Altered spin state equilibrium in the T309V mutant of cytochrome P450 2D6: a spectroscopic and computational study

Cytochrome P450 2D6 (CYP2D6) is one of the most important cytochromes P450 in humans. Resonance Raman data from the T309V mutant of CYP2D6 show that the substitution of the conserved I-helix threonine situated in the enzyme’s active site perturbs the heme spin equilibrium in favor of the six-coordinated low-spin species. A mechanistic hypothesis is introduced to explain the experimental observations, and its compatibility with the available structural and spectroscopic data is tested using quantum-mechanical density functional theory calculations on active-site models for both the CYP2D6 wild type and the T309V mutant

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Practical attacks against privacy and availability in 4G/LTE mobile communication systems

Mobile communication systems are now an essential part of life throughout the world. Fourth generation “Long Term Evolution” (LTE) mobile communication networks are being deployed. The LTE suite of specifications is considered to be significantly better than its predecessors not only in terms of functionality but also with respect to security and privacy for subscribers. We carefully analyzed LTE access network protocol specifications and uncovered several vulnerabilities. Using commercial LTE mobile devices in real LTE networks, we demonstrate inexpensive, and practical attacks exploiting these vulnerabilities. Our first class of attacks consists of three different ways of making an LTE device leak its location: In our experiments, a semi-passive attacker can locate an LTE device within a 2 km2 area in a city whereas an active attacker can precisely locate an LTE device using GPS co-ordinates or trilateration via cell-tower signal strength information. Our second class of attacks can persistently deny some or all services to a target LTE device. To the best of our knowledge, our work constitutes the first publicly reported practical attacks against LTE access network protocols. We present several countermeasures to resist our specific attacks. We also discuss possible trade-off considerations that may explain why these vulnerabilities exist. We argue that justification for these trade-offs may no longer valid. We recommend that safety margins introduced into future specifications to address such trade-offs should incorporate greater agility to accommodate subsequent changes in the trade-off equilibrium

Practical Attacks Against Privacy and Availability in 4G/LTE Mobile Communication Systems

Mobile communication systems are now an essential part of life throughout the world. Fourth generation “Long Term Evolution” (LTE) mobile communication networks are being deployed. The LTE suite of specifications is considered to be significantly better than its predecessors not only in terms of functionality but also with respect to security and privacy for subscribers. We carefully analyzed LTE access network protocol specifications and uncovered several vulnerabilities. Using commercial LTE mobile devices in real LTE networks, we demonstrate inexpensive, and practical attacks exploiting these vulnerabilities. Our first class of attacks consists of three different ways of making an LTE device leak its location: In our experiments, a semi-passive attacker can locate an LTE device within a 2 km2 area in a city whereas an active attacker can precisely locate an LTE device using GPS co-ordinates or trilateration via cell-tower signal strength information. Our second class of attacks can persistently deny some or all services to a target LTE device. To the best of our knowledge, our work constitutes the first publicly reported practical attacks against LTE access network protocols. We present several countermeasures to resist our specific attacks. We also discuss possible trade-off considerations that may explain why these vulnerabilities exist. We argue that justification for these trade-offs may no longer valid. We recommend that safety margins introduced into future specifications to address such trade-offs should incorporate greater agility to accommodate subsequent changes in the trade-off equilibrium

White-Stingray: Evaluating IMSI Catchers Detection Applications

IMSI catchers, also known as fake base station threats, have recently become a real concern. There are currently a few freely available tools to detect such threats, most of which are Android apps that warn users when they are connected to the fake cellular base station. In this paper, we evaluate these Android apps and test how resistant they are against various attacking techniques. Such an evaluation is important for not only measuring the available defense against IMSI catchers attacks but also identifying gaps to build effective solutions. We developed White-Stingray, a systematic framework with various attacking capabilities in 2G and 3G networks, and used it for our study. Our results of five popular Android apps are worrisome: none of these apps are resistant to basic privacy identifier catching techniques. Based on our results, we identify limitation of these apps and propose remedies for improving the current state of IMSI catchers detection on mobile devices

High-frequency deregulated expression of Wnt signaling pathway members in breast carcinomas

Zahid Khan,1 Maha Arafah,2 Jilani Purusottapatnam Shaik,1 Alka Mahale,3 Mohammad Saud Alanazi1 1Genome Research Chair, Department of Biochemistry, College of Science, King Saud University, Riyadh, 2Department of Pathology, College of Medicine, King Saud University, Riyadh, 3King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia Purpose: Breast carcinoma is the most common malignancy and leading cause of cancer-related deaths in women worldwide including Saudi Arabia. Breast cancer in Saudi women develops at a much early age with median age of onset of 49 years compared to 62 years observed in patients from USA. Aberrations in wingless and integration site growth factor (Wnt) signaling pathway have been pathologically implicated in development of breast cancers and hence its role was examined in Saudi patients.Materials and methods: We immunohistochemically examined various components of Wnt signaling pathway including &beta;-catenin, tumor suppressor proteins, adenomatous polyposis coli (APC), and Axin, expression of naturally occurring pathway antagonists such as Dickkopf Wnt signaling pathway inhibitor 3 (DKK3), FRP2, and WIF1, as well as Wnt target cyclin D1 and c-Myc to establish if the pathway is constitutively activated in breast cancers arising in Saudi women.Results: Cytoplasmic &beta;-catenin, indicative of activation of the pathway, was observed in 24% of cases. Expression of APC and Axin, which are components of &beta;-catenin destruction complex, was lost in 5% and 10% of tumors, respectively. Additionally, Wnt signaling inhibitors DKK3, FRP2, and Wnt inhibitory factor 1 (WIF1) were not expressed in 8%, 14%, and 5% breast tumors, respectively. Overall, accumulation of cytoplasmic &beta;-catenin and downregulation of other Wnt pathway proteins (APC/Axin/DKK3/FRP2/WIF1) were found in approximately half of the breast cancers (47%) in our cohort. Consistent with this, analysis of Wnt target genes demonstrated moderate-to-strong expression of c-Myc in 58% and cyclin D1 in 50% of breast cancers. Deregulation of Wnt pathway was not associated with age of onset of the disease, tumor grade, and triple-negative status of breast cancers.Conclusions: High level of deregulated expression of Wnt pathway proteins suggests its important role in pathogenesis of breast cancers arising in Saudi women who may benefit from development of therapeutic drugs targeting this pathway. Keywords: breast cancer, Wnt signaling pathway, immunohistochemistry, &beta;-catenin&nbsp