Alzheimer's disease (AD) is characterized by deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain, accompanied by synaptic dysfunction and neurodegeneration. Antibody-based immunotherapy against Aβ to trigger its clearance or mitigate its neurotoxicity has so far been unsuccessful. Here we report the generation of aducanumab, a human monoclonal antibody that selectively targets aggregated Aβ. In a transgenic mouse model of AD, aducanumab is shown to enter the brain, bind parenchymal Aβ, and reduce soluble and insoluble Aβ in a dose-dependent manner. In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner. This is accompanied by a slowing of clinical decline measured by Clinical Dementia Rating-Sum of Boxes and Mini Mental State Examination scores. The main safety and tolerability findings are amyloid-related imaging abnormalities. These results justify further development of aducanumab for the treatment of AD. Should the slowing of clinical decline be confirmed in ongoing phase 3 clinical trials, it would provide compelling support for the amyloid hypothesis.

Bismuth telluride based thermoelectric materials have been commercialized for a wide range of applications in power generation and refrigeration. However, the poor machinability and susceptibility to brittle fracturing of commercial ingots often impose significant limitations on the manufacturing process and durability of thermoelectric devices. In this study, melt spinning combined with a plasma‐activated sintering (MS‐PAS) method is employed for commercial p‐type zone‐melted (ZM) ingots of Bi0.5Sb1.5Te3. This fast synthesis approach achieves hierarchical structures and in‐situ nanoscale precipitates, resulting in the simultaneous improvement of the thermoelectric performance and the mechanical properties. Benefitting from a strong suppression of the lattice thermal conductivity, a peak ZT of 1.22 is achieved at 340 K in MS‐PAS synthesized structures, representing about a 40% enhancement over that of ZM ingots. Moreover, MS‐PAS specimens with hierarchical structures exhibit superior machinability and mechanical properties with an almost 30% enhancement in their fracture toughness, combined with an eightfold and a factor of six increase in the compressive and flexural strength, respectively. Accompanied by an excellent thermal stability up to 200 °C for the MS‐PAS synthesized samples, the MS‐PAS technique demonstrates great potential for mass production and large‐scale applications of Bi2Te3 related thermoelectrics.

Background Aducanumab is a human monoclonal antibody that selectively targets aggregated forms of Aβ, including soluble oligomers and insoluble fibrils. EMERGE and ENGAGE are two 18‐month, randomized, double‐blind, placebo‐controlled, global Phase 3 studies with identical design that evaluated the efficacy and safety of aducanumab in patients aged 50–85 years with early Alzheimer’s disease (MCI due to AD or mild AD dementia). Method Key inclusion criteria included positive amyloid PET, MMSE score of 24–30, CDR Global score of 0.5, and an RBANS‐DMI score ≤85. During the 18‐month placebo‐controlled period, patients were randomized 1:1:1 to low‐dose aducanumab, high‐dose aducanumab, or placebo, administered via IV infusion every 4 weeks. The primary endpoint for EMERGE and ENGAGE was change from baseline at Week 78 on the CDR‐SB. Secondary endpoints included change from baseline on MMSE, ADAS‐Cog13, and ADCS‐ADL‐MCI. Result Following pre‐planned futility analysis, analysis of the data from the final database lock showed that EMERGE met its primary endpoint, based on the pre‐specified statistical analysis plan. Patients treated with high dose aducanumab showed a significant reduction of clinical decline from baseline in CDR‐SB scores at 78 weeks (22% versus placebo, P = 0.01). ENGAGE did not meet its primary endpoint. However, data from patients in ENGAGE who achieved sufficient exposure to high dose aducanumab supported the findings of EMERGE. Conclusion EMERGE met its primary endpoint, based on the pre‐specified statistical analysis plan. Data from a subset of patients in ENGAGE support the results of EMERGE. The safety and tolerability profile of aducanumab in EMERGE and ENGAGE was consistent with previous studies of aducanumab.

SummaryAll above-ground plant organs are derived from shoot apical meristems (SAMs). Global analyses of gene expression were conducted on maize (Zea mays L.) SAMs to identify genes preferentially expressed in the SAM. The SAMs were collected from 14-day-old B73 seedlings via laser capture microdissection (LCM). The RNA samples extracted from LCM-collected SAMs and from seedlings were hybridized to microarrays spotted with 37 660 maize cDNAs. Approximately 30% (10 816) of these cDNAs were prepared as part of this study from manually dissected B73 maize apices. Over 5000 expressed sequence tags (ESTs) (about 13% of the total) were differentially expressed (P < 0.0001) between SAMs and seedlings. Of these, 2783 and 2248 ESTs were up-and down-regulated in the SAM, respectively. The expression in the SAM of several of the differentially expressed ESTs was validated via quantitative RT-PCR and/or in situ hybridization. The up-regulated ESTs included many regulatory genes including transcription factors, chromatin remodeling factors and components of the gene-silencing machinery, as well as about 900 genes with unknown functions. Surprisingly, transcripts that hybridized to 62 retrotransposon-related cDNAs were also substantially up-regulated in the SAM. Complementary DNAs derived from the LCM-collected SAMs were sequenced to identify additional genes that are expressed in the SAM. This generated around 550 000 ESTs (454-SAM ESTs) from two genotypes. Consistent with the microarray results, approximately 14% of the 454-SAM ESTs from B73 were retrotransposon-related. Possible roles of genes that are preferentially expressed in the SAM are discussed.

Amyloid positron emission tomography (PET) imaging is being investigated as a screening tool to identify amyloid-positive patients as an enrichment strategy for Alzheimer disease (AD) clinical trial enrollment. In a multicenter, phase 1b trial, patients meeting clinical criteria for prodromal or mild AD underwent florbetapir PET scanning at screening. PET, magnetic resonance imaging, and coregistered PET/magnetic resonance imaging scans were reviewed by 2 independent readers and binary visual readings tabulated. Semiquantitative values of cortical to whole cerebellar standard uptake value ratios were computed (threshold 1.10). Of 278 patients with an evaluable PET scan, 170 (61%) and 185 (67%) were amyloid-positive by visual reading and quantitative analysis, respectively; 39% were excluded from the study due to an amyloid-negative scan based on visual readings. More ApoE ε4 carriers than noncarriers were amyloid-positive (80% vs. 43%). Comparison of visual readings with quantitative results identified 21 discordant cases (92% agreement). Interreader and intrareader agreements from visual readings were 98% and 100%, respectively. Amyloid PET imaging is an effective and feasible screening tool for enrollment of amyloid-positive patients with early stages of AD into clinical trials.