNF films in 100% aqueous solution with three different aminosilanes, including 3-aminopropyl trimethoxysilane (APMS), 2-aminoethyl 3-aminopropyl trimethoxysilane (DAMS)and 3-2-(2-aminoethylamino) ethylamino propyl-trimethoxysilane (TAMS) is reported for the fabrication of contact active antimicrobial materials. Grafted CNF films were comprehensively characterized by FTIR, TGA, contact angle, elemental analysis, solid-state 29 Si NMR, FEG-SEM and SEM-EDX. It was found that all the silanes were grafted on the surface of nanofibers without any change in the morphology or fibril structure through different grafting efficiency, depending on the aminoalkyl chain length. The effect of variable aminoalkyl length and initial grafting concentration was analyzed against gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli) by qualitative and quantitative standards. The most promising results were obtained with 3-2-(2-aminoethylamino) ethylamino propyl-trimethoxysilane at very low concentration which completely restrict bacterial growth after 24h with Gram-positive bacteria. This study, for the first time, established the relationship between the aminoalkyl chain length and its corresponding antibacterial activity., (Copyright © 2017 Elsevier B.V. All rights reserved.)

C9orf72 repeat expansions are a common cause of amyotrophic lateral sclerosis and frontotemporal dementia. To date, no large-scale study of dementia with Lewy bodies (DLB) has been undertaken to assess the role of C9orf72 repeat expansions in the disease. Here, we investigated the prevalence of C9orf72 repeat expansions in a large cohort of DLB cases and identified no pathogenic repeat expansions in neuropathologically or clinically defined cases, showing that C9orf72 repeat expansions are not causally associated with DLB., Competing Interests: statement Ronald C. Petersen reports consultancies with Roche, Inc, Merck, Inc, Genentech, Inc, Biogen, Inc, and Eli Lilly. Brad F. Boeve reports GE Healthcare, FORUM Pharmaceuticals, and C2N Diagnostics as research support and advisory board member of the Tau Consortium. The remaining authors report no competing interests., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We have screened sporadic early-onset Alzheimer's disease (sEOAD, n = 408) samples using the NeuroX array for known causative and predicted pathogenic variants in 16 genes linked to familial forms of neurodegeneration. We found 2 sEOAD individuals harboring a known causative variant in PARK2 known to cause early-onset Parkinson's disease; p.T240M (n = 1) and p.Q34fs delAG (n = 1). In addition, we identified 3 sEOAD individuals harboring a predicted pathogenic variant in MAPT (p.A469T), which has previously been associated with AD. It is currently unknown if these variants affect susceptibility to sEOAD, further studies would be needed to establish this. This work highlights the need to screen sEOAD individuals for variants that are more classically attributed to other forms of neurodegeneration., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Current investigations deal with new surface functionalization strategy of nanocrystalline cellulose-based substrates to impart active molecule release properties. In this study, cellulose nanocrystals (CNC) were surface-functionalized with β-cyclodextrin (β-CD) using succinic acid (SA) and fumaric acid (FA) as bridging agents. The main objective of this surface modification performed only in aqueous media was to obtain new active materials able to release antibacterial molecules over a prolonged period of time. The reactions were conducted by immersing the CNC film into a solution composed of β-CD, SA and FA, leading to CNC grafting. The materials were characterized by infrared spectroscopy (FT-IR), Quartz crystal microbalance-dissipation (QCM-D), AFM and phenolphthalein (PhP) was used to determine the efficiency of CNC grafting with β-CD. The results indicated that β-CD was successfully attached to the CNC backbone through the formation of ester bonds. Furthermore, carvacrol was entrapped by the attached β-CD and a prolonged release was confirmed. In particular, CNC grafted to β-CD in the presence of FA was selected as the best solution. The antibacterial activity and the controlled release were studied for this sample. Considerably longer bacterial activity against B. subtilis was observed for CNC grafted to β-CD compared to CNC and CNC-FA, confirming the promising impact of the present strategy., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In this study, a composite film based on TEMPO-oxidized cellulose nanofibers (TOCN), polyvinyl alcohol (PVA) and polypyrrole (PPy) was synthesized in situ by a chemical polymerization, resulting in the induced absorption of PPy on the surface of the TOCN. The composite films were investigated with scanning electron microscopy, thermogravimetric analysis, contact angle measurements, mechanical tests, and evaluation of antibacterial properties. The developed composite has nearly identical Young modulus (3.4GPa), elongation (2.6%) and tensile stress (about 51MPa) to TOCN even if PPy, which as poor properties by itself, was incorporated. From the energy-dispersive X-ray spectroscopy (EDX) results, it was shown that PPy is mainly located on the composite surface. Results confirmed by an increase from 54.5 to 83° in contact angle, an increased heat protection (Thermogravimetric analysis) and a decrease in surface energy. The nanocomposites were also evaluated for antibacterial activity against bacteria occasionally found in food: Gram-positive Bacillus subtilis (B. subtilis) and Gram-negative bacteria Escherichia coli (E. coli). The results indicate that the nanocomposites are effective against all of the bacteria studied as shown by the decrease of 5.2logcolonyformingunits (CFU) for B. subtilis and 6.5logCFU for E. coli. Resulting in the total destruction of the studied bacteria. The perfect match between the resulting inhibition zone and the composite surface area has demonstrated that our composite was contact active with a slight leaching of PPy. Our composite was successful as an active packaging on meat (liver) as bacteria were killed by contact, thereby preventing the spread of possible diseases. While it has not been tested on bacteria found in medicine, TOCN/PVA-PPy film may be able to act as an active sterile packaging for surgical instruments., (Copyright © 2016 Elsevier B.V. All rights reserved.)

A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1, DCC, ERBB4, KIT, MAPK2, MITF, PTEN, and TP53. The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer's disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyze the single independent and joint effect of rare and low-frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, and CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North-American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low-frequency coding variant (p.G215S, rs72973581, minor allele frequency = 4.3%) conferring a modest but statistically significant protection against AD (p-value = 0.024, odds ratio = 0.57, 95% confidence interval = 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provides new insights that should address functional studies., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

We have previously reported the whole genome genotyping analysis of 2 consanguineous siblings clinically diagnosed with early onset Alzheimer's disease (AD). In this analysis, we identified several large regions of homozygosity shared between both affected siblings, which we suggested could be candidate loci for a recessive genetic lesion underlying the early onset AD in these cases. We have now performed exome sequencing in one of these siblings and identified the potential cause of disease: the CTSF c.1243G>A:p.Gly415Arg mutation in homozygosity. Biallelic mutations in this gene have been shown to cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis with some cases resembling the impairment seen in AD., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Early-onset Alzheimer's disease (EOAD) can be familial (FAD) or sporadic EOAD (sEOAD); both have a disease onset ≤65 years of age. A total of 451 sEOAD samples were screened for known causative mutations in exons 16 and 17 of the amyloid precursor protein (APP) gene. Four samples were shown to be heterozygous for 1 of 3 known causative mutations: p.A713T, p.V717I, and p.V717G; this highlights the importance of screening EOAD patients for causative mutations. Additionally, we document an intronic 6 base pair (bp) deletion located 83 bp downstream of exon 17 (rs367709245, IVS17 83-88delAAGTAT), which has a nonsignificantly increased minor allele frequency in our sEOAD cohort (0.006) compared to LOAD (0.002) and controls (0.002). To assess the effect of the 6-bp deletion on splicing, COS-7 and BE(2)-C cells were transfected with a minigene vector encompassing exon 17. There was no change in splicing of exon 17 from constructs containing either wild type or deletion inserts. Sequencing of cDNA generated from cerebellum and temporal cortex of a patient harboring the deletion found no evidence of transcripts with exon 17 removed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Our objective was to design a genotyping platform that would allow rapid genetic characterization of samples in the context of genetic mutations and risk factors associated with common neurodegenerative diseases. The platform needed to be relatively affordable, rapid to deploy, and use a common and accessible technology. Central to this project, we wanted to make the content of the platform open to any investigator without restriction. In designing this array we prioritized a number of types of genetic variability for inclusion, such as known risk alleles, disease-causing mutations, putative risk alleles, and other functionally important variants. The array was primarily designed to allow rapid screening of samples for disease-causing mutations and large population studies of risk factors. Notably, an explicit aim was to make this array widely available to facilitate data sharing across and within diseases. The resulting array, NeuroX, is a remarkably cost and time effective solution for high-quality genotyping. NeuroX comprises a backbone of standard Illumina exome content of approximately 240,000 variants, and over 24,000 custom content variants focusing on neurologic diseases. Data are generated at approximately $50-$60 per sample using a 12-sample format chip and regular Infinium infrastructure; thus, genotyping is rapid and accessible to many investigators. Here, we describe the design of NeuroX, discuss the utility of NeuroX in the analyses of rare and common risk variants, and present quality control metrics and a brief primer for the analysis of NeuroX derived data., (Published by Elsevier Inc.)

The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raise the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Nanofibrillated cellulose (NFC) and their derivatives were prepared using three chemical surface modification strategies. All grafting was characterized by FTIR and contact angle measurements in order to evaluate the efficiency of grafting. Antibacterial activities of neat and grafted samples were investigated against two kinds of bacteria (i.e. Gram+ (Staphylococcus aureus) and Gram- (Klebsiella pneumoniae)). All the grafted samples displayed promising results with at least bacteriostatic effect or bactericidal properties. They also strongly enhanced the photo-catalytic antimicrobial effect of TiO2. This study proves that it is better to use grafted NFC either alone or for functionalization with TiO2 if anti-bacterial properties are desired. The cellulose backbone is known to be easily biodegradable in different biodegradation conditions and environments. The chemical surface modifications applied on NFC in the present work did not negatively influence this valuable property of cellulose but help for monitoring this property, which could be very useful for paper, packaging and composites., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Malaria is one of the world׳s most widespread parasitic diseases. The parasitic protozoans of the genus Plasmodium have developed resistance to several antimalarial drugs. Some patients are therefore infected by two or more strains with different levels of antimalarial drug sensitivity. We previously developed a model to estimate the drug concentration (IC50) that inhibits 50% of the growth of the parasite isolated from a patient infected with one strain. We propose here a new Two-Slopes model for patients infected by two strains. This model involves four parameters: the proportion of each strain and their IC50, and the sigmoidicity parameter. To estimate the parameters of this model, we have developed a new algorithm called PGBO (Population Genetics-Based Optimizer). It is based on the Metropolis-Hasting algorithm and is implemented in the statistical software R. We performed a simulation study and defined three evaluation criteria to evaluate its properties and compare it with three other algorithms (Gauss-Newton, Levenberg-Marquardt, and a simulated annealing). We also evaluated it using in vitro data and three ex vivo datasets from the French Malaria Reference Center. Our evaluation criteria in the simulation show that PGBO gives good estimates of the parameters even if the concentration design is poor. Moreover, our algorithm is less sensitive than Gauss-Newton algorithms to initial values. Although parameter estimation is good, interpretation of the results can be difficult if the proportion of the second strain is close to 0 or 1. For these reasons, this approach cannot yet be implemented routinely., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Early-onset Alzheimer's disease (EOAD) represents 1%-2% of the Alzheimer's disease (AD) cases, and it is generally characterized by a positive family history and a rapidly progressive symptomatology. Rare coding and fully penetrant variants in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the only causative mutations reported for autosomal dominant AD. Thus, in this study we used exome sequencing data to rapidly screen rare coding variability in APP, PSEN1, and PSEN2, in a British cohort composed of 47 unrelated EOAD cases and 179 elderly controls, neuropathologically proven. We report 2 novel and likely pathogenic variants in PSEN1 (p.L166V and p.S230R). A comprehensive catalog of rare pathogenic variants in the AD Mendelian genes is pivotal for a premortem diagnosis of autosomal dominant EOAD and for the differential diagnosis with other early onset dementias such as frontotemporal dementia (FTD) and Creutzfeldt-Jakob disease (CJD)., (Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.)

TREM2 mutations were first identified in Nasu-Hakola disease, a rare autosomal recessive disease characterized by recurrent fractures because of bone cysts and presenile dementia. Recently, homozygous and compound heterozygous TREM2 mutations were identified in rare families with frontotemporal lobar degeneration (FTLD) but without bone involvement. We identified a p.Thr66Met heterozygous mutation in a new consanguineous Italian family. Two sibs had early onset autosomal recessive FTLD without severe bone disorders. Atypical signs were present in this family: early parietal and hippocampus involvement, parkinsonism, epilepsy, and corpus callosum thickness on brain magnetic resonance imaging. This study further demonstrates the implication of TREM2 mutations in FTLD phenotypes. It illustrates the variability of bone phenotype and underlines the frequency of atypical signs in TREM2 carriers. This and previous studies evidence that TREM2 mutation screening should be limited to autosomal recessive FTLD with atypical phenotypes characterized by: (1) a very young age at onset (20-50 years); (2) early parietal and hippocampal deficits; (3) the presence of seizures and parkinsonism; (4) suggestive extensive white matter lesions and corpus callosum thickness on brain magnetic resonance imaging., (Copyright © 2014 Elsevier Inc. All rights reserved.)

This study aims to develop a high-performance delivery system using microfibrillated cellulose (MFC)-coated papers as a controlled release system combined with the well-known drug delivery agent, β-cyclodextrin (βCD). Chlorhexidine digluconate (CHX), an antibacterial molecule, was mixed with a suspension of MFC or a βCD solution or mixed with both the substances, before coating onto a cellulosic substrate. The intermittent diffusion of CHX (i.e., diffusion interrupted by the renewal of the release medium periodically) was conducted in an aqueous medium, and the release mechanism of CHX was elucidated by field emission gun-scanning electron microscopy, SEM, NMR, and Fourier transform infrared analyses. According to the literature, both βCD and MFC are efficient controlled delivery systems. This study indicated that βCD releases CHX more gradually and over a longer period of time compared to MFC, which is mainly due to the ability of βCD to form an inclusion complex with CHX. Furthermore from the release study, a complementary action when the two compounds were combined was deduced. MFC mainly affected the burst effect, while βCD primarily controlled the amount of CHX released over time. In this paper, two different types of controlled release systems are proposed and compared. Depending on the final application, the use of βCD alone would release low amounts of active molecules over time (slow delivery), whereas the combination of β-cyclodextrin and MFC would be more suitable for the release of higher amounts of active molecules over time (rapid delivery)., (Copyright © 2014 Elsevier B.V. All rights reserved.)

TREM and TREM-like receptors are a structurally similar protein family encoded by genes clustered on chromosome 6p21.11. Recent studies have identified a rare coding variant (p.R47H) in TREM2 that confers a high risk for Alzheimer's disease (AD). In addition, common single nucleotide polymorphisms in this genomic region are associated with cerebrospinal fluid biomarkers for AD and a common intergenic variant found near the TREML2 gene has been identified to be protective for AD. However, little is known about the functional variant underlying the latter association or its relationship with the p.R47H. Here, we report comprehensive analyses using whole-exome sequencing data, cerebrospinal fluid biomarker analyses, meta-analyses (16,254 cases and 20,052 controls) and cell-based functional studies to support the role of the TREML2 coding missense variant p.S144G (rs3747742) as a potential driver of the meta-analysis AD-associated genome-wide association studies signal. Additionally, we demonstrate that the protective role of TREML2 in AD is independent of the role of TREM2 gene as a risk factor for AD., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) have been shown to be a powerful approach to identify risk loci for neurodegenerative diseases. Recent GWAS in Parkinson's disease (PD) have been successful in identifying numerous risk variants pointing to novel pathways potentially implicated in the pathogenesis of PD. Contributing to these GWAS efforts, we performed genotyping of previously identified risk alleles in PD patients and control subjects from Greece. We showed that previously published risk profiles for Northern European and American populations are also applicable to the Greek population. In addition, although our study was largely underpowered to detect individual associations, we replicated 5 of 32 previously published risk variants with nominal p values <0.05. Genome-wide complex trait analysis revealed that known risk loci explain disease risk in 1.27% of Greek PD patients. Collectively, these results indicate that there is likely a substantial genetic component to PD in Greece, similarly to other worldwide populations, that remains to be discovered., (Published by Elsevier Inc.)

Rare variants in TREM2 cause susceptibility to late-onset Alzheimer's disease. Here we use microarray-based expression data generated from 101 neuropathologically normal individuals and covering 10 brain regions, including the hippocampus, to understand TREM2 biology in human brain. Using network analysis, we detect a highly preserved TREM2-containing module in human brain, show that it relates to microglia, and demonstrate that TREM2 is a hub gene in 5 brain regions, including the hippocampus, suggesting that it can drive module function. Using enrichment analysis we show significant overrepresentation of genes implicated in the adaptive and innate immune system. Inspection of genes with the highest connectivity to TREM2 suggests that it plays a key role in mediating changes in the microglial cytoskeleton necessary not only for phagocytosis, but also migration. Most importantly, we show that the TREM2-containing module is significantly enriched for genes genetically implicated in Alzheimer's disease, multiple sclerosis, and motor neuron disease, implying that these diseases share common pathways centered on microglia and that among the genes identified are possible new disease-relevant genes., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Recently 2 groups have independently identified a mutation in the gene 'vacuolar protein sorting 35 homolog' (VPS35 c.1858G>A; p.Asp620Asn) as a possible cause of autosomal dominant Parkinson's disease (PD). In order to assess the frequency of the reported mutation and to search for other possible disease-causing variants in this gene, we sequenced all 17 exons of VPS35 in 96 familial PD cases, and exon 15 (in which the reported mutation is found) in an additional 64 familial PD cases, 175 young-onset PD cases, and 262 sporadic, neuropathologically confirmed PD cases. We identified 1 individual with the p.Asp620Asn mutation and an autosomal dominant family history of PD. Subsequent follow-up of the family confirmed an affected sibling and cousin who also carried the same mutation. No other potentially disease-causing mutations were identified. We conclude that the VPS35 c.1858G>A mutation is an uncommon cause of familial Parkinson's disease in our population., (Copyright © 2012 Elsevier Inc. All rights reserved.)

In neuroblastoma (NB) patients, minimal residual disease (MRD) can be detected by real-time quantitative PCR (qPCR) using NB-specific target genes, such as PHOX2B and TH. However, it is unknown whether the mRNA levels of these targets vary either during treatment or at relapse. If marker genes are not stably expressed, estimation of MRD levels in bone marrow (BM) or peripheral blood will be hampered. We studied the stability of a panel of qPCR markers in primary tumors at diagnosis compared with i) paired metastasis (n = 7), ii) treated (n = 10), and iii) relapse (n = 6) tumors. We also compared relative expression of the targets in iv) primary tumors and BM at diagnosis (n = 17), v) BM and peripheral blood at diagnosis (n = 20), vi) BM at diagnosis and during treatment (n = 26), and vii) BM from different puncture sides (n = 110). Especially at diagnosis, PCR target expression is quite stable. Accurate quantification is possible when expression level can be related to the primary tumor; however, PCR target expression can alter on treatment and at relapse. If the median value of relative expression of a panel of PCR targets is used, most variations due to treatment and outgrowth of subclones level out, allowing for reliable application and quantification of MRD-PCR targets in NB patients., (Copyright © 2012 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: To identify independent risk factors of severe falciparum malaria among travelers to endemic regions., Materials and Methods: A retrospective study on imported malaria into metropolitan France. The World's Health Organization severity criteria were used to classify malarial episodes., Results: Nine hundred and twenty-one malarial cases were studied; 81 were severe. Independent risk factors of severe malaria were aged above 40 years, high level of parasitized erythrocytes (more than 4%), parasite acquisition in the south-eastern asian region, infection with a chloroquine resistant Plasmodium falciparum (P. falciparum) phenotype and a self administered antimalarial treatment., Conclusion: This study points out two particularly interesting results: severe malaria is significantly associated with the infection by a chloroquine resistant P. falciparum phenotype and with the parasite's acquisition in the south-eastern asian region., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Xylan has been used as a raw material in the synthesis of butyl, octyl and decyl glycosides. Mixtures of D-xylose-, L-arabinose- and D-glucose-based surfactants were obtained under smooth conditions with high yields in a one-pot process. The surface activities of octyl and decyl glycosides thus obtained have been studied and compared with that of pure alkyl D-xylosides. The results have confirmed that the new synthetic approach described in this paper is a potentially economical and efficient method for the preparation of environmentally friendly surfactants., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Wilms tumor is the most common pediatric renal neoplasm, but few molecular prognostic markers have been identified for this tumor. Somatic deletion in the long arm of chromosome 16 (16q) is known to predict a less favorable outcome in Wilms tumor, but the underlying molecular mechanisms are not known. We show that 16q deletions are typically confined to immature anaplastic-blastic tumor elements, while deletions are absent in maturing tumor components. The smallest region of deletion overlap mapped to a 1.8-Mb segment containing the IRXB gene cluster including IRX3, IRX5, and IRX6, of which IRX3 is a recently identified regulator of tubular maturation during nephrogenesis. Tumors with 16q deletion showed a lower overall mRNA expression of IRXB genes, and 16q-deleted tumor cells failed to express IRX3 while it was expressed in differentiating tubular tumor elements with intact 16q. Consistent with a role for IRX3 in tubular differentiation, gene sets linked to Notch signaling, Rho signaling, and ion channel activity were enriched in tumors with high IRX3 expression, while WTs with low expression were enriched for gene sets linked to cell cycle progression. Low mRNA levels of IRXB genes were associated with diffuse anaplasia, high-stage disease, and death. A disturbed balance between tubular differentiation and self-renewal of anaplastic-blastic elements may thus be one mechanism linking 16q deletion to adverse outcome in Wilms tumor.

Mutations in the gene encoding beta-glucocerebrosidase, a lysosomal degrading enzyme, have recently been associated with the development of Parkinson disease. Here we report the results found in a cohort of Portuguese Parkinson disease patients and healthy age-matched controls for mutations in the aforementioned gene. This screening was accomplished by sequencing the complete open-reading frame, as well as intron/exon boundaries, of the glucocerebrosidase gene, in a total of 230 patients and 430 controls. We have found an increased number of Parkinson disease patients presenting mutations in GBA when compared to controls. These results, together with recent literature, clearly suggest a role of glucocerebrosidase in the development of Parkinson disease.

Unlabelled: Only few drugs for uncomplicated Plasmodium falciparum malaria are available in children. Atovaquone-proguanil is a recent antimalarial drug licensed in France for the uncomplicated P. falciparum malaria in adults. Few paediatric studies have evaluated atovaquone-proguanil in children for uncomplicated malaria in endemic area, but no study have evaluated this treatment for imported malaria., Objective: To evaluate treatment by atovaquone-proguanil for uncomplicated and imported P. falciparum malaria in children., Methods: We retrospectively evaluated the tolerance and the efficacy of atovaquone-proguanil in the children admitted in Robert-Debré Hospital (Paris) for a P. falciparum malaria. From January 2004 to December 2005, 48 children with a median age of 7,5 years (IQR 4-11) were treated with atovaquone-proguanil for a uncomplicated P. falciparum malaria, except for 5 children who had an isolated hyperparasitemia greater or equal to 5%., Results: Atovaquone-proguanil was stopped for 3/48 children because of vomiting. Fever resolved in all the children between Day 3 and 7, following the beginning of the treatment. One child, with a favourable outcome, had a positive parasitemia at Day 4 equal to the initial parasitemia (0,1%). No late therapeutic failure was observed among the 24 children evaluated up to one month after starting treatment., Conclusion: Atovaquone-proguanil is an efficient and well-tolerated antimalarial treatment for uncomplicated P. falciparum malaria in children. The risk of vomiting should lead to a systematic initial hospitalisation of children treated with atovaquone-proguanil.

Plasmodium falciparum resistance to atovaquone-proguanil has so far been associated with Y268S or Y268N mutations in cytochrome b, although these changes were identified in only seven of the 11 treatment failures. Here, we describe 10 new cases of atovaquone-proguanil treatment failures among which the parasite resistance was confirmed in six cases, either by identifying correct plasma drug concentrations or by observing in vitro atovaquone resistance. Resistance was consistently associated with codon 268 mutations (Y268S or a previously unidentified mutation, Y268C). Notably, mutations were not detected before the treatment but only after the drug exposure.

Drug resistant malaria is mostly due to Plasmodium falciparum, the highly prevalent species in tropical Africa, Amazon, and Southeast Asia. P. falciparum is responsible for severe involvement of fever or anemia causing more than a million deaths per year. Rationale for treatment is becoming weak as multiple drug resistance against well-tolerated drugs develops. P. falciparum drug resistant malaria originates from chromosomal mutations. Analyses using molecular, genetic and biochemical approaches showed that: 1) impaired uptake of chloroquine by the parasite vacuole is a common characteristic of resistant strains, this phenotype correlates with pfmdr1 and pfcrt gene mutations; 2) one S108N to four (N51I, C59R, I164L) point mutations of dihydrofolate reductase, the enzyme target of antifolinics (pyrimethamine and proguanil), give moderate to high level of resistance to these drugs; 3) resistance to sulfonamides and sulfones involves mutations of dihydropteroate synthase (A437G, K540E), their enzyme target, impairing their capacity to potentiate antifolinic drugs; 4) resistance to atovaquone plus proguanil involves one single mutation on atovaquone target, cytochrome b (Y268S, C or N); 5) resistance to mefloquine is thought to be linked to the over expression of pfmdr1, a pump expelling toxic waste from eukaryotic cells. P. falciparum resistance levels may differ according to places and time, depending on malaria transmission and drug pressure. Coupling in vivo to in vitro tests, and using molecular tests is essential for the surveillance of replacement drugs. Low cost biochemical tools are urgently needed for a prospective monitoring of resistance.

Objective: The feasibility of carotid stenting (CS) is no longer questionable, although its indications remain debatable. Until the results of randomized trials are available, personal series and registries should help in the comparison of long-term results of CS with those of endarterectomy. We report here the long-term results of a large series of CS in our department with a long follow-up. This retrospective study reviews a single surgeon's 11-year experience with CS. Our results are compared with those of conventional surgery emanating from our own series and the North American Symptomatic Carotid Endarterectomy Trial (NASCET), European Carotid Surgery Trial (ECST), and Asymptomatic Carotid Atherosclerosis Study (ACAS)., Materials and Methods: CS has been performed in our department in a single, semi-private institution for 12 years. Patients with high lesions, and postradiotherapy and postendarterectomy stenoses were treated with CS, as were patients at high risk for surgery. The others were operated on with conventional endarterectomy. During the study, we performed 221 CS procedures on 193 patients (150 men and 43 women). The average follow-up was 2.7 years (1 month to 9.3 years). We analyzed the late results in terms of prevention from stroke, the freedom from new neurologic events, and also patency rates of the treated carotid vessels. We also identified predictors for neurologic complication and in-stent restenosis by using univariate analysis., Results: Life-table analyses at 10 years gave a 96% (confidence interval [CI] = 3%) rate for stroke freedom, a 98% (CI = 2%) rate for fatal stroke freedom, and a primary assisted patency rate of 95% (CI = 3%). Predictors for neurologic complication were [corrected] age >70 ( P = .041), and [corrected] potential renal insufficiency ( P = .056 [corrected] In-stent restenosis occurrence extended from 2 months to 4.5 years after the procedure. The restenosis rates at 6 months, 1, 2, and 4.5 years were, respectively, 1.4%, 2.3%, 3.7%, and 5.9% (13/221). No factors were found to be strong predictors of in-stent restenosis [corrected], Conclusion: These long-term results show that CS is competitive with conventional surgery. A more accurate selection for CS or surgery might reduce the rate of complications after carotid stenosis repair.

The purpose of this study is to provide an overview of cases of Carney's triad and to discuss the clinical implications of this diagnosis. A search was made of the English-language literature for original articles, reviews and abstracts addressing Carney's triad. A new patient was described and added to the number of known patients. In literature 40 patients were found with a complete or incomplete triad. There exists no agreement on the pathology and possible common origin of these tumours. Directions are given for diagnostics and therapy. The diagnosis of Carney's triad has specific clinical implications that make a good knowledge of this syndrome mandatory.