Multi-Prover Commitments Against Non-Signaling Attacks

We reconsider the concept of multi-prover commitments, as introduced in the late eighties in the seminal work by Ben-Or et al. As was recently shown by Cr\'{e}peau et al., the security of known two-prover commitment schemes not only relies on the explicit assumption that the provers cannot communicate, but also depends on their information processing capabilities. For instance, there exist schemes that are secure against classical provers but insecure if the provers have quantum information processing capabilities, and there are schemes that resist such quantum attacks but become insecure when considering general so-called non-signaling provers, which are restricted solely by the requirement that no communication takes place. This poses the natural question whether there exists a two-prover commitment scheme that is secure under the sole assumption that no communication takes place; no such scheme is known. In this work, we give strong evidence for a negative answer: we show that any single-round two-prover commitment scheme can be broken by a non-signaling attack. Our negative result is as bad as it can get: for any candidate scheme that is (almost) perfectly hiding, there exists a strategy that allows the dishonest provers to open a commitment to an arbitrary bit (almost) as successfully as the honest provers can open an honestly prepared commitment, i.e., with probability (almost) 1 in case of a perfectly sound scheme. In the case of multi-round schemes, our impossibility result is restricted to perfectly hiding schemes. On the positive side, we show that the impossibility result can be circumvented by considering three provers instead: there exists a three-prover commitment scheme that is secure against arbitrary non-signaling attacks

Apparent correlation of palaeomagnetic intensity and climatic records in deep-sea sediments

Most reports of a correlation between Pleistocene climate and geomagnetic field intensity rely strongly on the assumption that sediment natural remanent magnetic (NRM) intensity provides a record of geomagnetic field strength and is not sensitive to local changes in properties of the sediment. Critical assessment of relevant data presented here and elsewhere from deep-sea sediment cores shows that a pronounced dependence of NRM intensity on sediment composition can occur which implies that this assumption is unlikely to be generally valid. As sediment composition often reflects varying depositional conditions induced by climatic change, the significance of correlations proposed between Pleistocene palaeomagnetism and climatic indicators in deep-sea sediments may be less dramatic than sometimes supposed

Lipoprotein(a) and the Risk for Recurrent Atherosclerotic Cardiovascular Events Among Adults With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study

Rationale & Objective: Many adults with chronic kidney disease (CKD) and atherosclerotic cardiovascular disease (ASCVD) have high lipoprotein(a) levels. It is unclear whether high lipoprotein(a) levels confer an increased risk for recurrent ASCVD events in this population. We estimated the risk for recurrent ASCVD events associated with lipoprotein(a) in adults with CKD and prevalent ASCVD. Study Design: Observational cohort study. Setting & Participants: We included 1,439 adults with CKD and prevalent ASCVD not on dialysis enrolled in the Chronic Renal Insufficiency Cohort study between 2003 and 2008. Exposure: Baseline lipoprotein(a) mass concentration, measured using a latex-enhanced immunoturbidimetric assay. Outcomes: Recurrent ASCVD events (primary outcome), kidney failure, and death (exploratory outcomes) through 2019. Analytical Approach: We used Cox proportional-hazards regression models to estimate adjusted HR (aHRs) and 95% CIs. Results: Among participants included in the current analysis (mean age 61.6 years, median lipoprotein(a) 29.4 mg/dL [25th-75th percentiles 9.9-70.9 mg/dL]), 641 had a recurrent ASCVD event, 510 developed kidney failure, and 845 died over a median follow-up of 6.6 years. The aHR for ASCVD events associated with 1 standard deviation (SD) higher log-transformed lipoprotein(a) was 1.04 (95% CI, 0.95-1.15). In subgroup analyses, 1 SD higher log-lipoprotein(a) was associated with an increased risk for ASCVD events in participants without diabetes (aHR, 1.23; 95% CI, 1.02-1.48), but there was no evidence of an association among those with diabetes (aHR, 0.99; 95% CI, 0.88-1.10, P comparing aHRs = 0.031). The aHR associated with 1 SD higher log-lipoprotein(a) in the overall study population was 1.16 (95% CI, 1.04-1.28) for kidney failure and 1.02 (95% CI, 0.94-1.11) for death. Limitations: Lipoprotein(a) was not available in molar concentration. Conclusions: Lipoprotein(a) was not associated with the risk for recurrent ASCVD events in adults with CKD, although it was associated with a risk for kidney failure

Competing risk and heterogeneity of treatment effect in clinical trials

It has been demonstrated that patients enrolled in clinical trials frequently have a large degree of variation in their baseline risk for the outcome of interest. Thus, some have suggested that clinical trial results should routinely be stratified by outcome risk using risk models, since the summary results may otherwise be misleading. However, variation in competing risk is another dimension of risk heterogeneity that may also underlie treatment effect heterogeneity. Understanding the effects of competing risk heterogeneity may be especially important for pragmatic comparative effectiveness trials, which seek to include traditionally excluded patients, such as the elderly or complex patients with multiple comorbidities. Indeed, the observed effect of an intervention is dependent on the ratio of outcome risk to competing risk, and these risks – which may or may not be correlated – may vary considerably in patients enrolled in a trial. Further, the effects of competing risk on treatment effect heterogeneity can be amplified by even a small degree of treatment related harm. Stratification of trial results along both the competing and the outcome risk dimensions may be necessary if pragmatic comparative effectiveness trials are to provide the clinically useful information their advocates intend

Perturbation with Intrabodies Reveals That Calpain Cleavage Is Required for Degradation of Huntingtin Exon 1

Background: Proteolytic processing of mutant huntingtin (mHtt), the protein that causes Huntington's disease (HD), is critical for mHtt toxicity and disease progression. mHtt contains several caspase and calpain cleavage sites that generate N-terminal fragments that are more toxic than full-length mHtt. Further processing is then required for the degradation of these fragments, which in turn, reduces toxicity. This unknown, secondary degradative process represents a promising therapeutic target for HD. Methodology/Principal Findings: We have used intrabodies, intracellularly expressed antibody fragments, to gain insight into the mechanism of mutant huntingtin exon 1 (mHDx-1) clearance. Happ1, an intrabody recognizing the proline-rich region of mHDx-1, reduces the level of soluble mHDx-1 by increasing clearance. While proteasome and macroautophagy inhibitors reduce turnover of mHDx-1, Happ1 is still able to reduce mHDx-1 under these conditions, indicating Happ1-accelerated mHDx-1 clearance does not rely on these processes. In contrast, a calpain inhibitor or an inhibitor of lysosomal pH block Happ1-mediated acceleration of mHDx-1 clearance. These results suggest that mHDx-1 is cleaved by calpain, likely followed by lysosomal degradation and this process regulates the turnover rate of mHDx-1. Sequence analysis identifies amino acid (AA) 15 as a potential calpain cleavage site. Calpain cleavage of recombinant mHDx-1 in vitro yields fragments of sizes corresponding to this prediction. Moreover, when the site is blocked by binding of another intrabody, V_L12.3, turnover of soluble mHDx-1 in living cells is blocked. Conclusions/Significance: These results indicate that calpain-mediated removal of the 15 N-terminal AAs is required for the degradation of mHDx-1, a finding that may have therapeutic implications

Assessing and reporting heterogeneity in treatment effects in clinical trials: a proposal

Mounting evidence suggests that there is frequently considerable variation in the risk of the outcome of interest in clinical trial populations. These differences in risk will often cause clinically important heterogeneity in treatment effects (HTE) across the trial population, such that the balance between treatment risks and benefits may differ substantially between large identifiable patient subgroups; the "average" benefit observed in the summary result may even be non-representative of the treatment effect for a typical patient in the trial. Conventional subgroup analyses, which examine whether specific patient characteristics modify the effects of treatment, are usually unable to detect even large variations in treatment benefit (and harm) across risk groups because they do not account for the fact that patients have multiple characteristics simultaneously that affect the likelihood of treatment benefit. Based upon recent evidence on optimal statistical approaches to assessing HTE, we propose a framework that prioritizes the analysis and reporting of multivariate risk-based HTE and suggests that other subgroup analyses should be explicitly labeled either as primary subgroup analyses (well-motivated by prior evidence and intended to produce clinically actionable results) or secondary (exploratory) subgroup analyses (performed to inform future research). A standardized and transparent approach to HTE assessment and reporting could substantially improve clinical trial utility and interpretability

‘Trendy’ cities: exploring the adoption of different types of social media by Portuguese municipalities

What are the determinants of social media adoption by local government? This ongoing research provides a tentative answer to this question by analysing the 308 municipalities in Portugal. Extending previous analyses of Facebook and/or Twitter usage levels, we examine why local governments adopt a particular social media platform. More concretely, we explore, with statistical analyses, the determinants of the adoption of different types of social media. We investigate the adoption of three extremely popular social media (i.e. Facebook, Twitter and YouTube) as well as possible alternatives to those, more popular, applications. Since these platforms have distinct natures and can serve diverse purposes, we examine to what extent aspects such as local government’s commitment to transparency and participation, administrative capacity, media landscape, and socio-demographic and economic factors can explain the adoption of certain social media platforms. The results show that, indeed, demographic characteristics and administrative capacity are important factors for the adoption of less popular social media. Surprisingly, we also observe a geographical difference in municipalities’ social media adoption, with the south, in this regard, being ‘trendier’, or more innovative, than the north.This paper is a result of the project “SmartEGOV: Harnessing EGOV for Smart Governance (Foundations, methods, Tools)/NORTE-01-0145-FEDER-000037”, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (EFDR). António Tavares acknowledges the financial support of the Portuguese Foundation for Science and Technology and the Portuguese Ministry of Education and Science through national funds [Grant No. UID/CPO/0758/2019]

Declining Rates in Male Circumcision amidst Increasing Evidence of its Public Health Benefit

BACKGROUND: Recent experimental evidence has demonstrated the benefits of male circumcision for the prevention of human immunodeficiency virus (HIV) infection. Studies have also shown that male circumcision is cost-effective and reduces the risk for certain ulcerative sexually transmitted diseases (STDs). The epidemiology of male circumcision in the United States is poorly studied and most prior reports were limited by self-reported measures. The study objective was to describe male circumcision trends among men attending the San Francisco municipal STD clinic, and to correlate the findings with HIV, syphilis and sexual orientation. METHODS AND FINDINGS: A cross sectional study was performed by reviewing all electronic records of males attending the San Francisco municipal STD clinic between 1996 and 2005. The prevalence of circumcision over time and by subpopulation such as race/ethnicity and sexual orientation were measured. The findings were further correlated with the presence of syphilis and HIV infection. Circumcision status was determined by physical examination and disease status by clinical evaluation with laboratory confirmation. Among 58,598 male patients, 32,613 (55.7%, 95% Confidence Interval (CI) 55.2-56.1) were circumcised. Male circumcision varied significantly by decade of birth (increasing between 1920 and 1950 and declining overall since the 1960's), race/ethnicity (Black: 62.2%, 95% CI 61.2-63.2, White: 60.0%, 95% CI 59.46-60.5, Asian Pacific Islander: 48.2%, 46.9-49.5 95% CI, and Hispanic: 42.2%, 95% CI 41.3-43.1), and sexual orientation (gay/bisexual: 73.0%, 95% CI 72.6-73.4; heterosexual: 66.0%, 65.5-66.5). Male circumcision may have been modestly protective against syphilis in HIV-uninfected heterosexual men (PR 0.92, 95% C.I. 0.83-1.02, P = 0.06). CONCLUSIONS: Male circumcision was common among men seeking STD services in San Francisco but has declined substantially in recent decades. Male circumcision rates differed by race/ethnicity and sexual orientation. Given recent studies suggesting the public health benefits of male circumcision, a reconsideration of national male circumcision policy is needed to respond to current trends

DNA Ligase C and Prim-PolC participate in base excision repair in mycobacteria

Prokaryotic Ligase D is a conserved DNA repair apparatus processing DNA double-strand breaks in stationary phase. An orthologous Ligase C (LigC) complex also co-exists in many bacterial species but its function is unknown. Here, we show that the LigC complex interacts with core BER enzymes in vivo and demonstrate that together these factors constitute an excision repair apparatus capable of repairing damaged bases and abasic sites. The polymerase component, which contains a conserved C-terminal structural loop, preferentially binds to and fills-in short gapped DNA intermediates with RNA and LigC ligates the resulting nicks to complete repair. Components of the LigC complex, like LigD, are expressed upon entry into stationary phase and cells lacking either of these pathways exhibit increased sensitivity to oxidising genotoxins. Together, these findings establish that the LigC complex is directly involved in an excision repair pathway(s) that repairs DNA damage with ribonucleotides during stationary phase

Therapeutic DNA vaccine induces broad T cell responses in the gut and sustained protection from viral rebound and AIDS in SIV-infected rhesus macaques.

Immunotherapies that induce durable immune control of chronic HIV infection may eliminate the need for life-long dependence on drugs. We investigated a DNA vaccine formulated with a novel genetic adjuvant that stimulates immune responses in the blood and gut for the ability to improve therapy in rhesus macaques chronically infected with SIV. Using the SIV-macaque model for AIDS, we show that epidermal co-delivery of plasmids expressing SIV Gag, RT, Nef and Env, and the mucosal adjuvant, heat-labile E. coli enterotoxin (LT), during antiretroviral therapy (ART) induced a substantial 2-4-log fold reduction in mean virus burden in both the gut and blood when compared to unvaccinated controls and provided durable protection from viral rebound and disease progression after the drug was discontinued. This effect was associated with significant increases in IFN-γ T cell responses in both the blood and gut and SIV-specific CD8+ T cells with dual TNF-α and cytolytic effector functions in the blood. Importantly, a broader specificity in the T cell response seen in the gut, but not the blood, significantly correlated with a reduction in virus production in mucosal tissues and a lower virus burden in plasma. We conclude that immunizing with vaccines that induce immune responses in mucosal gut tissue could reduce residual viral reservoirs during drug therapy and improve long-term treatment of HIV infection in humans