Dimerization of the transmembrane domain of amyloid precursor proteins and familial Alzheimer's disease mutants

<p>Abstract</p> <p>Background</p> <p>Amyloid precursor protein (APP) is enzymatically cleaved by γ-secretase to form two peptide products, either Aβ40 or the more neurotoxic Aβ42. The Aβ42/40 ratio is increased in many cases of familial Alzheimer's disease (FAD). The transmembrane domain (TM) of APP contains the known dimerization motif GXXXA. We have investigated the dimerization of both wild type and FAD mutant APP transmembrane domains.</p> <p>Results</p> <p>Using synthetic peptides derived from the APP-TM domain, we show that this segment is capable of forming stable transmembrane dimers. A model of a dimeric APP-TM domain reveals a putative dimerization interface, and interestingly, majority of FAD mutations in APP are localized to this interface region. We find that FAD-APP mutations destabilize the APP-TM dimer and increase the population of APP peptide monomers.</p> <p>Conclusion</p> <p>The dissociation constants are correlated to both the Aβ42/Aβ40 ratio and the mean age of disease onset in AD patients. We also show that these TM-peptides reduce Aβ production and Aβ42/Aβ40 ratios when added to HEK293 cells overexpressing the Swedish FAD mutation and γ-secretase components, potentially revealing a new class of γ-secretase inhibitors.</p

Nitrate modulates stem cell dynamics in Arabidopsis shoot meristems through cytokinins

The shoot apical meristem (SAM) is responsible for the generation of all the aerial parts of plants. Given its critical role, dynamical changes in SAM activity should play a central role in the adaptation of plant architecture to the environment. Using quantitative microscopy, grafting experiments, and genetic perturbations, we connect the plant environment to the SAM by describing the molecular mechanism by which cytokinins signal the level of nutrient availability to the SAM. We show that a systemic signal of cytokinin precursors mediates the adaptation of SAM size and organogenesis rate to the availability of mineral nutrients by modulating the expression of WUSCHEL, a key regulator of stem cell homeostasis. In time-lapse experiments, we further show that this mechanism allows meristems to adapt to rapid changes in nitrate concentration, and thereby modulate their rate of organ production to the availability of mineral nutrients within a few days. Our work sheds light on the role of the stem cell regulatory network by showing that it not only maintains meristem homeostasis but also allows plants to adapt to rapid changes in the environment

Comparison of Three Clinical Trial Treatments for Autism Spectrum Disorder Through Multivariate Analysis of Changes in Metabolic Profiles and Adaptive Behavior

Several studies associate autism spectrum disorder (ASD) pathophysiology with metabolic abnormalities related to DNA methylation and intracellular redox homeostasis. In this regard, three completed clinical trials are reexamined in this work: treatment with (i) methylcobalamin (MeCbl) in combination with low-dose folinic acid (LDFA), (ii) tetrahydrobiopterin, and (iii) high-dose folinic acid (HDFA) for counteracting abnormalities in the folate-dependent one-carbon metabolism (FOCM) and transsulfuration (TS) pathways and also for improving ASD-related symptoms and behaviors. Although effects of treatment on individual metabolites and behavioral measures have previously been investigated, this study is the first to consider the effect of interventions on a set of metabolites of the FOCM/TS pathways and to correlate FOCM/TS metabolic changes with behavioral improvements across several studies. To do so, this work uses data from one case–control study and the three clinical trials to develop multivariate models for considering these aspects of treatment. Fisher discriminant analysis (FDA) is first used to establish a model for distinguishing individuals with ASD from typically developing (TD) controls, which is subsequently evaluated on the three treatment data sets, along with one data set for a placebo, to characterize the shift of FOCM/TS metabolism toward that of the TD population. Treatment with MeCbl plus LDFA and, separately, treatment with tetrahydrobiopterin significantly shifted the metabolites toward the values of the control group. Contrary to this, treatment with HDFA had a lesser, though still noticeable, effect whilst the placebo group showed marginal, but not insignificant, variations in metabolites. A second analysis is then performed with non-linear kernel partial least squares (KPLS) regression to predict changes in adaptive behavior, quantified by the Vineland Adaptive Behavior Composite, from changes in FOCM/TS biochemical measurements provided by treatment. Incorporating the 74 samples receiving any treatment, including placebo, into the regression analysis yields an R2 of 0.471 after cross-validation when using changes in six metabolic measurements as predictors. These results are suggestive of an ability to effectively improve pathway-wide FOCM/TS metabolic and behavioral abnormalities in ASD with clinical treatment

Sensitivity of markers of DNA stability and DNA repair activity to folate supplementation in healthy volunteers

We have previously reported that supplementation with folic acid (1.2 mg day−1 for 12 week) elicited a significant improvement in the folate status of 61 healthy volunteers. We have examined effects of this supplement on markers of genomic stability. Little is known about the effect of folate supplementation on DNA stability in a cohort, which is not folate deficient. Preintervention, there was a significant inverse association between uracil misincorporation in lymphocyte DNA and red cell folate (P<0.05). In contrast, there were no associations between folate status and DNA strand breakage, global DNA methylation or DNA base excision repair (measured as the capacity of the lymphocyte extract to repair 8-oxoGua ex vivo). Folate supplementation elicited a significant reduction in uracil misincorporation (P<0.05), while DNA strand breakage and global DNA methylation remained unchanged. Increasing folate status significantly decreased the base excision repair capacity in those volunteers with the lowest preintervention folate status (P<0.05). Uracil misincorporation was more sensitive to changes in folate status than other measures of DNA stability and therefore could be considered a specific and functional marker of folate status, which may also be relevant to cancer risk in healthy people

The XXL Survey: VI. The 1000 brightest X-ray point sources

X-ray extragalactic surveys are ideal laboratories for the study of the evolution and clustering of active galactic nuclei (AGN). The XXL Survey spans two fields of a combined 50 $deg^2$ observed for more than 6Ms with XMM-Newton, occupying the parameter space between deep surveys and very wide area surveys; at the same time it benefits from a wealth of ancillary data. This paper marks the first release of the XXL point source catalogue selected in the 2-10 keV energy band with limiting flux $F_{2-10keV}=4.8\cdot10^{-14}\rm{erg\,s^{-1}\,cm^{-2}}$. We use both public and proprietary data sets to identify the counterparts of the X-ray point-like sources and improved upon the photometric redshift determination for AGN by applying a Random Forest classification trained to identify for each object the optimal photometric redshift model library. We also assign a probability to each source to be a star or an outlier. We model with Bayesian analysis the X-ray spectra assuming a power-law model with the presence of an absorbing medium. We find an average unabsorbed photon index of $\Gamma=1.85$ and average hydrogen column density $\log{N_{H}}=21.07 cm^{-2}$. We find no trend of $\Gamma$ or $N_H$ with redshift and a fraction of 26% absorbed sources ($\log N_{H}>22$). We show that the XXL-1000-AGN number counts extended the number counts of the COSMOS survey to higher fluxes and are fully consistent with the Euclidean expectation. We constrain the intrinsic luminosity function of AGN in the 2-10 keV energy band where the unabsorbed X-ray flux is estimated from the X-ray spectral fit up to z=3. Finally, we demonstrate the presence of a supercluster size structure at redshift 0.14, identified by means of percolation analysis of the XXL-1000-AGN sample. The XXL survey, reaching a medium flux limit and covering a wide area is a stepping stone between current deep fields and planned wide area surveys

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing

The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19

Genomic Characterization of the Human Heterotrimeric G Protein α, β, and γ Subunit Genes

Heterotrimeric guanine nucleotide binding proteins (G proteins) transduce extracellular signals received by transmembrane receptors to effector proteins. Each subunit of the G protein complex is encoded by a member of one of three corresponding gene families. Currently, 16 different members of the α subunit family, 5 different members of the β subunit family, and 11 different members of the γ subunit family have been described in mammals. Here we have identified and characterized Bacterial Artificial Chromosomes (BACs) containing the human homologs of each of the α, β, and γ subunit genes as well as a Gα11 pseudogene and a previously undiscovered Gγ5-like gene. The gene structure and chromosome location of each gene was determined, as were the orientations of paired genes. These results provide greater insight into the evolution and functional diversity of the mammalian G protein subunit genes