Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer???s disease

The absence of effective therapeutics against Alzheimer???s disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-?? (A??), metal-A??, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets??? reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.ope

Comparing selection mechanisms for gaze input techniques in head-mounted displays

Head movements are a common input modality on VR/AR headsets. However, although they enable users to control a cursor, they lack an integrated method to trigger actions. Many approaches exist to fill this gap: dedicated "clickers", on-device buttons, mid-air gestures, dwell, speech and new input techniques based on matching head motions to those of visually presented targets. These proposals are diverse and there is a current lack of empirical data on the performance of, experience of, and preference for these different techniques. This hampers the ability of designers to select appropriate input techniques to deploy. We conduct two studies that address this problem. A Fitts' Law study compares five traditional selection techniques and concludes that clicker (hands-on) and dwell (hands-free) provide optimal combinations of precision, speed and physical load. A follow-up study compares clicker and dwell to a motion matching implementation. While clicker remains fastest and dwell most accurate, motion matching may provide a valuable compromise between these two poles

Designing Socially Acceptable Hand-to-Face Input

Wearable head-mounted displays combine rich graphical out- put with an impoverished input space. Hand-to-face gestures have been proposed as a way to add input expressivity while keeping control movements unobtrusive. To better understand how to design such techniques, we describe an elicitation study conducted in a busy public space in which pairs of users were asked to generate unobtrusive, socially acceptable hand- to-face input actions. Based on the results, we describe five design strategies: miniaturizing, obfuscating, screening, camouflaging and re-purposing. We instantiate these strategies in two hand-to-face input prototypes, one based on touches to the ear and the other based on touches of the thumbnail to the chin or cheek. Performance assessments characterize time and error rates with these devices. The paper closes with a validation study in which pairs of users experience the prototypes in a public setting and we gather data on the social acceptability of the designs and reflect on the effectiveness of the different strategies

Gesture Authentication for Smartphones: Evaluation of Gesture Password Selection Policies

Touchscreen gestures are attracting research attention as an authentication method. While studies have showcased their usability, it has proven more complex to determine, let alone enhance, their security. Problems stem both from the small scale of current data sets and the fact that gestures are matched imprecisely -- by a distance metric. This makes it challenging to assess entropy with traditional algorithms. To address these problems, we captured a large set of gesture passwords (N=2594) from crowd workers, and developed a security assessment framework that can calculate partial guessing entropy estimates, and generate dictionaries that crack 23.13% or more gestures in online attacks (within 20 guesses). To improve the entropy of gesture passwords, we designed novel blacklist and lexical policies to, respectively, restrict and inspire gesture creation. We close by validating both our security assessment framework and policies in a new crowd-sourced study (N=4000). Our blacklists increase entropy and resistance to dictionary based guessing attacks

VprBP/DCAF1 Triggers Melanomagenic Gene Silencing through Histone H2A Phosphorylation

Vpr binding protein (VprBP), also known as DDB1- and CUL4-associated factor1 (DCAF1), is a recently identified atypical kinase and plays an important role in downregulating the transcription of tumor suppressor genes as well as increasing the risk for colon and prostate cancers. Melanoma is the most aggressive form of skin cancer arising from pigment-producing melanocytes and is often associated with the dysregulation of epigenetic factors targeting histones. Here, we demonstrate that VprBP is highly expressed and phosphorylates threonine 120 (T120) on histone H2A to drive the transcriptional inactivation of growth-regulatory genes in melanoma cells. As is the case for its epigenetic function in other types of cancers, VprBP acts to induce a gene silencing program dependent on H2AT120 phosphorylation (H2AT120p). The significance of VprBP-mediated H2AT120p is further underscored by the fact that VprBP knockdown- or VprBP inhibitor-induced lockage of H2AT120p mitigates melanoma tumor growth in xenograft models. Collectively, our results establish VprBP-mediated H2AT120p as a key epigenetic signal for melanomagenesis and suggest the therapeutic potential of targeting VprBP kinase activity for effective melanoma treatment

H3K27me1 is essential for MMP-9-dependent H3N-terminal tail proteolysis during osteoclastogenesis

Abstract Background MMP-9 plays a direct role in the activation of pro-osteoclastogenic genes by cleaving histone H3N-terminal tail (H3NT) and altering chromatin architecture. Although H3 acetylation at K18 has been shown to stimulate MMP-9 enzymatic activity toward H3NT, nothing is known about the influence of other H3NT modifications on this epigenetic reaction. Results We show that H3 monomethylation at lysine 27 (H3K27me1) is essential for MMP-9-dependent H3NT proteolysis during RANKL-induced osteoclast differentiation. Through the recognition of H3K27me1 mark, MMP-9 localizes and generates H3NT proteolysis at the genes encoding osteoclast differentiation factors. By using RNAi and small molecule inhibitor approaches, we also confirmed that G9a is the major methyltransferase to catalyze H3K27me1 for MMP-9-dependent H3NT proteolysis and trigger the expression of osteoclast-specific genes. Conclusions Our data establish new functions for G9a-mediated H3K27me1 in MMP-9-dependent H3NT proteolysis and demonstrate how histone modification can be exploited to regulate osteoclastogenic gene expression at the molecular level. Further studies are warranted to investigate the detailed mechanism by which G9a overexpression with concomitant dysregulation of osteoclastogenesis contributes to the pathogenesis of bone disorders

DNMT and HDAC inhibitors modulate MMP-9-dependent H3 N-terminal tail proteolysis and osteoclastogenesis

Abstract Background MMP-9-dependent proteolysis of histone H3 N-terminal tail (H3NT) is an important mechanism for activation of gene expression during osteoclast differentiation. Like other enzymes targeting their substrates within chromatin structure, MMP-9 enzymatic activity toward H3NT is tightly controlled by histone modifications such as H3K18 acetylation (H3K18ac) and H3K27 monomethylation (H3K27me1). Growing evidence indicates that DNA methylation is another epigenetic mechanism controlling osteoclastogenesis, but whether DNA methylation is also critical for regulating MMP-9-dependent H3NT proteolysis and gene expression remains unknown. Results We show here that treating RANKL-induced osteoclast progenitor (OCP) cells with the DNMT inhibitor 5-Aza-2′-deoxycytidine (5-Aza-CdR) induces CpG island hypomethylation and facilitates MMP-9 transcription. This increase in MMP-9 expression results in a significant enhancement of H3NT proteolysis and OCP cell differentiation. On the other hand, despite an increase in levels of H3K18ac, treatment with the HDAC inhibitor trichostatin A (TSA) leads to impairment of osteoclastogenic gene expression. Mechanistically, TSA treatment of OCP-induced cells stimulates H3K27ac with accompanying reduction in H3K27me1, which is a key modification to facilitate stable interaction of MMP-9 with nucleosomes for H3NT proteolysis. Moreover, hypomethylated osteoclastogenic genes in 5-Aza-CdR-treated cells remain transcriptionally inactive after TSA treatment, because H3K27 is highly acetylated and cannot be modified by G9a. Conclusions These findings clearly indicate that DNA methylation and histone modification are important mechanisms in regulating osteoclastogenic gene expression and that their inhibitors can be used as potential therapeutic tools for treating bone disorders

Effect of metabolic health and obesity on all-cause death and CVD incidence in Korean adults: a retrospective cohort study

Abstract This study aimed to investigate the risk of all-cause mortality and incidence of CVD according to metabolic health and body mass index (BMI) in Korean adults. This study was retrospectively designed using the National Health Insurance Service-National Health Screening Cohort data. Participants were divided into six groups according to two category of metabolic syndrome and three categories of BMI. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the composite outcome (all-cause mortality and incidence of CVDs) were estimated using multivariable Cox proportional hazards regression models. 151,706 participants aged ≥ 40 years were enrolled; median follow-up period was 9.7 years in the study. Compared to metabolically healthy normal weight, the fully adjusted HRs (95% CIs) of metabolically healthy overweight, metabolically healthy obese, metabolically unhealthy normal weight, metabolically unhealthy overweight, and metabolically unhealthy obese for composite outcome were 1.07 (1.03–1.12), 1.12 (1.07–1.17), 1.33 (1.25–1.41), 1.28 (1.22–1.34), and 1.31 (1.26–1.37), respectively, in men, and 1.10 (1.05–1.16), 1.22 (1.16–1.29), 1.34 (1.26–1.43), 1.27 (1.19–1.34), and, 1.40 (1.34–1.47), respectively, in women. High BMI and metabolic unhealthiness were associated with an increased risk on the composite of all-cause mortality and incidence of CVD in both sexes