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To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case–control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STHand KANSL1genes that was found in four cases, including one de novorearrangement, and was absent in controls. The increased MAPTgene dosage led to a 1.6–1.9-fold expression of the MAPTmessenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPTduplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPTduplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-β deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.

Line profiles of faint $\ion{Si}{ii}$lines of astrophysical interest are observed in a conventional shock tube. Electron density is $1.3\times 10^{23}~\rm m^{-3}$, and the temperature is 11 000 K. The Stark effect is the dominant broadening mechanism. The $\ion{Si}{ii}$line at λ419.07 nm (multiplet 7.26, Moore [CITE]) Stark width is measured and compared with theoretical prediction.

The SORL1 protein plays a protective role against the secretion of the amyloid ß peptide, a key event in the pathogeny of Alzheimer’s disease. We assessed the impact of SORL1rare variants in early-onset Alzheimer’s disease (EOAD) in a case–control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency =1%), we detected an enrichment of disruptive and predicted damaging missense SORL1variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02–14.99), P=7.49.10-5). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35–27.31), P=3.82.10-7). We conclude that predicted damaging rare SORL1variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.

The behavior of palladium C-bound enolates [Pd(CH2C(O)CR3)Cl(PPh3)2] (R = H, 1; R = Me, 2) and [Pd(CH2C(O)CR3)(PPh3)2(NCMe)](BF4) (R = H, 5; R = Me, 6) has been studied. Dimeric species with bridging enolate moieties are formed in solution when a coordination site on the metal is made available, either with Pd2{μ-κ²-C,O-CH2C(O)CR3}2 or with mixed Pd2{μ-κ²-C,O-CH2C(O)CR3}(μ-X) (X = Cl, OH) bridges. It is proposed that π back-donation is important to stabilize oxygen bonding. Complexes 1 and 2 undergo exchange between free and coordinated phosphine in solution. Kinetic experiments support an intramolecular associative mechanism which could involve an oxoallyl-like transition state. The reactivity of the complexes has been explored. Some reactions typical of Pd-alkyls have been observed such as insertion of CO to give CR3C(O)CH2COOH. Electrophilic attack on oxygen is very important:  the hydrolysis of the enolate complexes has been studied and also the reaction with ClSiMe3 to give silyl enol ethers.