Detecting and characterizing lateral phishing at scale

We present the first large-scale characterization of lateral phishing attacks, based on a dataset of 113 million employee-sent emails from 92 enterprise organizations. In a lateral phishing attack, adversaries leverage a compromised enterprise account to send phishing emails to other users, benefit-ting from both the implicit trust and the information in the hijacked user's account. We develop a classifier that finds hundreds of real-world lateral phishing emails, while generating under four false positives per every one-million employee-sent emails. Drawing on the attacks we detect, as well as a corpus of user-reported incidents, we quantify the scale of lateral phishing, identify several thematic content and recipient targeting strategies that attackers follow, illuminate two types of sophisticated behaviors that attackers exhibit, and estimate the success rate of these attacks. Collectively, these results expand our mental models of the 'enterprise attacker' and shed light on the current state of enterprise phishing attacks

Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold.

The ordered assembly of tau protein into abnormal filaments is a defining characteristic of Alzheimer's disease (AD) and other neurodegenerative disorders. It is not known if the structures of tau filaments vary within, or between, the brains of individuals with AD. We used a combination of electron cryo-microscopy (cryo-EM) and immuno-gold negative-stain electron microscopy (immuno-EM) to determine the structures of paired helical filaments (PHFs) and straight filaments (SFs) from the frontal cortex of 17 cases of AD (15 sporadic and 2 inherited) and 2 cases of atypical AD (posterior cortical atrophy). The high-resolution structures of PHFs and SFs from the frontal cortex of 3 cases of AD, 2 sporadic and 1 inherited, were determined by cryo-EM. We also used immuno-EM to study the PHFs and SFs from a number of cortical and subcortical brain regions. PHFs outnumbered SFs in all AD cases. By cryo-EM, PHFs and SFs were made of two C-shaped protofilaments with a combined cross-β/β-helix structure, as described previously for one case of AD. The higher resolution structures obtained here showed two additional amino acids at each end of the protofilament. The immuno-EM findings, which indicated the presence of repeats 3 and 4, but not of the N-terminal regions of repeats 1 and 2, of tau in the filament cores of all AD cases, were consistent with the cryo-EM results. These findings show that there is no significant variation in tau filament structures between individuals with AD. This knowledge will be crucial for understanding the mechanisms that underlie tau filament formation and for developing novel diagnostics and therapies

Cryo-EM structures of amyloid-beta filaments with the Arctic mutation (E22G) from human and mouse brains

The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-β (Aβ)], causes dominantly inherited Alzheimer’s disease. Here, we report the high-resolution cryo-EM structures of Aβ filaments from the frontal cortex of a previously described case (AβPParc1) with the Arctic mutation. Most filaments consist of two pairs of non-identical protofilaments that comprise residues V12–V40 (human Arctic fold A) and E11–G37 (human Arctic fold B). They have a substructure (residues F20–G37) in common with the folds of type I and type II Aβ42. When compared to the structures of wild-type Aβ42 filaments, there are subtle conformational changes in the human Arctic folds, because of the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant Aβ molecules and promote filament formation. A minority of Aβ42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of Aβ filaments with the Arctic mutation from mouse knock-in line AppNL−G−F. Most filaments are made of two identical mutant protofilaments that extend from D1 to G37 (AppNL−G−F murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The AppNL−G−F murine Arctic fold differs from the human Arctic folds, but shares some substructure

Cryo-EM structures of amyloid-β 42 filaments from human brains

Alzheimer’s disease is characterized by a loss of memory and other cognitive functions and the filamentous assembly of Aβ and tau in the brain. The assembly of Aβ peptides into filaments that end at residue 42 is a central event. Yang et al. used electron cryo–electron microscopy to determine the structures of Aβ42 filaments from human brain (see the Perspective by Willem and Fändrich). They identified two types of related S-shaped filaments, each consisting of two identical protofilaments. These structures will inform the development of better in vitro and animal models, inhibitors of Aβ42 assembly, and imaging agents with increased specificity and sensitivity. —SM

A Large-Scale Analysis of Attacker Activity in Compromised Enterprise Accounts

We present a large-scale characterization of attacker activity across 111 real-world enterprise organizations. We develop a novel forensic technique for distinguishing between attacker activity and benign activity in compromised enterprise accounts that yields few false positives and enables us to perform fine-grained analysis of attacker behavior. Applying our methods to a set of 159 compromised enterprise accounts, we quantify the duration of time attackers are active in accounts and examine thematic patterns in how attackers access and leverage these hijacked accounts. We find that attackers frequently dwell in accounts for multiple days to weeks, suggesting that delayed (non-real-time) detection can still provide significant value. Based on an analysis of the attackers’ timing patterns, we observe two distinct modalities in how attackers access compromised accounts, which could be explained by the existence of a specialized market for hijacked enterprise accounts: where one class of attackers focuses on compromising and selling account access to another class of attackers who exploit the access such hijacked accounts provide. Ultimately, our analysis sheds light on the state of enterprise account hijacking and highlights fruitful directions for a broader space of detection methods, ranging from new features that hone in on malicious account behavior to the development of non-real-time detection methods that leverage malicious activity after an attack’s initial point of compromise to more accurately identify attacks

Renate Bethge, Dietrich Bonhoeffer. Eine Skizze seines Lebens, Gütersloh, Gütersloher Verlagshaus, 2004

Arnold Matthieu. Renate Bethge, Dietrich Bonhoeffer. Eine Skizze seines Lebens, Gütersloh, Gütersloher Verlagshaus, 2004. In: Revue d'histoire et de philosophie religieuses, 86e année n°4, Octobre-Décembre 2006. p. 576

Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau

Acknowledgements: This work was supported by the Electron Microscopy Facility of the MRC Laboratory of Molecular Biology. We thank Jake Grimmett, Toby Darling and Ivan Clayson for help with high-performance computing, and Sofia Lövestam for helpful discussions. We also thank the staff at ARES and the LMB Biological Services Group for their help with mouse husbandry and tissue collection. For the purpose of open access, the MRC Laboratory of Molecular Biology has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising.Mice transgenic for human mutant P301S tau are widely used as models for human tauopathies. They develop neurodegeneration and abundant filamentous inclusions made of human mutant four-repeat tau. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the brains of Tg2541 and PS19 mice. Both lines express human P301S tau (0N4R for Tg2541 and 1N4R for PS19) on mixed genetic backgrounds and downstream of different promoters (murine Thy1 for Tg2541 and murine Prnp for PS19). The structures of tau filaments from Tg2541 and PS19 mice differ from each other and those of wild-type tau filaments from human brains. The structures of tau filaments from the brains of humans with mutations P301L, P301S or P301T in MAPT are not known. Filaments from the brains of Tg2541 and PS19 mice share a substructure at the junction of repeats 2 and 3, which comprises residues I297-V312 of tau and includes the P301S mutation. The filament core from the brainstem of Tg2541 mice consists of residues K274-H329 of tau and two disconnected protein densities. Two non-proteinaceous densities are also in evidence. The filament core from the cerebral cortex of line PS19 extends from residues G271-P364 of tau. One strong non-proteinaceous density is also present. Unlike the tau filaments from human brains, the sequences following repeat 4 are missing from the cores of tau filaments from the brains of Tg2541 and PS19 mice

Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau

Acknowledgements: This work was supported by the Electron Microscopy Facility of the MRC Laboratory of Molecular Biology. We thank Jake Grimmett, Toby Darling and Ivan Clayson for help with high-performance computing, and Sofia Lövestam for helpful discussions. We also thank the staff at ARES and the LMB Biological Services Group for their help with mouse husbandry and tissue collection. For the purpose of open access, the MRC Laboratory of Molecular Biology has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising.Mice transgenic for human mutant P301S tau are widely used as models for human tauopathies. They develop neurodegeneration and abundant filamentous inclusions made of human mutant four-repeat tau. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the brains of Tg2541 and PS19 mice. Both lines express human P301S tau (0N4R for Tg2541 and 1N4R for PS19) on mixed genetic backgrounds and downstream of different promoters (murine Thy1 for Tg2541 and murine Prnp for PS19). The structures of tau filaments from Tg2541 and PS19 mice differ from each other and those of wild-type tau filaments from human brains. The structures of tau filaments from the brains of humans with mutations P301L, P301S or P301T in MAPT are not known. Filaments from the brains of Tg2541 and PS19 mice share a substructure at the junction of repeats 2 and 3, which comprises residues I297-V312 of tau and includes the P301S mutation. The filament core from the brainstem of Tg2541 mice consists of residues K274-H329 of tau and two disconnected protein densities. Two non-proteinaceous densities are also in evidence. The filament core from the cerebral cortex of line PS19 extends from residues G271-P364 of tau. One strong non-proteinaceous density is also present. Unlike the tau filaments from human brains, the sequences following repeat 4 are missing from the cores of tau filaments from the brains of Tg2541 and PS19 mice