Analysis of operating system diversity for intrusion tolerance

One of the key benefits of using intrusion-tolerant systems is the possibility of ensuring correct behavior in the presence of attacks and intrusions. These security gains are directly dependent on the components exhibiting failure diversity. To what extent failure diversity is observed in practical deployment depends on how diverse are the components that constitute the system. In this paper, we present a study with operating system's (OS's) vulnerability data from the NIST National Vulnerability Database (NVD). We have analyzed the vulnerabilities of 11 different OSs over a period of 18 years, to check how many of these vulnerabilities occur in more than one OS. We found this number to be low for several combinations of OSs. Hence, although there are a few caveats on the use of NVD data to support definitive conclusions, our analysis shows that by selecting appropriate OSs, one can preclude (or reduce substantially) common vulnerabilities from occurring in the replicas of the intrusion-tolerant system

Unsupervised discovery of tissue architecture in multiplexed imaging

Multiplexed imaging and spatial transcriptomics enable highly resolved spatial characterization of cellular phenotypes, but still largely depend on laborious manual annotation to understand higher-order patterns of tissue organization. As a result, higher-order patterns of tissue organization are poorly understood and not systematically connected to disease pathology or clinical outcomes. To address this gap, we developed an approach called UTAG to identify and quantify microanatomical tissue structures in multiplexed images without human intervention. Our method combines information on cellular phenotypes with the physical proximity of cells to accurately identify organ-specific microanatomical domains in healthy and diseased tissue. We apply our method to various types of images across healthy and disease states to show that it can consistently detect higher-level architectures in human tissues, quantify structural differences between healthy and diseased tissue, and reveal tissue organization patterns at the organ scale

The dynamics of replication licensing in live Caenorhabditis elegans embryos

Accurate DNA replication requires proper regulation of replication licensing, which entails loading MCM-2-7 onto replication origins. In this paper, we provide the first comprehensive view of replication licensing in vivo, using video microscopy of Caenorhabditis elegans embryos. As expected, MCM-2-7 loading in late M phase depended on the prereplicative complex (pre-RC) proteins: origin recognition complex (ORC), CDC-6, and CDT-1. However, many features we observed have not been described before: GFP-ORC-1 bound chromatin independently of ORC-2-5, and CDC-6 bound chromatin independently of ORC, whereas CDT-1 and MCM-2-7 DNA binding was interdependent. MCM-3 chromatin loading was irreversible, but CDC-6 and ORC turned over rapidly, consistent with ORC/CDC-6 loading multiple MCM-2-7 complexes. MCM-2-7 chromatin loading further reduced ORC and CDC-6 DNA binding. This dynamic behavior creates a feedback loop allowing ORC/CDC-6 to repeatedly load MCM-2-7 and distribute licensed origins along chromosomal DNA. During S phase, ORC and CDC-6 were excluded from nuclei, and DNA was overreplicated in export-defective cells. Thus, nucleocytoplasmic compartmentalization of licensing factors ensures that DNA replication occurs only once

IL-13 Augments Compressive Stress–Induced Tissue Factor Expression in Human Airway Epithelial Cells

Tissue factor (TF) is best known as a cellular initiator of coagulation, but it is also a multifunctional protein that has been implicated in multiple pathophysiologic conditions, including asthma. In the lung, airway epithelial cells express TF, but it is unknown how TF expression is regulated by asthma-associated mediators. We investigated the role of IL-13, a type 2 cytokine, alone and in combination with compressive stress, which mimics asthmatic bronchoconstriction, on TF expression and release of TF-positive extracellular vesicles from primary normal human bronchial epithelial cells. Well-differentiated normal human bronchial epithelial cells were treated with IL-13 and compressive stress, alone and in combination. TF mRNA, protein and activity were measured in the cells and conditioned media. TF was also measured in the bronchoalveolar lavage (BAL) fluid of allergen-challenged mice and patients with asthma. IL-13 and compressive stress increased TF expression, but only compressive stress induced TF-positive extracellular vesicle release. Pretreatment with IL-13 augmented compressive stress–induced TF expression and release. TF protein and activity in BAL fluid were increased in allergen-sensitized and -challenged mice. TF was elevated in the BAL fluid of patients with mild asthma after an allergen challenge. Our in vitro and in vivo data indicate close cooperation between mechanical and inflammatory stimuli on TF expression and release of TF-positive extracellular vesicles in the lungs, which may contribute to pathophysiology of asthma

Protocol for an open label: phase I trial within a cohort of foetal cell transplants in people with Huntington’s disease

Huntington’s disease is a progressive neurodegenerative disorder characterised by motor, cognitive and psychiatric symptoms. Currently, no disease-modifying therapies are available to slow or halt disease progression. Huntington’s disease is characterised by relatively focal and specific loss of striatal medium spiny neurons, which makes it suitable for cell replacement therapy, a process involving the transplantation of donor cells to replace those lost due to disease. TRIDENT (TRIal DEsigns for delivery of Novel Therapies in neurodegeneration) is a phase I Trial Within a Cohort (TWiC) designed to assess safety and feasibility of transplanting human fetalstriatal cells into the striatum of people with Huntington’s disease. A minimum of 18 participants will be enrolled in the study cohort, and up to five eligible participants will be randomly selected to undergo transplantation of 12-22 million fetal cells in a dose escalation paradigm. Independent reviewers will assess safety outcomes (lack of significant infection, bleeding or new neurological deficit) four weeks after surgery, and ongoing safety will be established before conducting each subsequent surgery. All participants will undergo detailed clinical and functional assessment at baseline, 6 and 12 months. Surgery will be performed one month after baseline, and transplant participants will undergo regular clinical follow-up for at least 12 months. Evaluation of trial processes will also be undertaken. Transplant participants and their carers will be interviewed approximately one month before and after surgery. Interviews will also be conducted with non-transplanted participants and healthcare staff delivering the intervention and involved in the clinical care of participants. Evaluation of clinical and functional efficacy outcomes and intervention costs will be carried out to explore plausible trial designs for subsequent randomised controlled trials aimed at evaluating efficacy and cost-effectiveness of cell replacement therapy. TRIDENT will enable the assessment of the safety, feasibility, acceptability and cost of fetalcell transplants in people with Huntington’s disease. The data collected will inform trial designs for complex intracranial interventions in a range of neurodegenerative conditions and facilitate the development of stable surgical pipelines for delivery of future stem cell trials

Reverse genetics with a full-length infectious cDNA of the Middle East respiratory syndrome coronavirus

The identification of a novel, emerging human coronavirus with ∼50% mortality, designated Middle East respiratory syndrome coronavirus (MERS-CoV), emphasizes the importance of the rapid development of reagents that can be used to (i) characterize the replication and pathogenesis of emerging pathogens and (ii) develop therapeutics for treatment. In this report, we describe the development of a cassette-based infectious cDNA clone of MERS-CoV and verify that it functions similarly to the wild-type isolate in terms of replication, protein and RNA expression, and spike attachment protein processing. We also show that the virus replicates preferentially in differentiated primary lung cells

Orthopedic Surgeon's Awareness Can Improve Osteoporosis Treatment Following Hip Fracture: A Prospective Cohort Study

Through retrospective Jeju-cohort study at 2005, we found low rates of detection of osteoporosis (20.1%) and medication for osteoporosis (15.5%) in those who experienced hip fracture. This study was to determine the orthopedic surgeons' awareness could increase the osteoporosis treatment rate after a hip fracture and the patient barriers to osteoporosis management. We prospectively followed 208 patients older than 50 yr who were enrolled for hip fractures during 2007 in Jeju-cohort. Thirty four fractures in men and 174 in women were treated at the eight hospitals. During the study period, orthopedic surgeons who worked at these hospitals attended two education sessions and were provided with posters and brochures. Patients were interviewed 6 months after discharge using an evaluation questionnaire regarding their perceptions of barriers to osteoporosis treatment. The patients were followed for a minimum of one year. Ninety-four patients (45.2%) underwent detection of osteoporosis by dual energy x-ray absorptiometry and 67 (32.2%) were prescribed medication for osteoporosis at the time of discharge. According to the questionnaire, the most common barrier to treatment for osteoporosis after a hip fracture was patients reluctance. The detection and medication rate for osteoporosis after hip fracture increased twofold after orthopedic surgeons had attended the intervention program. Nevertheless, the osteoporosis treatment rate remains inadequate

Protein phosphatase 1 recruitment by Rif1 regulates DNA replication origin firing by counteracting DDK activity

The eukaryotic genome is replicated according to a strict temporal program. Here, Bianchi and colleagues find that Rif1, a master regulator of the DNA replication program in yeast and mammals, exerts its effect on DNA replication origins by recruiting protein phosphatase 1 (PP1) to chromosomes. Rif1/PP1 counteracts the positive action of the DDK kinase on the replicative kinase MCM. In a final twist, kinase action on Rif1 is proposed to eventually release PP1 and allow origin firing