Callisto: a cryptographic approach to detecting serial perpetrators of sexual misconduct

Sexual misconduct is prevalent in workplace and education settings but stigma and risk of further damage deter many victims from seeking justice. Callisto, a non-profit that has created an online sexual assault reporting platform for college campuses, is expanding its work to combat sexual assault and harassment in other industries. In this new product, users will be invited to an online "matching escrow" that will detect repeat perpetrators and create pathways to support for victims. Users submit encrypted data about their perpetrator, and this data can only be decrypted by the Callisto Options Counselor (a lawyer), when another user enters the identity of the same perpetrator. If the perpetrator identities match, both users will be put in touch independently with the Options Counselor, who will connect them to each other (if appropriate) and help them determine their best path towards justice. The client relationships with the Options Counselors are structured so that any client-counselor communications would be privileged. A combination of client-side encryption, encrypted communication channels, oblivious pseudo-random functions, key federation, and Shamir Secret Sharing keep data confidential in transit, at rest, and during the matching process with the guarantee that only the lawyer ever has access to user submitted data, and even then only when a match is identified.Accepted manuscrip

From usability to secure computing and back again

Secure multi-party computation (MPC) allows multiple parties to jointly compute the output of a function while preserving the privacy of any individual party’s inputs to that function. As MPC protocols transition from research prototypes to realworld applications, the usability of MPC-enabled applications is increasingly critical to their successful deployment and widespread adoption. Our Web-MPC platform, designed with a focus on usability, has been deployed for privacy-preserving data aggregation initiatives with the City of Boston and the Greater Boston Chamber of Commerce. After building and deploying an initial version of the platform, we conducted a heuristic evaluation to identify usability improvements and implemented corresponding application enhancements. However, it is difficult to gauge the effectiveness of these changes within the context of real-world deployments using traditional web analytics tools without compromising the security guarantees of the platform. This work consists of two contributions that address this challenge: (1) the Web-MPC platform has been extended with the capability to collect web analytics using existing MPC protocols, and (2) as a test of this feature and a way to inform future work, this capability has been leveraged to conduct a usability study comparing the two versions ofWeb-MPC. While many efforts have focused on ways to enhance the usability of privacy-preserving technologies, this study serves as a model for using a privacy-preserving data-driven approach to evaluate and enhance the usability of privacy-preserving websites and applications deployed in realworld scenarios. Data collected in this study yields insights into the relationship between usability and security; these can help inform future implementations of MPC solutions.Published versio

Targeted Disruption of Ephrin B1 in Cells of Myeloid Lineage Increases Osteoclast Differentiation and Bone Resorption in Mice

Disruption of ephrin B1 in collagen I producing cells in mice results in severe skull defects and reduced bone formation. Because ephrin B1 is also expressed during osteoclast differentiation and because little is known on the role of ephrin B1 reverse signaling in bone resorption, we examined the bone phenotypes in ephrin B1 conditional knockout mice, and studied the function of ephrin B1 reverse signaling on osteoclast differentiation and resorptive activity. Targeted deletion of ephrin B1 gene in myeloid lineage cells resulted in reduced trabecular bone volume, trabecular number and trabecular thickness caused by increased TRAP positive osteoclasts and bone resorption. Histomorphometric analyses found bone formation parameters were not changed in ephrin B1 knockout mice. Treatment of wild-type precursors with clustered soluble EphB2-Fc inhibited RANKL induced formation of multinucleated osteoclasts, and bone resorption pits. The same treatment of ephrin B1 deficient precursors had little effect on osteoclast differentiation and pit formation. Similarly, activation of ephrin B1 reverse signaling by EphB2-Fc treatment led to inhibition of TRAP, cathepsin K and NFATc1 mRNA expression in osteoclasts derived from wild-type mice but not conditional knockout mice. Immunoprecipitation with NHERF1 antibody revealed ephrin B1 interacted with NHERF1 in differentiated osteoclasts. Treatment of osteoclasts with exogenous EphB2-Fc resulted in reduced phosphorylation of ezrin/radixin/moesin. We conclude that myeloid lineage produced ephrin B1 is a negative regulator of bone resorption in vivo, and that activation of ephrin B1 reverse signaling inhibits osteoclast differentiation in vitro in part via a mechanism that involves inhibition of NFATc1 expression and modulation of phosphorylation status of ezrin/radixin/moesin

Accessible privacy-preserving web-based data analysis for assessing and addressing economic inequalities

An essential component of initiatives that aim to address pervasive inequalities of any kind is the ability to collect empirical evidence of both the status quo baseline and of any improvement that can be attributed to prescribed and deployed interventions. Unfortunately, two substantial barriers can arise preventing the collection and analysis of such empirical evidence: (1) the sensitive nature of the data itself and (2) a lack of technical sophistication and infrastructure available to both an initiative's beneficiaries and to those spearheading it. In the last few years, it has been shown that a cryptographic primitive called secure multi-party computation (MPC) can provide a natural technological resolution to this conundrum. MPC allows an otherwise disinterested third party to contribute its technical expertise and resources, to avoid incurring any additional liabilities itself, and (counterintuitively) to reduce the level of data exposure that existing parties must accept to achieve their data analysis goals. However, achieving these benefits requires the deliberate design of MPC tools and frameworks whose level of accessibility to non-technical users with limited infrastructure and expertise is state-of-the-art. We describe our own experiences designing, implementing, and deploying such usable web applications for secure data analysis within the context of two real-world initiatives that focus on promoting economic equality.Published versio

Serum uric acid as a potential marker for heart failure risk in men on antihypertensive treatment: The British Regional Heart Study.

The role of serum uric acid (SUA) as a prognostic marker for incident heart failure (HF) in hypertensive subjects is uncertain. We have prospectively examined the relationship between SUA and incident HF in 3440 men aged 60-79years separately in those on and not on antihypertensive treatment who were followed up for a mean period of 15years. Men on SUA lowering drugs and those with history of HF or myocardial infarction were excluded. There were 260 incident HF cases. The men were divided into three groups of SUA concentrations/levels (410μmol/L). Raised SUA was associated with significantly increased risk of HF in men on antihypertensive treatment (N=949) but not in those without (N=2491) (p=0.003 for interaction). In men on antihypertensive treatment those with hyperuricemia (>410μmol/L) had the most adverse biological risk profile for HF including the highest rates of atrial fibrillation and renal dysfunction and the highest mean level of BMI, c-reactive protein and cardiac function (cardiac troponin T). Treated hypertensive men with SUA levels>410μmol/L showed an increase in risk of HF of more than twofold compared to those on treatment with levels <350μmol/L even after adjustment for lifestyle characteristics and biological risk factors [adjusted hazard ratio 2.26 (1.23,4.15)]. SUA improved prediction of HF beyond routine conventional risk factors (p=0.02 for improvement in c-statistics). SUA as a marker of increased xanthine oxidase activity may be a useful prognostic marker for HF risk in older men on antihypertensive treatment

Single-molecule imaging reveals receptor-G protein interactions at cell surface hot spots

G-protein-coupled receptors mediate the biological effects of many hormones and neurotransmitters and are important pharmacological targets. They transmit their signals to the cell interior by interacting with G proteins. However, it is unclear how receptors and G proteins meet, interact and couple. Here we analyse the concerted motion of G-protein-coupled receptors and G proteins on the plasma membrane and provide a quantitative model that reveals the key factors that underlie the high spatiotemporal complexity of their interactions. Using two-colour, single-molecule imaging we visualize interactions between individual receptors and G proteins at the surface of living cells. Under basal conditions, receptors and G proteins form activity-dependent complexes that last for around one second. Agonists specifically regulate the kinetics of receptor-G protein interactions, mainly by increasing their association rate. We find hot spots on the plasma membrane, at least partially defined by the cytoskeleton and clathrin-coated pits, in which receptors and G proteins are confined and preferentially couple. Imaging with the nanobody Nb37 suggests that signalling by G-protein-coupled receptors occurs preferentially at these hot spots. These findings shed new light on the dynamic interactions that control G-protein-coupled receptor signalling

Mutations in GDP-mannose pyrophosphorylase b cause congenital and limb-girdle muscular dystrophies associated with hypoglycosylation of α-dystroglycan

Congenital muscular dystrophies with hypoglycosylation of α-dystroglycan (α-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of α-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated α-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including α-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced α-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of α-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of α-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-DG. © 2013 The American Society of Human Genetics.Funding for UK10K was provided by the Wellcome Trust under award WT091310

Examining the effectiveness of general practitioner and nurse promotion of electronic cigarettes versus standard care for smoking reduction and abstinence in hardcore smokers with smoking-related chronic disease:protocol for a randomised controlled trial

BACKGROUND: Despite the clear harm associated with smoking tobacco, many people with smoking-related chronic diseases or serious mental illnesses (SMI) are unwilling or unable to stop smoking. In many cases, these smokers have tried and exhausted all methods to stop smoking and yet clinicians are repeatedly mandated to offer them during routine consultations. Providing nicotine through electronic cigarettes (e-cigarettes) may reduce the adverse health consequences associated with tobacco smoking, but these are not currently offered. The aim of this study is to examine the feasibility, acceptability and effectiveness of general practitioners (GPs) and nurses delivering a brief advice intervention on e-cigarettes and offering an e-cigarette starter pack and patient support resources compared with standard care in smokers with smoking-related chronic diseases or SMI who are unwilling to stop smoking. METHODS/DESIGN: This is an individually randomised, blinded, two-arm trial. Smokers with a smoking-related chronic condition or SMI with no intention of stopping smoking will be recruited through primary care registers. Eligible participants will be randomised to one of two groups if they decline standard care for stopping smoking: a control group who will receive no additional support beyond standard care; or an intervention group who will receive GP or nurse-led brief advice about e-cigarettes, an e-cigarette starter pack with accompanying practical support booklet, and telephone support from experienced vapers and online video tutorials. The primary outcome measures will be smoking reduction, measured through changes in cigarettes per day and 7-day point-prevalence abstinence at 2 months. Secondary outcomes include smoking reduction, 7-day point-prevalence abstinence and prolonged abstinence at 8 months. Other outcomes include patient recruitment and follow-up, patient uptake and use of e-cigarettes, nicotine intake, contamination of randomisation and practitioner adherence to the delivery of the intervention. Qualitative interviews will be conducted in a subsample of practitioners, patients and the vape team to garner their reactions to the programme. DISCUSSION: This is the first randomised controlled trial to investigate whether e-cigarette provision alongside a brief intervention delivered by practitioners leads to reduced smoking and abstinence among smokers with smoking-related chronic diseases or SMI. TRIAL REGISTRATION: ISRCTN registry, ISRCTN59404712. Registered 28/11/17

Shedding Light on the Galaxy Luminosity Function

From as early as the 1930s, astronomers have tried to quantify the statistical nature of the evolution and large-scale structure of galaxies by studying their luminosity distribution as a function of redshift - known as the galaxy luminosity function (LF). Accurately constructing the LF remains a popular and yet tricky pursuit in modern observational cosmology where the presence of observational selection effects due to e.g. detection thresholds in apparent magnitude, colour, surface brightness or some combination thereof can render any given galaxy survey incomplete and thus introduce bias into the LF. Over the last seventy years there have been numerous sophisticated statistical approaches devised to tackle these issues; all have advantages -- but not one is perfect. This review takes a broad historical look at the key statistical tools that have been developed over this period, discussing their relative merits and highlighting any significant extensions and modifications. In addition, the more generalised methods that have emerged within the last few years are examined. These methods propose a more rigorous statistical framework within which to determine the LF compared to some of the more traditional methods. I also look at how photometric redshift estimations are being incorporated into the LF methodology as well as considering the construction of bivariate LFs. Finally, I review the ongoing development of completeness estimators which test some of the fundamental assumptions going into LF estimators and can be powerful probes of any residual systematic effects inherent magnitude-redshift data.Comment: 95 pages, 23 figures, 3 tables. Now published in The Astronomy & Astrophysics Review. This version: bring in line with A&AR format requirements, also minor typo corrections made, additional citations and higher rez images adde

Identification of a BRCA2-Specific modifier locus at 6p24 related to breast cancer risk

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9×10−8). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer