The Alzheimer's disease risk gene CD2AP functions in dendritic spines by remodeling F-actin.

CD2AP was identified as a genetic risk factor for late-onset Alzheimer's disease (LOAD). However, it is unclear how CD2AP contributes to LOAD synaptic dysfunction underlying AD memory deficits. We have shown that loss of CD2AP function increases ß-amyloid (Aß) endocytic production, but it is unknown whether it contributes to synapse dysfunction. As CD2AP is an actin-binding protein, it may also function in F-actin-rich dendritic spines, which are the excitatory postsynaptic compartments. Here, we demonstrate that CD2AP colocalizes with F-actin in dendritic spines of primary mouse cortical neurons of both sexes. Cell-autonomous depletion of CD2AP specifically reduces spine density and volume, resulting in a functional decrease in synapse formation and neuronal network activity. Post-synaptic reexpression of CD2AP, but not blocking Aß-production, is sufficient to rescue spine density. CD2AP overexpression increases spine density, volume, and synapse formation, while a rare LOAD CD2AP mutation induces aberrant F-actin spine-like protrusions without functional synapses. CD2AP controls postsynaptic actin turnover, with the LOAD mutation in CD2AP decreasing F-actin dynamicity. Our data support that CD2AP risk variants could contribute to LOAD synapse dysfunction by disrupting spine formation and growth by deregulating actin dynamics.Significance statement CD2AP is a candidate genetic risk factor of late-onset Alzheimer's disease (LOAD) expressed in neurons with an unknown impact on synapse dysfunction, one of the causal LOAD mechanisms. Our research has revealed CD2AP as a new synaptic protein and established a connection between a LOAD genetic variant in CD2AP and synaptic dysfunction independent of beta-amyloid accumulation. This study suggests an explanation for the CD2AP-mediated predisposition to AD. Furthermore, we have found that controlling CD2AP's impact on spinal F-actin could be a potential target for therapeutic intervention against LOAD.

Cell autonomous microglia defects in a stem cell model of frontotemporal dementia.

Neuronal dysfunction has been extensively studied as a central feature of neurodegenerative tauopathies. However, across neurodegenerative diseases, there is strong evidence for active involvement of immune cells like microglia in driving disease pathophysiology. Here, we demonstrate that tau mRNA and protein are expressed in microglia in human brains and in human induced pluripotent stem cell (iPSC)-derived microglia like cells (iMGLs). Using iMGLs harboring the MAPT IVS10+16 mutation and isogenic controls, we demonstrate that a tau mutation is sufficient to alter microglial transcriptional states. We discovered that MAPT IVS10+16 microglia exhibit cytoskeletal abnormalities, stalled phagocytosis, disrupted TREM2/TYROBP networks, and altered metabolism. Additionally, we found that secretory factors from MAPT IVS10+16 iMGLs impact neuronal health, reducing synaptic density in neurons. Key features observed in vitro were recapitulated in human brain tissue and cerebrospinal fluid from MAPT mutations carriers. Together, our findings that MAPT IVS10+16 drives cell-intrinsic dysfunction in microglia that impacts neuronal health has major implications for development of therapeutic strategies.

Defects in lysosomal function and lipid metabolism in human microglia harboring a TREM2 loss of function mutation.

TREM2 is an innate immune receptor expressed by microglia in the adult brain. Genetic variation in the TREM2 gene has been implicated in risk for Alzheimer's disease and frontotemporal dementia, while homozygous TREM2 mutations cause a rare leukodystrophy, Nasu-Hakola disease (NHD). Despite extensive investigation, the role of TREM2 in NHD pathogenesis remains poorly understood. Here, we investigate the mechanisms by which a homozygous stop-gain TREM2 mutation (p.Q33X) contributes to NHD. Induced pluripotent stem cell (iPSC)-derived microglia (iMGLs) were generated from two NHD families: three homozygous TREM2 p.Q33X mutation carriers (termed NHD), two heterozygous mutation carriers, one related non-carrier, and two unrelated non-carriers. Transcriptomic and biochemical analyses revealed that iMGLs from NHD patients exhibited lysosomal dysfunction, downregulation of cholesterol genes, and reduced lipid droplets compared to controls. Also, NHD iMGLs displayed defective activation and HLA antigen presentation. This defective activation and lipid droplet content were restored by enhancing lysosomal biogenesis through mTOR-dependent and independent pathways. Alteration in lysosomal gene expression, such as decreased expression of genes implicated in lysosomal acidification (ATP6AP2) and chaperone mediated autophagy (LAMP2), together with reduction in lipid droplets were also observed in post-mortem brain tissues from NHD patients, thus closely recapitulating in vivo the phenotype observed in iMGLs in vitro. Our study provides the first cellular and molecular evidence that the TREM2 p.Q33X mutation in microglia leads to defects in lysosomal function and that compounds targeting lysosomal biogenesis restore a number of NHD microglial defects. A better understanding of how microglial lipid metabolism and lysosomal machinery are altered in NHD and how these defects impact microglia activation may provide new insights into mechanisms underlying NHD and other neurodegenerative diseases.

Enhancing the efficiency and stability of perovskite solar cells based on moisture-resistant dopant free hole transport materials by using a 2D-BA2PbI4 interfacial layer.

In this work, the photovoltaic performance and stability of perovskite solar cells (PSCs) based on a dopant-free hole transport layer (HTL) are efficiently improved by inserting a two-dimensional (2D) interfacial layer. The benzyl ammonium lead iodide (BA2PbI4) 2D perovskite is used as an interfacial layer between the 3D CH3NH3PbI3 perovskite and two moisture-resistant dopant-free HTLs including poly[[2,3-bis(3-octyloxyphenyl)-5,8-quinoxalinediyl]-2,5-thiophenediyl] (TQ1) and poly(3-hexylthiophene) (P3HT). TQ1 with a facile synthesis procedure has a higher moisture resistivity compared to P3HT which can improve the stability of PSCs. The 2D BA2PbI4 perovskite with a less-volatile bulkier organic cation efficiently passivates the defects at the perovskite/HTL interface, leading to 11.95% and 15.04% efficiency for the modified TQ1 and P3HT based cells, respectively. For a better understanding, the structural, optical, and electrical properties of PSCs comprising P3HT and TQ1 HTLs with and without interface modification are studied. The interface modified PSCs show slower open-circuit voltage decay and longer carrier lifetimes compared to unmodified cells. In addition, impedance spectroscopy reveals lower charge transport resistance and higher recombination resistance for the modified devices, which could be associated with the modification of the interface between the 3D CH3NH3PbI3 perovskite and HTL caused by the 2D interfacial layer. Also after aging under ambient conditions for about 800 hours, the modified PCSs retain more than 80% of their initial PCEs. These results give us the hope of achieving simpler, cheaper, and more stable PSCs with dopant-free HTLs through 2D interfacial layers, which have great potential for commercialization.

An overview of filtration efficiency through the masks: Mechanisms of the aerosols penetration.

The masks have always been mentioned as an effective tool against environmental threats. They are considered as protective equipment to preserve the respiratory system against the non-desirable air droplets and aerosols such as the viral or pollution particles. The aerosols can be pollution existence in the air, or the infectious airborne viruses initiated from the sneezing, coughing of the infected people. The filtration efficiency of the different masks against these aerosols are not the same, as the particles have different sizes, shapes, and properties. Therefore, the challenge is to fabricate the filtration masks with higher efficiency to decrease the penetration percentage at the nastiest conditions. To achieve this concept, knowledge about the mechanisms of the penetration of the aerosols through the masks at different effective environmental conditions is necessary. In this paper, the literature about the different kinds of face masks and respiratory masks, common cases of their application, and the advantages and disadvantages of them in this regard have been reviewed. Moreover, the related mechanisms of the penetration of the aerosols through the masks are discussed. The environmental conditions affecting the penetration as well as the quality of the fabrication are studied. Finally, special attention was given to the numerical simulation related to the different existing mechanisms.

Abundance and distribution of beach litter with acutely toxic metal concentrations.

We determined if colour, category (e.g., food packaging) or intertidal activity could explain the occurrence of litter with acute levels of metals. Six beaches were sampled; an industrial site, a local and remote park and three beaches. Food packaging accounted for 66% of litter with acute levels of metals found in 10% of samples. Acute levels were independent of colour and category, but dependent on intertidal region and its anthropogenic use. Litter with acute levels of cadmium and lead were recovered from the industrial intertidal and high concentrations of zinc and cadmium associated with candy wrappers were found on recreational beaches. In addition to the intrinsic and extrinsic loads that litter carries, also too are memory effects, i.e., the previous use of the item carries over its trace metal burden posing extreme risks to marine ecosystems. In the managing of risk associated with beach litter, legacy contaminants need be considered.

Intracellular Trafficking Mechanisms of Synaptic Dysfunction in Alzheimer's Disease.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by progressive memory loss. Although AD neuropathological hallmarks are extracellular amyloid plaques and intracellular tau tangles, the best correlate of disease progression is synapse loss. What causes synapse loss has been the focus of several researchers in the AD field. Synapses become dysfunctional before plaques and tangles form. Studies based on early-onset familial AD (eFAD) models have supported that synaptic transmission is depressed by ß-amyloid (Aß) triggered mechanisms. Since eFAD is rare, affecting only 1% of patients, research has shifted to the study of the most common late-onset AD (LOAD). Intracellular trafficking has emerged as one of the pathways of LOAD genes. Few studies have assessed the impact of trafficking LOAD genes on synapse dysfunction. Since endocytic traffic is essential for synaptic function, we reviewed Aß-dependent and independent mechanisms of the earliest synaptic dysfunction in AD. We have focused on the role of intraneuronal and secreted Aß oligomers, highlighting the dysfunction of endocytic trafficking as an Aß-dependent mechanism of synapse dysfunction in AD. Here, we reviewed the LOAD trafficking genes APOE4, ABCA7, BIN1, CD2AP, PICALM, EPH1A, and SORL1, for which there is a synaptic link. We conclude that in eFAD and LOAD, the earliest synaptic dysfunctions are characterized by disruptions of the presynaptic vesicle exo- and endocytosis and of postsynaptic glutamate receptor endocytosis. While in eFAD synapse dysfunction seems to be triggered by Aß, in LOAD, there might be a direct synaptic disruption by LOAD trafficking genes. To identify promising therapeutic targets and biomarkers of the earliest synaptic dysfunction in AD, it will be necessary to join efforts in further dissecting the mechanisms used by Aß and by LOAD genes to disrupt synapses.

Understanding the global hydrological droughts of 2003-2016 and their relationships with teleconnections.

Droughts often evolve gradually and cover large areas, and therefore, affect many people and activities. This motivates developing techniques to integrate different satellite observations, to cover large areas, and understand spatial and temporal variability of droughts. In this study, we apply probabilistic techniques to generate satellite derived meteorological, hydrological, and hydro-meteorological drought indices for the world's 156 major river basins covering 2003-2016. The data includes Terrestrial Water Storage (TWS) estimates from the Gravity Recovery And Climate Experiment (GRACE) mission, along with soil moisture, precipitation, and evapotranspiration reanalysis. Different drought characteristics of trends, occurrences, areal-extent, and frequencies corresponding to 3-, 6-, 12-, and 24-month timescales are extracted from these indices. Drought evolution within selected basins of Africa, America, and Asia is interpreted. Canonical Correlation Analysis (CCA) is then applied to find the relationship between global hydro-meteorological droughts and satellite derived Sea Surface Temperature (SST) changes. This relationship is then used to extract regions, where droughts and teleconnections are strongly interrelated. Our numerical results indicate that the 3- to 6-month hydrological droughts occur more frequently than the other timescales. Longer memory of water storage changes (than water fluxes) has found to be the reason of detecting extended hydrological droughts in regions such as the Middle East and Northern Africa. Through CCA, we show that the El Niño Southern Oscillation (ENSO) has major impact on the magnitude and evolution of hydrological droughts in regions such as the northern parts of Asia and most parts of the Australian continent between 2006 and 2011, as well as droughts in the Amazon basin, South Asia, and North Africa between 2010 and 2012. The Indian ocean Dipole (IOD) and North Atlantic Oscillation (NAO) are found to have regional influence on the evolution of hydrological droughts.

A non-invasive methodology for ATAA rupture risk estimation.

Ascending thoracic aortic aneurysms (ATAA) are a life-threatening pathology provoking an irreversible dilation with a high associated risk of aortic rupture or dissection and death of the patient. Rupture or dissection of ATAAs remains unpredictable and has been documented to occur at diameters less than 4.5 cm for nearly 60% of patients. Other factors than the aneurysm diameter may highly affect the predisposition to rupture. In order to have a better insight in rupture risk prediction, a bulge inflation bench was developed to test ATAAs samples collected on patients during surgical interventions. Preoperative dynamic CT scans on a cohort of 13 patients were analyzed to estimate volumetric and cross-sectional distensibility. A failure criteria based on in vitro ultimate stretch showed a significant correlation with the aortic membrane stiffness deduced from in vivo distensibility. These results reinforce the significance of stretch-based rupture criteria and their possible non-invasive prediction in clinical practice.

Effect of two different concentrations of sodium hypochlorite on postoperative pain following single-visit root canal treatment: a triple-blind randomized clinical trial.

AIM: To compare the effects of two different concentrations of NaOCl solution on postoperative pain following single-visit root canal treatment in mandibular molars with irreversible pulpitis. METHODOLOGY: A total of 122 patients who had mandibular molars with irreversible pulpitis were treated. The patients were randomly divided into two groups according to the concentration of NaOCl used during root canal instrumentation - either 2.5% or 5.25%. RaCe rotary instruments were used for root canal preparation, and all root canals were filled in one visit. Postoperative pain was evaluated using the visual analogue scale. Data were analysed by independent t-test, chi-square and Mann-Whitney tests. RESULTS: Twelve patients were excluded for various reasons. Pain reported by 110 patients who were eligible to be included in the study was analysed. No significant differences were found in the age and gender of the patients between the two groups (P = 0.50, P = 0.51, respectively). The patients who had 5.25% NaOCl reported significantly lower postoperative pain compared to those who had 2.5% NaOCl during the first 72 h following treatment (P = 0.021); however, there was no significant difference in pain felt by the patients during the rest of the study period, that is 4-7 days following treatment (P = 0.185) when the four-level pain categorization method was used. When the two-level pain categorization method was used, the results revealed that patients who had 5.25% NaOCl reported significantly less pain for the first 3 days after treatment (P = 0.026). The number of analgesics taken by patients who had 2.5% NaOCl was significantly higher than that taken by patients who had 5.25% NaOCl (P = 0.001). CONCLUSION: 5.25% NaOCl was associated with significantly lower postoperative pain compared to 2.5% NaOCl during the first 72 h following one-visit root canal treatment of mandibular molars with irreversible pulpitis.

Modeling human target reaching with an adaptive observer implemented with dynamic neural fields.

Humans can point fairly accurately to memorized states when closing their eyes despite slow or even missing sensory feedback. It is also common that the arm dynamics changes during development or from injuries. We propose a biologically motivated implementation of an arm controller that includes an adaptive observer. Our implementation is based on the neural field framework, and we show how a path integration mechanism can be trained from few examples. Our results illustrate successful generalization of path integration with a dynamic neural field by which the robotic arm can move in arbitrary directions and velocities. Also, by adapting the strength of the motor effect the observer implicitly learns to compensate an image acquisition delay in the sensory system. Our dynamic implementation of an observer successfully guides the arm toward the target in the dark, and the model produces movements with a bell-shaped velocity profile, consistent with human behavior data.

Multi-scale finite element model of growth plate damage during the development of slipped capital femoral epiphysis.

Slipped capital femoral epiphysis (SCFE) is one of the most common disorders of adolescent hips. A number of works have related the development of SCFE to mechanical factors. Due to the difficulty of diagnosing SCFE in its early stages, the disorder often progresses over time, resulting in serious side effects. Therefore, the development of a tool to predict the initiation of damage in the growth plate is needed. Because the growth plate is a heterogeneous structure, to develop a precise and reliable model, it is necessary to consider this structure from both macro- and microscale perspectives. Thus, the main objective of this work is to develop a numerical multi-scale model that links damage occurring at the microscale to damage occurring at the macroscale. The use of this model enables us to predict which regions of the growth plate are at high risk of damage. First, we have independently analyzed the microscale to simulate the microstructure under shear and tensile tests to calibrate the damage model. Second, we have employed the model to simulate damage occurring in standardized healthy and affected femurs during the heel-strike stage of stair climbing. Our results indicate that on the macroscale, damage is concentrated in the medial region of the growth plate in both healthy and affected femurs. Furthermore, damage to the affected femur is greater than damage to the healthy femur from both the micro- and macrostandpoints. Maximal damage is observed in territorial matrices. Furthermore, simulations illustrate that little damage occurs in the reserve zone. These findings are consistent with previous findings reported in well-known experimental works.

Is physical activity a potential preventive factor for vascular dementia? A systematic review.

BACKGROUND: Physical exercise has several beneficial effects, including reduced risk for Alzheimer's disease. Although several studies of potential risk factors for vascular dementia (VaD) exist, including physical activity, the studies have usually included few participants and there are no meta-analyses addressing this key topic. METHODS: The MEDLINE database was searched using the key words 'physical exercise' 'activity' or 'walking' in combination with 'dementia' and 'vascular dementia'. Potentially relevant studies were assessed and summarised by two of the authors, and longitudinal studies with operationalized definition of physical activity providing risk for VaD in both groups were included in the meta-analysis using pooled estimates from a random effects model. RESULTS: A total of 24 longitudinal studies, including 1378 patients with VaD, were included in the review. The majority of individual studies did not report significant associations. Five studies fulfilled criteria for meta-analysis, including 10,108 non-demented control subjects and 374 individuals with VaD. The meta-analysis demonstrated a significant association between physical exercise and a reduced risk of developing VaD: OR 0.62 (95% CI 0.42-0.92). CONCLUSIONS: We conclude that there is evidence supporting the hypothesis that physical activity is likely to prevent the development of VaD, and should be highlighted as part of secondary prevention programmes in people at risk for cerebrovascular disease.

Clinical inhibitor-resistant mutants of the beta-lactamase TEM-1 at amino-acid position 69. Kinetic analysis and molecular modelling.

The kinetic parameters of three IRT (Inhibitor-Resistant-TEM-derived-) beta-lactamases (IRT-5, IRT-6 and IRT-I69) were determined for substrates and the beta-lactamase inhibitors: clavulanic acid, sulbactam and tazobactam, and compared with those of TEM-1 beta-lactamase. The catalytic behaviour of the beta-lactamases towards substrates and inhibitors was correlated with the properties of the amino acid at position ABL69. The three IRT beta-lactamases contain at that position a residue Ile, Leu and Val, amino acids whose side-chain are branched. Molecular modelling shows that the methyl groups of Ile-69 (C gamma 2) and Val-69 (C gamma 1) produced steric constraints with the side chain of Asn-170 as well as the main chain nitrogen of Ser-70, a residue contributing to the oxyanion hole. We suggest that hydrophobicity could be the main factor responsible for the kinetic properties of Met69Leu (IRT-5), as no steric effects could be detected by molecular modelling. Hydrophobicity and steric constraints are combined in Met69Ile and Met69Val, IRT-I69 and IRT-6, respectively.

Characterization and amino acid sequence analysis of a new oxyimino cephalosporin-hydrolyzing class A beta-lactamase from Serratia fonticola CUV.

Serratia fonticola CUV produces two isoenzymes (forms I and II) with beta-lactamase activity which were purified by a five-step procedure. The isoenzymes had identical kinetic parameters and isoelectric point (pI = 8.12). They were characterized by a specific activity towards benzylpenicillin of 1650 U/mg. The beta-lactamase hydrolyzed benzylpenicillin, amoxycillin, ureidopenicillins, first- and second-generation cephalosporins. Carboxypenicillins and isoxazolylpenicillins were hydrolyzed to a lesser extent. Towards cefotaxime and ceftriaxone (third-generation cephalosporins), the S. fonticola enzyme exhibited catalytic efficiencies much higher than those of MEN-1 and extended-spectrum TEM derivative beta-lactamases. The beta-lactamase from S. fonticola was markedly inhibited by beta-lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam. The purified isoenzymes were digested by trypsin, endoproteinase Asp-N and chymotrypsin. Amino acid sequence determinations of the resulting peptides allowed the alignment of 267 amino acid residues (Swiss-Prot, accession number P 80545) for form I beta-lactamase. Form II is five residues shorter than form I at its N-terminus. From amino acid sequence comparisons, S. fonticola CUV beta-lactamase was found to share more than 69.3% identity with the chromosomally encoded beta-lactamases of Klebsiella oxytoca, Proteus vulgaris, Citrobacter diversus and the plasmid-mediated enzymes MEN-1 and Toho-1. Therefore, the oxyimino cephalosporin-hydrolyzing beta-lactamase of S. fonticola belongs to Ambler's class A. Contribution of the serine at ABL 237 in the broad-spectrum activity of these beta-lactamases is discussed.

Characterization and amino acid sequence of the OXY-2 group beta-lactamase of pI 5.7 isolated from aztreonam-resistant Klebsiella oxytoca strain HB60.

Klebsiella oxytoca strain HB60 is highly resistant to cefoperazone and aztreonam (MICs = 128 mg/L). It produces a chromosomally encoded beta-lactamase of pI 5.7 which was highly efficient against penicillins, first-generation cephalosporins and cefoperazone, a non-oxyimino third-generation cephalosporin. Aztreonam and oxyimino broad-spectrum cephalosporins were less good substrates. The beta-lactamase activity was susceptible to inhibition by clavulanic acid (IC50 = 1 microM). The enzyme purified to homogeneity had a specific activity towards benzylpenicillin of 3670 U/mg. The 263 amino acid residues of the protein were sequenced by Edman degradation of proteolytic peptides. The beta-lactamase was shown to belong to the OXY-2 group as it had only one amino acid substitution (Asn for Asp at ABL position 197) compared with the beta-lactamase (pI 5.2) from the aztreonam-susceptible K. oxytoca strain SL911 and two substitutions (Ala223 for Val and Asp255 for Asn) compared with the beta-lactamase (pI 6.4) from the aztreonam-resistant K. oxytoca strain D488. These three OXY-2-group enzymes behave in the same way towards beta-lactam antibiotics. The variability in the resistance of these K. oxytoca strains would thus seem to be due to variation in the level of production of the beta-lactamases rather than to structural alteration of the enzymes.

Implication of Ile-69 and Thr-182 residues in kinetic characteristics of IRT-3 (TEM-32) beta-lactamase.

The substitution of a methionine for an isoleucine at position 69 (Met69Ile), which causes inhibitor resistance to TEM-type beta-lactamases (IRT-3 and IRT-I69), altered the positions of the Asn-170 and Glu-166 side chains as well as the position of the catalytic water molecule. A novel hydrogen bond between the hydroxyl of Thr-182 and the carbonyl of Glu-64 was expected to be responsible for the increase in the catalytic activity of the IST-T182 and IRT-3 enzymes compared with those of TEM-1 and IRT-169, respectively.

An additional ionic bond suggested by molecular modelling of TEM-2 might induce a slight discrepancy between catalytic properties of TEM-1 and TEM-2 beta-lactamases.

The plasmid-mediated TEM-1 and TEM-2 beta-lactamases are the most commonly encountered among Gram-negative bacteria. They belong to molecular class A, and differ by one amino acid at position 39:TEM-1 have a glutamine and TEM-2 a lysine. Kinetic parameters (kcat and Km) and catalytic efficiency (kcat/Km) of TEM-1 and TEM-2 beta-lactamases are slightly, but significantly different. For all antibiotics except methicillin and cefazolin, the catalytic efficiency values of TEM-2 are clearly greater than that of TEM-1. Molecular modelling of TEM-2, when compared to that of TEM-1, showed an additional ionic bond between Lys-39 and Glu-281.