Timed Implementation Relations for the Distributed Test Architecture

In order to test systems that have physically distributed interfaces, called ports, we might use a distributed approach in which there is a separate tester at each port. If the testers do not synchronise during testing then we cannot always determine the relative order of events observed at different ports and this leads to new notions of correctness that have been described using corresponding implementation relations. We study the situation in which each tester has a local clock and timestamps its observations. If we know nothing about how the local clocks relate then this does not affect the implementation relation while if the local clocks agree exactly then we can reconstruct the sequence of observations made. In practice, however, we are likely to be between these extremes: the local clocks will not agree exactly but we have some information regarding how they can differ. We start by assuming that a local tester interacts synchronously with the corresponding port of the system under test and then extend this to the case where communications can be asynchronous, considering both the first-in-first-out (FIFO) case and the non-FIFO case. The new implementation relations are stronger than implementation relations for distributed testing that do not use timestamps but still reflect the distributed nature of observations. This paper explores these alternatives and derives corresponding implementation relations

The use of wet-laid techniques to obtain flax nonwovens with different thermoplastic binding fibers for technical insulation applications

[EN] In this work, the wet-laid technique has been used to obtain flax nonwovens thermally bonded with different contents of polyvinyl alcohol (PVA) and bicomponent polyamide 6/copolyamide (PA6/CoPA) fibers in the 10-30 wt.% range. Scanning electron microscopy has been used to evaluate the formation of interlock points through melted polymer and flax fibers. Volume porosity has been estimated through determination of thickness and surface mass. Tensile strength and elongation at break have been determined on longitudinal (preferential) and transversal directions to evaluate anisotropy. The sound absorption properties of stacked sheets of flax: PVA and flax: PA6/CoPA nonwovens have been evaluated. In addition, the thermal insulating properties of individual nonwovens have been obtained. Mechanical characterization shows slight anisotropy. The absorption coefficient is interesting in the medium frequencies range, and relatively low thermal conductivity and thermal resistance values are obtained with these nonwovens (in the 0.020-0.025Wm(-1) K-1 range for flax: PVA nonwovens and in the 0.09-0.10Wm(-1) K-1 range for flax: PA6/CoPA nonwovens). By taking into account these features, these nonwoven substrates could find interesting applications as sound absorbers and/or thermal insulation materials in technical applications.This work is part of the project IPT-310000-2010-037, "ECOTEXCOMP: Research and development of textile structures useful as reinforcement of composite materials with marked ecological character", and was supported by the "Ministerio de Ciencia e Innovacion", with a grant of (sic)189,540.20, within the Plan Nacional de Investigacion Cientifica, Desarrollo e Innovacion Tecnologica 2008-2011 and funded by the European Union through FEDER funds, Technology Fund 2007-2013 and Operational Programme on R + D + i for and on behalf of the companies. The project is also known as "WET-TEX: Implementacion de la tecnologia wet-laid en el desarrollo de nuevos textiles medico-sanitario" with expedient number IMIDIC/2010/137 (total grant of (sic)284,400) and the project "WET-TEX II: Implementacion de la tecnologia wet-laid en la investigacion y desarrollo de paneles para aplicaciones tecnicas a partir de residuos procedentes de la industria textil" with expedient number IMDEEA/2011/167 (total grant of (sic)255,000) funded by IMPIVA and cofunded (80%) by the European Union through FEDER funds, Valencian Community Operational 2007-2012.Fages, E.; Cano, MA.; Gironés, S.; Boronat Vitoria, T.; Fenollar Gimeno, OÁ.; Balart Gimeno, RA. (2013). The use of wet-laid techniques to obtain flax nonwovens with different thermoplastic binding fibers for technical insulation applications. Textile Research Journal. 83(4):426-437. https://doi.org/10.1177/0040517512454183S42643783

Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression

PURPOSE: Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS: We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS: We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway (KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION: SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models

Internal Ribosomal Entry Site-Mediated Translation Is Important for Rhythmic PERIOD1 Expression

The mouse PERIOD1 (mPER1) plays an important role in the maintenance of circadian rhythm. Translation of mPer1 is directed by both a cap-dependent process and cap-independent translation mediated by an internal ribosomal entry site (IRES) in the 5′ untranslated region (UTR). Here, we compared mPer1 IRES activity with other cellular IRESs. We also found critical region in mPer1 5′UTR for heterogeneous nuclear ribonucleoprotein Q (HNRNPQ) binding. Deletion of HNRNPQ binding region markedly decreased IRES activity and disrupted rhythmicity. A mathematical model also suggests that rhythmic IRES-dependent translation is a key process in mPER1 oscillation. The IRES-mediated translation of mPer1 will help define the post-transcriptional regulation of the core clock genes

Graft-vs-tumor effect in patients with advanced nasopharyngeal cancer treated with nonmyeloablative allogeneic PBSC transplantation

While nonmyeloablative peripheral blood stem cell transplantation (NST) has shown efficacy against several solid tumors, it is untested in nasopharyngeal cancer (NPC). In a phase II clinical trial, 21 patients with pretreated metastatic NPC underwent NST with sibling PBSC allografts, using CY conditioning, thymic irradiation and in vivo T-cell depletion with thymoglobulin. Stable lymphohematopoietic chimerism was achieved in most patients and prophylactic CYA was tapered at a median of day +30. Seven patients (33%) showed partial response and three (14%) achieved stable disease. Four patients were alive at 2 years and three showed prolonged disease control of 344, 525 and 550 days. With a median follow-up of 209 (4–1147) days, the median PFS was 100 days (95% confidence interval (CI), 66–128 days), and median OS was 209 days (95% CI, 128–236 days). Patients with chronic GVHD had better survival—median OS 426 days (95% CI, 194–NE days) vs 143 days (95% CI, 114–226 days) (P=0.010). Thus, NST may induce meaningful clinical responses in patients with advanced NPC

Brain perfusion imaging with voxel-based analysis in secondary progressive multiple sclerosis patients with a moderate to severe stage of disease: a boon for the workforce

Background: The present study was carried out to evaluate cerebral perfusion in multiple sclerosis (MS) patients with a moderate to severe stage of disease. Some patients underwent hyperbaric oxygen therapy (HBOT) and brain perfusion between before and after that was compared. Methods: We retrospectively reviewed 25 secondary progressive (SP)-MS patients from the hospital database. Neurological disability evaluated by Expanded Disability Status Scale Score (EDSS). Brain perfusion was performed by (99 m) Tc-labeled bicisate (ECD) brain SPECT and the data were compared using statistical parametric mapping (SPM). In total, 16 patients underwent HBOT. Before HBOT and at the end of 20 sessions of oxygen treatment, 99mTc-ECD brain perfusion single photon emission computed tomography (SPECT) was performed again then the results were evaluated and compared. Brain perfusion was performed by (99 m) Tc-labeled bicisate (ECD) brain SPECT and the data were compared using statistical parametric mapping (SPM). Results: A total of 25 SP-MS patients, 14 females (56 %) and 11 males (44 %) with a mean age of 38.92 ± 11. 28 years included in the study. The mean disease duration was 8.70 ± 5.30 years. Of the 25 patients, 2 (8 %) had a normal SPECT and 23 (92 %) had abnormal brain perfusion SPECT studies. The study showed a significant association between severity of perfusion impairment with disease duration and also with EDSS (P <0.05). There was a significant improvement in pre- and post-treatment perfusion scans (P <0.05), but this did not demonstrate a significant improvement in the clinical subjective and objective evaluation of patients (P >0.05). Conclusions: This study depicted decreased cerebral perfusion in SP-MS patients with a moderate to severe disability score and its association with clinical parameters. Because of its accessibility, rather low price, practical ease, and being objective quantitative information, brain perfusion SPECT can be complementing to other diagnostic modalities such as MRI and clinical examinations in disease surveillance and monitoring. The literature on this important issue is extremely scarce, and follow up studies are required to assess these preliminary results

Vaccinia-Related Kinase 1 Is Required for the Maintenance of Undifferentiated Spermatogonia in Mouse Male Germ Cells

Vaccinia-related kinase 1 (VRK1) is a crucial protein kinase for mitotic regulation. VRK1 is known to play a role in germ cell development, and its deficiency results in sterility. Here we describe that VRK1 is essential for the maintenance of spermatogonial stem cells. To determine whether VRK1 plays a role in these cells, we assessed the population size of undifferentiated spermatogonia. Flow cytometry analyses showed that the number of undifferentiated spermatogonia was markedly reduced in VRK1-deficient testes. VRK1 was highly expressed in spermatogonial populations, and approximately 66% of undifferentiated spermatogonia that were sorted as an Ep-CAM+/c-kit−/alpha-6-integrin+ population showed a positive signal for VRK1. Undifferentiated stem cells expressing Plzf and Oct4 but not c-kit also expressed VRK1, suggesting that VRK1 is an intrinsic factor for the maintenance of spermatogonial stem cells. Microarray analyses of the global testicular transcriptome and quantitative RT-PCR of VRK1-deficient testes revealed significantly reduced expression levels of undifferentiated spermatogonial marker genes in early postnatal mice. Together, these results suggest that VRK1 is required for the proliferation and differentiation of undifferentiated spermatogonia, which are essential for spermatogenic cell maintenance

Systems Biology: A Therapeutic Target for Tumor Therapy

Tumor-related activities that seem to be operationally induced by the division of function, such as inflammation, neoangiogenesis, Warburg effect, immune response, extracellular matrix remodeling, cell proliferation rate, apoptosis, coagulation effects, present itself from a systems perspective as an enhancement of complexity. We hypothesized, that tumor systems-directed therapies might have the capability to use aggregated action effects, as adjustable sizes to therapeutically modulate the tumor systems’ stability, homeostasis, and robustness. We performed a retrospective analysis of recently published data on 224 patients with advanced and heavily pre-treated (10% to 63%) vascular sarcoma, melanoma, renal clear cell, cholangiocellular, carcinoma, hormone-refractory prostate cancer, and multivisceral Langerhans’ cell histiocytosis enrolled in nine multi-center phase II trials (11 centers). Each patient received a multi-targeted systems-directed therapy that consisted of metronomic low-dose chemotherapy, a COX-2 inhibitor, combined with one or two transcription modulators, pioglitazone +/− dexamethasone or IFN-alpha. These treatment schedules may attenuate the metastatic potential, tumor-associated inflammation, may exert site-specific activities, and induce long-term disease stabilization followed by prolonged objective response (3% to 48%) despite poor monoactivity of the respective drugs. Progression-free survival data are comparable with those of reductionist-designed standard first-line therapies. The differential response patterns indicate the therapies’ systems biological activity. Understanding systems biology as adjustable size may break through the barrier of complex tumor-stroma-interactions in a therapeutically relevant way: Comparatively high efficacy at moderate toxicity. Structured systems-directed therapies in metastatic cancer may get a source for detecting the topology of tumor-associated complex aggregated action effects as adjustable sizes available for targeted biomodulatory therapies