An Italian cost-effectiveness analysis of paclitaxel albumin (nab-paclitaxel) versus conventional paclitaxel for metastatic breast cancer patients: the COSTANza study

PubMed Central

Lazzaro, Carlo; Bordonaro, Roberto; Cognetti, Francesco; Fabi, Alessandra; De Placido, Sabino; Arpino, Grazia; Marchetti, Paolo; Botticelli, Andrea; Pronzato, Paolo; Martelli, Elisa

2013-01-01

Purpose Paclitaxel albumin (nab-paclitaxel) is a nanoparticle albumin-bound paclitaxel formulation aimed at increasing therapeutic index in metastatic breast cancer. When compared to conventional paclitaxel, nab-paclitaxel has a reported longer time to progression, higher response, lower incidence of neutropenia, no need for premedication, shorter time of administration, and in pretreated metastatic breast cancer patients, extended overall survival. This study investigates the cost-effectiveness of nab-paclitaxel versus conventional paclitaxel for pretreated metastatic breast cancer patients in Italy. Materials and methods A Markov model with progression-free, progressed, and dead states was developed to estimate costs, outcomes, and quality adjusted life years over 5 years from the Italian National Health Service viewpoint. Patients were assumed to receive nab-paclitaxel 260 mg/m2 three times weekly or conventional paclitaxel 175 mg/m2 three times weekly. Data on health care resource consumption was collected from a convenience sample of five Italian centers. Resources were valued at Euro (€) 2011. Published utility weights were applied to health states to estimate the impact of response, disease progression, and adverse events on quality adjusted life years. Three sensitivity analyses tested the robustness of the base case incremental cost-effectiveness ratio (ICER). Results and conclusion Compared to conventional paclitaxel, nab-paclitaxel gains an extra 0.165 quality adjusted life years (0.265 life years saved) and incurs additional costs of €2506 per patient treated. This translates to an ICER of €15,189 (95% confidence interval: €11,891–€28,415). One-way sensitivity analysis underscores that ICER for nab-paclitaxel remains stable despite varying taxanes cost. Threshold analysis shows that ICER for nab-paclitaxel exceeds €40,000 only if cost per mg of conventional paclitaxel is set to zero. Probabilistic sensitivity analysis highlights that nab

[A Case of Shock Due to nabPTX Administration Successfully Treated with Cytokine Adsorption Therapy].

PubMed

Yoshikawa, Katsuhiro; Yamamoto, Daigo; Tsubota, Yu; Sueoka, Noriko; Chiba, Tsukuru; Ishizuka, Mariko; Kon, Masanori

2017-11-01

The patient was a 71-year-old woman with ER(+), PgR(-), HER2(3+), and Ki-674 2% breast cancer. After surgery for left breast cancer(Bt+Ax), epirubicin, cyclophosphamide therapy was administered as postoperative adjuvant chemotherapy, and nabPTX plus trastuzumab therapy was started sequentially. The patient was hospitalized due to severe neutrope- nia(neutrophils 0/mm3)from nabPTX, but her condition stabilized after admission. However, the patient suddenly went into shock after 3 days and was thus transferred to the ICU. Her general condition was rapidly improved through cytokine adsorption therapy in the ICU. After 5 days, she was extubated and wheeled back to a general ward. She was discharged without problems in the succeeding months. In this case, FN or cardiovascular diseases was ruled out, and engraftment syndrome was considered given that cytokine adsorption therapy significantly improved the patient's condition. Considering the risk for severe neutropenia in nabPTX administration, clinicians should exercise caution when administering the drug.

Inversion-mediated gene fusions involving NAB2-STAT6 in an unusual malignant meningioma.

PubMed

Gao, F; Ling, C; Shi, L; Commins, D; Zada, G; Mack, W J; Wang, K

2013-08-20

Meningiomas are the most common primary intracranial tumours, with ∼3% meeting current histopathologic criteria for malignancy. In this study, we explored the transcriptome of meningiomas using RNA-Seq. Inversion-mediated fusions between two adjacent genes, NAB2 and STAT6, were detected in one malignant tumour, creating two novel in-frame transcripts that were validated by RT-PCR and Sanger sequencing. Gene fusions of NAB2-STAT6 were recently implicated in the pathogenesis of solitary fibrous tumours; our study suggested that similar fusions may also have a role in a malignant meningioma with unusual histopathologic features.

Meningeal hemangiopericytoma and solitary fibrous tumors carry the NAB2-STAT6 fusion and can be diagnosed by nuclear expression of STAT6 protein.

PubMed

Schweizer, Leonille; Koelsche, Christian; Sahm, Felix; Piro, Rosario M; Capper, David; Reuss, David E; Pusch, Stefan; Habel, Antje; Meyer, Jochen; Göck, Tanja; Jones, David T W; Mawrin, Christian; Schittenhelm, Jens; Becker, Albert; Heim, Stephanie; Simon, Matthias; Herold-Mende, Christel; Mechtersheimer, Gunhild; Paulus, Werner; König, Rainer; Wiestler, Otmar D; Pfister, Stefan M; von Deimling, Andreas

2013-05-01

Non-central nervous system hemangiopericytoma (HPC) and solitary fibrous tumor (SFT) are considered by pathologists as two variants of a single tumor entity now subsumed under the entity SFT. Recent detection of frequent NAB2-STAT6 fusions in both, HPC and SFT, provided additional support for this view. On the other hand, current neuropathological practice still distinguishes between HPC and SFT. The present study set out to identify genes involved in the formation of meningeal HPC. We performed exome sequencing and detected the NAB2-STAT6 fusion in DNA of 8/10 meningeal HPC thereby providing evidence of close relationship of these tumors with peripheral SFT. Due to the considerable effort required for exome sequencing, we sought to explore surrogate markers for the NAB2-STAT6 fusion protein. We adopted the Duolink proximity ligation assay and demonstrated the presence of NAB2-STAT6 fusion protein in 17/17 HPC and the absence in 15/15 meningiomas. More practical, presence of the NAB2-STAT6 fusion protein resulted in a strong nuclear signal in STAT6 immunohistochemistry. The nuclear reallocation of STAT6 was detected in 35/37 meningeal HPC and 25/25 meningeal SFT but not in 87 meningiomas representing the most important differential diagnosis. Tissues not harboring the NAB2-STAT6 fusion protein presented with nuclear expression of NAB2 and cytoplasmic expression of STAT6 proteins. In conclusion, we provide strong evidence for meningeal HPC and SFT to constitute variants of a single entity which is defined by NAB2-STAT6 fusion. In addition, we demonstrate that this fusion can be rapidly detected by STAT6 immunohistochemistry which shows a consistent nuclear reallocation. This immunohistochemical assay may prove valuable for the differentiation of HPC and SFT from other mesenchymal neoplasms.

A Phase Ib study of ruxolitinib + gemcitabine ± nab-paclitaxel in patients with advanced solid tumors.

PubMed

Bauer, Todd M; Patel, Manish R; Forero-Torres, Andres; George, Thomas J; Assad, Albert; Du, Yining; Hurwitz, Herbert

2018-01-01

Aberrant activation of the Janus-associated kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is associated with increased malignant cell proliferation and survival. This Phase Ib study evaluated ruxolitinib, a potent JAK1/2 inhibitor, in combination with gemcitabine with or without nab-paclitaxel in patients with advanced solid tumors. Patients received ruxolitinib + gemcitabine (regimen A) or ruxolitinib + gemcitabine + nab-paclitaxel (regimen B). The objective of the dose-finding phase was to identify the maximum tolerated doses (MTDs) of ruxolitinib plus gemcitabine with or without nab-paclitaxel. Among 42 patients enrolled, the median age was 62.5 years, 81.0% had pancreatic cancer, and almost 62% had received prior systemic therapy. Regimen A was tolerated with standard doses of gemcitabine; regimen B was tolerated with reduced doses of gemcitabine/nab-paclitaxel or concomitant granulocyte colony-stimulating factor. The sponsor decided to terminate the study early due to the interim analysis results of the Phase III JANUS 1 study. Discontinuations were mainly due to radiologic or clinical disease progression (81.0% of patients). Median treatment durations were 55.5 days (cohort A0) and 150.5 days (pooled B cohorts). Four patients (pooled B cohorts) had dose-limiting toxicities: grade 3 pneumonia (n=1), grade 4 neutropenia (n=1), and grade 4 thrombocytopenia (n=2). The most common grade 3/4 hematologic adverse events (AEs) were anemia, thrombocytopenia, and neutropenia. Serious AEs occurring in ≥2 patients in cohort A0 or pooled B cohorts were abdominal pain, sepsis (cohort A0), dehydration, anemia, and asthenia (pooled B cohorts). Overall response rates (ORRs) were 12.5% in cohort A0 and 38.5% in pooled B cohorts. Among patients with pancreatic cancer, ORR was 23.5% (14.0% cohort A0 30.0% pooled B cohorts). The study was terminated early prior to reaching MTDs per sponsor decision; although ruxolitinib plus gemcitabine with or

Nutrient dynamics in streams and the role of J-NABS

Treesearch

Patrick J. Mulholland; Jackson R. Webster

2010-01-01

Nutrient dynamics in streams has been an important topic of research since the 1960s. Here we review this topic and the significant role played by J-NABS in its development. We limit this review almost exclusively to studies of N and P because these elements have been shown to limit productivity in streams. We use the expression nutrient dynamics for studies that...

A genetic screen for terminator function in yeast identifies a role for a new functional domain in termination factor Nab3

PubMed Central

Loya, Travis J.; O’Rourke, Thomas W.; Reines, Daniel

2012-01-01

The yeast IMD2 gene encodes an enzyme involved in GTP synthesis. Its expression is controlled by guanine nucleotides through a set of alternate start sites and an intervening transcriptional terminator. In the off state, transcription results in a short non-coding RNA that starts upstream of the gene. Transcription terminates via the Nrd1-Nab3-Sen1 complex and is degraded by the nuclear exosome. Using a sensitive terminator read-through assay, we identified trans-acting Terminator Override (TOV) genes that operate this terminator. Four genes were identified: the RNA polymerase II phosphatase SSU72, the RNA polymerase II binding protein PCF11, the TRAMP subunit TRF4 and the hnRNP-like, NAB3. The TOV phenotype can be explained by the loss of function of these gene products as described in models in which termination and RNA degradation are coupled to the phosphorylation state of RNA polymerase II's repeat domain. The most interesting mutations were those found in NAB3, which led to the finding that the removal of merely three carboxy-terminal amino acids compromised Nab3's function. This region of previously unknown function is distant from the protein's well-known RNA binding and Nrd1 binding domains. Structural homology modeling suggests this Nab3 ‘tail’ forms an α-helical multimerization domain that helps assemble it onto an RNA substrate. PMID:22564898

A genetic screen for terminator function in yeast identifies a role for a new functional domain in termination factor Nab3.

PubMed

Loya, Travis J; O'Rourke, Thomas W; Reines, Daniel

2012-08-01

The yeast IMD2 gene encodes an enzyme involved in GTP synthesis. Its expression is controlled by guanine nucleotides through a set of alternate start sites and an intervening transcriptional terminator. In the off state, transcription results in a short non-coding RNA that starts upstream of the gene. Transcription terminates via the Nrd1-Nab3-Sen1 complex and is degraded by the nuclear exosome. Using a sensitive terminator read-through assay, we identified trans-acting Terminator Override (TOV) genes that operate this terminator. Four genes were identified: the RNA polymerase II phosphatase SSU72, the RNA polymerase II binding protein PCF11, the TRAMP subunit TRF4 and the hnRNP-like, NAB3. The TOV phenotype can be explained by the loss of function of these gene products as described in models in which termination and RNA degradation are coupled to the phosphorylation state of RNA polymerase II's repeat domain. The most interesting mutations were those found in NAB3, which led to the finding that the removal of merely three carboxy-terminal amino acids compromised Nab3's function. This region of previously unknown function is distant from the protein's well-known RNA binding and Nrd1 binding domains. Structural homology modeling suggests this Nab3 'tail' forms an α-helical multimerization domain that helps assemble it onto an RNA substrate.

Nab-paclitaxel after docetaxel hypersensitivity reaction: case report and literature review.

PubMed

Pellegrino, Benedetta; Boggiani, Daniela; Tommasi, Chiara; Palli, Dante; Musolino, Antonino

2017-10-23

Taxanes, including paclitaxel and docetaxel, are one of the most active cytotoxic agents in breast cancer  treatment  including  Her-2  positive  subtype characterized  by  aggressive  clinical  and pathological features since the early stage. However, their use is sometimes limited by the occurrence of hypersensivity reactions (HSRs) characterized by erythematous rashes, bronchospasm, respiratory distress, hypotension, and pulmonary edema. Cross-reactions between paclitaxel and docetaxel are described in literature with a rate ranging from 49% to 90%. Abraxane (nab-paclitaxel), an albumin-bound form of paclitaxel, has a different toxicity profile from solvent-based paclitaxel and a lower rate of HSRs. Interestingly, several authors have recently reported cases of patients who developed HSRs to taxanes, principally paclitaxel, and were then safety treated with Abraxane, suggesting the absence of cross-reactivity between these drugs. Based on these considerations, we report our clinical experience and perform a literature review on this topic with the aim to investigate the cross-reactivity between nab-paclitaxel and other taxanes, in particular with docetaxel.

Metastatic melanoma cells with BRAF G469A mutation: nab-paclitaxel better than vemurafenib?

PubMed

Porcelli, Letizia; Guida, Gabriella; Tommasi, Stefania; Guida, Michele; Azzariti, Amalia

2015-08-01

BRAF G469A is a missense mutation within exon 11 of the BRAF gene resulting in a constitutively activated enzyme frequently associated with MAP kinase cascade signaling activation. No evidence currently exists about its role in determining sensitivity/resistance to BRAF inhibitors, utilized in the treatment of patients carrying BRAF V600 mutations, and to chemotherapy. The newly established metastatic melanoma (MM) cell line MO-1 was characterized for its sensitivity to vemurafenib and nab-paclitaxel, both already utilized for the treatment of MM. All analyses were carried out by comparing results with those found in MM cells wild type for BRAF or mutated in V600. In addition, cellular effectors were investigated by ELISA kits, western blotting and flow cytometry. The exposure to vemurafenib inhibited MO-1 cell proliferation at concentrations similar to those obtained in vemurafenib-resistant melanoma models, and an explanation of this sensitivity is the strong activation of Erk1/2 and the low expression of MITF. Nab-paclitaxel strongly reduced proliferation of MO-1 cells perhaps for the very low expression level of PMEL17, transcriptionally regulated by MITF and negatively involved in determining sensitivity to taxanes. Thus, the mutation BRAF G469A in MM might be related to a weak effectiveness of therapy with BRAF inhibitors and a promising therapeutic approach may be with nab-paclitaxel.

Crystal Structure of human Karyopherin β2 bound to the PY-NLS of Saccharomyces cerevisiae Nab2

PubMed Central

Soniat, Michael; Sampathkumar, Parthasarathy; Collett, Garen; Gizzi, Anthony S.; Banu, Radhika N.; Bhosle, Rahul C.; Chamala, Swetha; Chowdhury, Sukanya; Fiser, Andras; Glenn, Alan S.; Hammonds, James; Hillerich, Brandan; Khafizov, Kamil; Love, James D.; Matikainen, Bridget; Seidel, Ronald D.; Toro, Rafael; Kumar, P. Rajesh; Bonanno, Jeffery B.; Chook, Yuh Min; Almo, Steven C.

2013-01-01

Import-Karyopherin or Importin proteins bind nuclear localization signals (NLSs) to mediate the import of proteins into the cell nucleus. Karyopherin β2 or Kapβ2, also known as Transportin, is a member of this transporter family responsible for the import of numerous RNA binding proteins. Kapβ2 recognizes a targeting signal termed the PY-NLS that lies within its cargos to target them through the nuclear pore complex. The recognition of PY-NLS by Kapβ2 is conserved throughout eukaryotes. Kap104, the Kapβ2 homolog in Saccharomyces cerevisiae, recognizes PY-NLSs in cargos Nab2, Hrp1, and Tfg2. We have determined the crystal structure of Kapβ2 bound to the PY-NLS of the mRNA processing protein Nab2 at 3.05-Å resolution. A seven-residue segment of the PY-NLS of Nab2 is observed to bind Kapβ2 in an extended conformation and occupies the same PY-NLS binding site observed in other Kapβ2•PY-NLS structures. PMID:23535894

An Italian cost-effectiveness analysis of paclitaxel albumin (nab-paclitaxel) + gemcitabine vs gemcitabine alone for metastatic pancreatic cancer patients: the APICE study.

PubMed

Lazzaro, Carlo; Barone, Carlo; Caprioni, Francesco; Cascinu, Stefano; Falcone, Alfredo; Maiello, Evaristo; Milella, Michele; Pinto, Carmine; Reni, Michele; Tortora, Giampaolo

2018-04-20

the APICE study evaluates the cost-effectiveness of nanoparticle albumin-bound paclitaxel (nab-paclitaxel - Nab-P) + gemcitabine (G) vs G alone in metastatic pancreatic cancer (MPC) from the Italian National Health Service (INHS) standpoint. A 4-year, 4 health states (progression-free; progressed; end of life; death) Markov model based on the MPACT trial was developed to estimate costs (Euro [€], 2017 values), and quality-adjusted life years (QALYs). Patients were assumed to receive intravenously Nab-P 125 mg/m 2  + G 1000 mg/m 2 on days 1, 8, and 15 every 4 weeks or G alone 1000 mg/m 2 weekly for 7 out of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles) until progression. One-way and probabilistic sensitivity analyses explored the uncertainty surrounding the baseline incremental cost-utility ratio (ICUR). Nab-P + G totals 0.154 incremental QALYs and €7082.68 incremental costs vs G alone. ICUR (€46,021.58) is lower than the informal threshold value of €87,330 adopted by the Italian Medicines Agency during 2010-2013 for reimbursing oncological drugs. Sensitivity analyses confirmed the robustness of the baseline findings. Nab-P + G in MPC patients can be considered cost-effective for the INHS.

Calibration and Characterization of the UNCB and Nab Detectors

NASA Astrophysics Data System (ADS)

Zeck, Bryan; UCNB Collaboration; Nab Collaboration

2017-09-01

The UCNB and Nab experiments are designed to produce precision measurements of the free neutron decay angular correlations B, a, and b. Measurements of B and a require a coincident detection of the proton and electron produced in neutron decay, while for b, which manifests as a subtle shift in the electron energy spectrum, energy resolution better than 3 keV is desired and excellent fidelity for energy reconstruction is required, including characterization of non-linearity to the 10-4 level. To this end, a thick segmented silicon detector with a 100 nm dead layer and a 100 cm active area has been extensively characterized at LANL. The thin dead layer allows protons accelerated to 30 keV to deposit energy above threshold in the active volume of the detector, and the paired amplifer chain, developed at LANL, has a risetime of approximately 40 ns. Comparison of simulation to experiment reveals a detector resolution better than σ = 2.5 keV. A complete characterization of the detector will be presented. This work has been supported by Grants from the US National Science Foundation and the Department of Energy.

Virus-driven Inflammation Is Associated With the Development of bNAbs in Spontaneous Controllers of HIV.

PubMed

Dugast, Anne-Sophie; Arnold, Kelly; Lofano, Giuseppe; Moore, Sarah; Hoffner, Michelle; Simek, Melissa; Poignard, Pascal; Seaman, Michael; Suscovich, Todd J; Pereyra, Florencia; Walker, Bruce D; Lauffenburger, Doug; Kwon, Douglas S; Keele, Brandon F; Alter, Galit

2017-04-15

Understanding the mechanism(s) by which broadly neutralizing antibodies (bNAbs) emerge naturally following infection is crucial for the development of a protective vaccine against human immunodeficiency virus (HIV). Although previous studies have implicated high viremia and associated immune activation as potential drivers for the development of bNAbs, here we sought to unlink the effect of these 2 parameters by evaluating the key inflammatory predictors of bNAb development in HIV-infected individuals who spontaneously control HIV in the absence of antiretroviral therapy ("controllers"). The breadth of antibody-mediated neutralization against 11 tier 2 or 3 viruses was assessed in 163 clade B spontaneous controllers of HIV. Plasma levels of 17 cytokines were screened in the same set of subjects. The relationship of the inflammatory signature was assessed in the context of viral blips or viral RNA levels in peripheral blood or gastrointestinal biopsies from aviremic controllers (<50 copies RNA/mL) and in the context of viral sequence diversity analysis in the plasma of viremic controllers (<50-2000 copies RNA/mL). A unique inflammatory profile, including high plasma levels of CXCL13, sCD40L, IP10, RANTES, and TNFα, was observed in HIV controllers who developed bNAbs. Interestingly, viral load and tissue viremia, but not intermittent viral blips, were associated with these cytokine profiles. However, viral diversity was not significantly associated with increased breadth in controllers. These results suggest that low antigenic diversity in the setting of a unique inflammatory profile associated with antigen persistence may be linked to the evolution of neutralizing antibody breadth. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

An XMM-Newton Study of the Bright Ultrasoft Narrow-Line Quasar NAB 0205+024

NASA Technical Reports Server (NTRS)

Brandt, Niel

2004-01-01

The broad-band X-ray continuum of NAB 0205424 is well constrained due to the excellent photon statistics obtained (about 97,700 counts), and its impressive soft X-ray excess is clearly apparent. The hard X-ray power law has become notably steeper than when NAB 0205424 was observed with ASCA, attesting to the presence of significant X-ray spectral variability. A strong and broad emission feature is detected from about 5 to 6.4 keV, and we have modeled this as a relativistic line emitted close to the black hole from a narrow annulus of the accretion disk. Furthermore, a strong X-ray flare is detected with a hard X-ray spectrum; this flare may be responsible for illuminating the inner line-emitting part of the accretion disk. The combined observational results can be broadly interpreted in terms of the "thundercloud model proposed by Merloni & Fabian (2001).

Phase I/II dose-finding study of nanoparticle albumin-bound paclitaxel (nab®-Paclitaxel) plus Cisplatin as Treatment for Metastatic Nasopharyngeal Carcinoma.

PubMed

Huang, Yan; Liang, Wenhua; Yang, Yunpeng; Zhao, Liping; Zhao, Hongyun; Wu, Xuan; Zhao, Yuanyuan; Zhang, Yang; Zhang, Li

2016-07-13

This phase I/II study aimed to determine the maximum tolerated dose (MTD) of nanoparticle albumin-bound paclitaxel (nab (®)-paclitaxel) plus cisplatin as treatment for metastatic nasopharyngeal carcinoma (NPC). Patients were enrolled into 1 of 3 dose cohorts, each with 21-day treatment cycles: 1) intravenous (IV) nab-paclitaxel 260 mg/m(2) on day 1; 2) IV nab-paclitaxel 140 mg/m(2) on days 1 and 8; 3) IV nab-paclitaxel 100 mg/m(2) on days 1, 8, and 15. All patients received IV cisplatin 75 mg/m(2) on day 1. Treatment continued for 4-6 cycles, or until progression or unacceptable toxicity. If more than one-third of the patients in a cohort experienced a dose-limiting toxicity (DLT), the dose used in the previous cohort would be designated the MTD. Secreted protein acidic and rich in cysteine (SPARC) expression was detected by immunohistochemistry staining. Sixty-nine patients were enrolled, of whom 64 and 67 were eligible for efficacy and safety analysis, respectively. Two DLTs occurred in cohort 1 (grade 4 febrile neutropenia, grade 3 myalgia), none occurred in cohort 2, and 2 occurred in cohort 3 (both grade 3 fatigue). The MTD was not reached. Partial responses were achieved by 42 patients, 15 had stable disease, and 7 had progressive disease, giving an overall response rate of 66 %. Median progression-free survival was 9 months (95 % CI, 6-12 months). Grade ≥ 3 adverse events were mainly hematologic. There was no significant difference between the 3 cohorts with respect to efficacy or safety. Biomarker analyses indicated that stromal, rather than tumoral, SPARC may predict the response to nab-paclitaxel in NPC. Our findings suggest that nab-paclitaxel plus cisplatin is a highly active regimen with moderate toxicity for the treatment of metastatic NPC, which warrants further investigation in a phase III study. ClinicalTrials.gov ID: NCT01735409 . The trial was registered on November 20th, 2012.

Suppression of NGB and NAB/ERabp1 in tomato modifies root responses to potato cyst nematode infestation.

PubMed

Dąbrowska-Bronk, Joanna; Czarny, Magdalena; Wiśniewska, Anita; Fudali, Sylwia; Baranowski, Łukasz; Sobczak, Mirosław; Święcicka, Magdalena; Matuszkiewicz, Mateusz; Brzyżek, Grzegorz; Wroblewski, Tadeusz; Dobosz, Renata; Bartoszewski, Grzegorz; Filipecki, Marcin

2015-05-01

Plant-parasitic nematodes cause significant damage to major crops throughout the world. The small number of genes conferring natural plant resistance and the limitations of chemical control require the development of new protective strategies. RNA interference or the inducible over-expression of nematicidal genes provides an environment-friendly approach to this problem. Candidate genes include NGB, which encodes a small GTP-binding protein, and NAB/ERabp1, which encodes an auxin-binding protein, which were identified as being up-regulated in tomato roots in a transcriptome screen of potato cyst nematode (Globodera rostochiensis) feeding sites. Real-time reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization confirmed the localized up-regulation of these genes in syncytia and surrounding cells following nematode infection. Gene-silencing constructs were introduced into tomato, resulting in a 20%-98% decrease in transcription levels. Nematode infection tests conducted on transgenic plants showed 57%-82% reduction in the number of G. rostochiensis females in vitro and 30%-46% reduction in pot trials. Transmission electron microscopy revealed a deterioration of cytoplasm, and degraded mitochondria and plastids, in syncytia induced in plants with reduced NAB/ERabp1 expression. Cytoplasm in syncytia induced in plants with low NGB expression was strongly electron translucent and contained very few ribosomes; however, mitochondria and plastids remained intact. Functional impairments in syncytial cytoplasm of silenced plants may result from NGB's role in ribosome biogenesis; this was confirmed by localization of yellow fluorescent protein (YFP)-labelled NGB protein in nucleoli and co-repression of NGB in plants with reduced NAB/ERabp1 expression. These results demonstrate that NGB and NAB/ERabp1 play important roles in the development of nematode-induced syncytia. © 2014 BSPP AND JOHN WILEY & SONS LTD.

Peritoneal metastasis as a predictive factor for nab-paclitaxel in patients with pretreated advanced gastric cancer: an exploratory analysis of the phase III ABSOLUTE trial.

PubMed

Takashima, Atsuo; Shitara, Kohei; Fujitani, Kazumasa; Koeda, Keisuke; Hara, Hiroki; Nakayama, Norisuke; Hironaka, Shuichi; Nishikawa, Kazuhiro; Kimura, Yutaka; Amagai, Kenji; Fujii, Hirofumi; Muro, Kei; Esaki, Taito; Choda, Yasuhiro; Takano, Toshimi; Chin, Keisho; Sato, Atsushi; Goto, Masahiro; Fukushima, Norimasa; Hara, Takuo; Machida, Nozomu; Ohta, Manabu; Boku, Narikazu; Shimura, Masashi; Morita, Satoshi; Koizumi, Wasaburo

2018-05-31

In the ABSOLUTE trial, weekly nanoparticle albumin-bound paclitaxel (w-nab-PTX) showed non-inferiority to weekly solvent-based paclitaxel (w-sb-PTX) for overall survival (OS). Thus, w-nab-PTX might be an option for second-line chemotherapy in advanced gastric cancer (AGC). However, predictive factors for efficacies of these agents have not been evaluated. Patients previously enrolled in the ABSOLUTE trial were divided into apparent peritoneal metastasis group (PM group) and no apparent peritoneal metastasis group (no PM group) based on baseline imaging evaluated by RECIST ver. 1.1 criteria and amount of ascites. OS, progression-free survival, and overall response rate were compared between two arms in each group. This study included 240 and 243 patients in the w-nab-PTX and w-sb-PTX arms, respectively. In the PM group, the w-nab-PTX arm (n = 88) had longer OS than the w-sb-PTX arm (n = 103), and median survival time (MST) of 9.9 and 8.7 months [hazard ratio (HR) 0.63; 95% CI 0.45-0.88; P = 0.0060], respectively. In the no PM group, the w-nab-PTX arm (n = 140) had shorter OS than the w-sb-PTX arm (n = 152), and MST of 11.6 and 15.7 months (HR 1.40; 95% CI 1.06-1.86; P = 0.0180), respectively. After adjusting for prognostic factors, the HR for OS in the w-nab-PTX arm versus the w-sb-PTX arm was 0.59 (95% CI 0.42-0.83; P = 0.0023; PM group) and 1.34 (95% CI 1.01-1.78; P = 0.0414; no PM group), with significant interaction between treatment efficacy and presence of peritoneal metastasis (P = 0.0003). The presence of apparent peritoneal metastasis might be a predictive factor for selecting w-nab-PTX for pretreated AGC patients. JapicCTI-132059.

Detection system for neutron β decay correlations in the UCNB and Nab experiments

DOE PAGES

Broussard, L. J.; Oak Ridge National Lab.; Zeck, B. A.; ...

2016-12-19

Here, we describe a detection system designed to precisely measure multiple correlations in neutron β decay. Furthermore, the system is based on thick, large area, highly segmented silicon detectors developed in collaboration with Micron Semiconductor, Ltd. The prototype system meets specifications of energy thresholds below 10 keV, energy resolution of ~3 keV FWHM, and rise time of ~50 ns with 19 of the 127 detector pixels instrumented. We have demonstrated the coincident detection of β particles and recoil protons from neutron β decay, using ultracold neutrons at the Los Alamos Neutron Science Center, . The fully instrumented detection system willmore » be implemented in the UCNB and Nab experiments, to determine the neutron β decay parameters B, a, and b.« less

Nuclear relocation of STAT6 reliably predicts NAB2-STAT6 fusion for the diagnosis of solitary fibrous tumour.

PubMed

Koelsche, Christian; Schweizer, Leonille; Renner, Marcus; Warth, Arne; Jones, David T W; Sahm, Felix; Reuss, David E; Capper, David; Knösel, Thomas; Schulz, Birte; Petersen, Iver; Ulrich, Alexis; Renker, Eva Kristin; Lehner, Burkhard; Pfister, Stefan M; Schirmacher, Peter; von Deimling, Andreas; Mechtersheimer, Gunhild

2014-11-01

Nuclear relocation of STAT6 has been shown in tumours with NAB2-STAT6 fusion, and has been proposed as an ancillary marker for the diagnosis of solitary fibrous tumours (SFTs). The aim of this study was to verify the utility of STAT6 immunohistology in diagnosing SFT. A total of 689 formalin-fixed paraffin-embedded tumours comprising 35 pleural SFTs and 654 other mesenchymal tumours were investigated for STAT6 expression using immunohistochemistry. Nine dedifferentiated liposarcomas (DDLSs) and five SFTs were also examined for the presence of NAB2-STAT6 fusion at the protein level using the proximity ligation assay (PLA), and for copy number variants (CNVs) with the Illumina Infinium Human Methylation450 array. Thirty-four of 35 SFTs showed strong nuclear STAT6 expression. Furthermore, five of 68 DDLSs, two of 130 undifferentiated pleomorphic sarcomas and one of 63 cases of nodular fasciitis showed moderate to strong nuclear STAT6 expression. The PLA indicated the presence of NAB2-STAT6 fusion protein in SFTs, but signal was also detected in some DDLSs. Copy number analysis showed an overall low frequency of chromosomal imbalances in SFTs, but complex karyotypes in DDLSs, including amplification of STAT6 and MDM2 loci. The detection of nuclear relocation of STAT6 with immunohistochemistry is a characteristic of SFTs, and may serve as a diagnostic marker that indicates NAB2-STAT6 fusion and helps to discriminate SFTs from histological mimics. © 2014 John Wiley & Sons Ltd.

75 FR 38129 - TRW Automotive, Kelsey-Hayes Company, NABS Division, Mt. Vernon, OH; Amended Certification...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-07-01

... DEPARTMENT OF LABOR Employment and Training Administration [TA-W-70,907] TRW Automotive, Kelsey... Adjustment Assistance on August 25, 2009, applicable to workers of TRW Automotive, NABS Division, Mt. Vernon... for the automotive industry. Information shows that some workers separated from employment at the...

Treatment Rationale and Design for J-SONIC: A Randomized Study of Carboplatin Plus Nab-paclitaxel With or Without Nintedanib for Advanced Non-Small-cell Lung Cancer With Idiopathic Pulmonary Fibrosis.

PubMed

Otsubo, Kohei; Kishimoto, Junji; Kenmotsu, Hirotsugu; Minegishi, Yuji; Ichihara, Eiki; Shiraki, Akira; Kato, Terufumi; Atagi, Shinji; Horinouchi, Hidehito; Ando, Masahiko; Kondoh, Yasuhiro; Kusumoto, Masahiko; Ichikado, Kazuya; Yamamoto, Nobuyuki; Nakanishi, Yoichi; Okamoto, Isamu

2018-01-01

We describe the treatment rationale and procedure for a randomized study (J-SONIC; University Hospital Medical Information Network Clinical Trials Registry identification no., UMIN000026799) of carboplatin plus nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without nintedanib for patients with advanced non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF). The study was designed to examine the efficacy and safety of nintedanib administered with carboplatin plus nab-paclitaxel versus carboplatin plus nab-paclitaxel alone in chemotherapy-naive patients with advanced NSCLC associated with IPF. Eligible patients (enrollment target, n = 170) will be randomized at a 1:1 ratio to receive 4 cycles of carboplatin (area under the curve, 6 on day 1) plus nab-paclitaxel (100 mg/m 2 on days 1, 8, and 15) administered every 3 weeks either without (arm A) or with (arm B) nintedanib (150 mg twice daily), to be followed in arm B by single-agent administration of nintedanib (150 mg twice daily). The present trial is the first randomized controlled study for the treatment of NSCLC associated with IPF. The goal of the study is to demonstrate that nintedanib combined with carboplatin plus nab-paclitaxel prolongs the interval to acute exacerbation of IPF compared with carboplatin plus nab-paclitaxel alone. Copyright © 2017 Elsevier Inc. All rights reserved.

Efficacy and safety of nab-paclitaxel in patients with previously treated metastatic colorectal cancer: a phase II COLO-001 trial.

PubMed

Ducreux, Michel; Bennouna, Jaafar; Adenis, Antoine; Conroy, Thierry; Lièvre, Astrid; Portales, Fabienne; Jeanes, Julie; Li, Li; Romano, Alfredo

2017-01-01

This single-arm, phase II trial evaluated nab-paclitaxel monotherapy in pretreated patients with metastatic colorectal cancer (mCRC). Patients with mCRC (RAS wild-type and RAS mutant cohorts) received nab-paclitaxel 125 mg/m 2 days 1, 8, and 15 (28-day cycle). The primary endpoint was investigator-assessed progression-free survival (PFS) rate at week 8; secondary endpoints included overall survival, overall response rate, and safety. Stage 1 planned enrollment was 15 patients per cohort per Simon 2-stage design. Stage 2 enrollment was to continue unless ≤8 of the first 15 patients per cohort achieved PFS at 8 weeks. Stage 1 enrolled 41 patients (RAS wild type: n = 18; RAS mutant: n = 23). In both RAS cohorts, 3 of 15 patients initially enrolled were progression-free at week 8 (20%; 95% CI 4.0-48.0). Median PFS was 8.1 weeks (95% CI 7.7-8.6) and 7.9 weeks (95% CI 7.6-8.0) for RAS wild-type and RAS mutant cohorts, respectively. There were no complete or partial responses. The overall disease control rate was 16% (95% CI 6.0-32.0), and rates were similar in the RAS wild-type and RAS mutant cohorts (18 and 15%, respectively). No new safety signals were reported; the most common grade ≥3 adverse events included neutropenia, asthenia, and peripheral neuropathy. This study did not progress to stage 2 per the preplanned statistical stopping rule. In patients with heavily pretreated mCRC, nab-paclitaxel did not demonstrate promising antitumor activity; further assessment of nab-paclitaxel monotherapy in this population of patients is not supported. NCT02103062.

Aspirin-triggered lipoxin A4 and lipoxin A4 up-regulate transcriptional corepressor NAB1 in human neutrophils.

PubMed

Qiu, F H; Devchand, P R; Wada, K; Serhan, C N

2001-12-01

Aspirin-triggered 15-epi-lipoxin A4 (ATL) is an endogenous lipid mediator that mimics the actions of native lipoxin A4, a putative "stop signal" involved in regulating resolution of inflammation. A metabolically more stable analog of ATL, 15-epi-16-(para-fluoro)-phenoxy-lipoxin A4 analog (ATLa), inhibits neutrophil recruitment in vitro and in vivo and displays potent anti-inflammatory actions. ATLa binds with high affinity to the lipoxin A4 receptor, a G protein-coupled receptor on the surface of leukocytes. In this study, we used freshly isolated human neutrophils to examine ATLa's potential for initiating rapid nuclear responses. Using differential display reverse transcription polymerase chain reaction, we identified a subset of genes that was selectively up-regulated upon short exposure of polymorphonuclear leukocytes to ATLa but not to the chemoattractant leukotriene B4 or vehicle alone. We further investigated ATLa regulation of one of the genes, NAB1, a transcriptional corepressor identified previously as a glucocorticoid-responsive gene in hamster smooth muscle cells. Treatment of human neutrophils with pertussis toxin blocked ATLa up-regulation of NAB1. In addition, ATLa stimulated NAB1 gene expression in murine lung vascular smooth muscle in vivo. These findings provide evidence for rapid transcriptional induction of a cassette of genes via an ATLa-stimulated G protein-coupled receptor pathway that is potentially protective and overlaps with the anti-inflammatory glucocorticoid regulatory circuit.

nab-paclitaxel potentiates gemcitabine activity by reducing cytidine deaminase levels in a mouse model of pancreatic cancer

PubMed Central

Cook, Natalie; Bapiro, Tashinga E.; Lolkema, Martijn P.; Jodrell, Duncan I.; Tuveson, David A.

2016-01-01

nab-paclitaxel, an albumin-stabilized paclitaxel formulation, demonstrates clinical activity when administered in combination with gemcitabine in patients with metastatic pancreatic ductal adenocarcinoma (PDA). The limited availability of patient tissue and exquisite sensitivity of xenografts to chemotherapeutics have limited our ability to address the mechanistic basis of this treatment regimen. Here, we used a mouse model of PDA to show that the co-administration of nab-paclitaxel and gemcitabine uniquely demonstrates evidence of tumor regression. Combination treatment increases intratumoral gemcitabine levels due to a marked decrease in the primary gemcitabine metabolizing enzyme, cytidine deaminase (Cda). Correspondingly, paclitaxel reduced Cda protein levels in cultured cells through reactive oxygen species-mediated degradation, resulting in the increased stabilization of gemcitabine. Our findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PDA and highlight the advantages of genetically engineered mouse models in preclinical therapeutic trials. PMID:22585996

Identification of NAB1, a repressor of NGFI-A- and Krox20-mediated transcription.

PubMed Central

Russo, M W; Sevetson, B R; Milbrandt, J

1995-01-01

NGFI-A (also called Egr1, Zif268, or Krox24) and the closely related proteins Krox20, NGFI-C, and Egr3 are zinc-finger transcription factors encoded by immediate-early genes which are induced by a wide variety of extracellular stimuli. NGFI-A has been implicated in cell proliferation, macrophage differentiation, synaptic activation, and long-term potentiation, whereas Krox20 is critical for proper hindbrain segmentation and peripheral nerve myelination. In previous work, a structure/function analysis of NGFI-A revealed a 34-aa inhibitory domain that was hypothesized to be the target of a cellular factor that represses NGFI-A transcriptional activity. Using the yeast two-hybrid system, we have isolated a cDNA clone which encodes a protein that interacts with this inhibitory domain and inhibits the ability of NGFI-A to activate transcription. This NGFI-A-binding protein, NAB1, is a 570-aa nuclear protein that bears no obvious sequence homology to known proteins. NAB1 also represses Krox20 activity, but it does not influence Egr3 or NGFI-G, thus providing a mechanism for the differential regulation of this family of immediate-early transcription factors. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:7624335

'Papillary' solitary fibrous tumor/hemangiopericytoma with nuclear STAT6 expression and NAB2-STAT6 fusion.

PubMed

Ishizawa, Keisuke; Tsukamoto, Yoshitane; Ikeda, Shunsuke; Suzuki, Tomonari; Homma, Taku; Mishima, Kazuhiko; Nishikawa, Ryo; Sasaki, Atsushi

2016-04-01

This report describes clinicopathological findings, including genetic data of STAT6, in a solitary fibrous tumor (SFT)/hemangiopericytoma (HPC) of the central nervous system in an 83-year-old woman with a bulge in the left forehead. She noticed it about 5 months before, and it had grown rapidly for the past 1 month. Neuroradiological studies disclosed a well-demarcated tumor that accompanied the destruction of the skull. The excised tumor showed a prominent papillary structure, where atypical cells were compactly arranged along the fibrovascular core ('pseudopapillary'). There was rich vasculature, some of which resembled 'staghorn' vessels. Mitotic figures were occasionally found. Whorls, psammoma bodies, or intra-nuclear pseudoinclusions were not identified. By immunohistochemistry, CD34 was strongly positive in the tumor cells, and STAT6 was localized in their nuclei. By reverse transcription-polymerase chain reaction (RT-PCR), an NAB2-STAT6 fusion gene, NAB2 exon6-STAT6 exon17, was detected, establishing a definite diagnosis of SFT/HPC. 'Papillary' SFT/HPC needs to be recognized as a possible morphological variant of SFT/HPC, and should be borne in mind in its diagnostic practice.

Strain measurement on stiff structures: experimental evaluation of three integrated measurement principles

NASA Astrophysics Data System (ADS)

Rausch, J.; Hatzfeld, C.; Karsten, R.; Kraus, R.; Millitzer, J.; Werthschützky, R.

2012-06-01

This paper presents an experimental evaluation of three different strain measuring principles. Mounted on a steel beam resembling a car engine mount, metal foil strain gauges, piezoresistive silicon strain gauges and piezoelectric patches are investigated to measure structure-borne forces to control an active mounting structure. FEA simulation determines strains to be measured in the range of 10-8 up to 10-5 m × m-1. These low strains cannot be measured with conventional metal foil strain gauges, as shown in the experiment conducted. Both piezoresistive and piezoelectric gauges show good results compared to a conventional piezoelectric force sensor. Depending on bandwidth, overload capacity and primary electronic costs, these principles seem to be worth considering in an adaptronic system design. These parameters are described in detail for the principles investigated.

A phase II study of nab-paclitaxel plus carboplatin in combination with thoracic radiation in patients with locally advanced non–small-cell lung cancer

PubMed Central

Hasegawa, Takaaki; Futamura, Yohei; Horiba, Akane; Yoshida, Tsutomu; Suzuki, Toshitaka; Kato, Tatsuo; Kaito, Daizo; Ohno, Yasuhi; Iida, Takayoshi; Hayashi, Shinya; Sawa, Toshiyuki

2016-01-01

We investigated the efficacy and safety of albumin-bound paclitaxel (nab-PTX) and carboplatin (CBDCA) with concurrent radiotherapy for unresectable locally advanced non–small-cell lung cancer (NSCLC). Patients with Stage III NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Concurrent chemoradiotherapy consisted of weekly administration of nab-PTX (40 mg/m2) plus CBDCA (area under the plasma concentration time curve (AUC) 2) and thoracic radiotherapy (60 Gy/30 fractions) for a total of 6 weeks. After concurrent chemoradiotherapy, patients received an additional two cycles of consolidation phase chemotherapy that consisted of 4-week cycles of nab-PTX (100 mg/m2 on Days 1, 8 and 15)/CBDCA (AUC 5 mg/ml/min on Day 1). Response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors. Progression-free survival and overall survival were estimated using the Kaplan–Meier method. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events. A total of 10 patients were enrolled in this trial between September 2013 and January 2014 from three institutes. The overall response rate was 40.0% and the median progression-free survival was 6.7 months. Treatment-related death occurred in two patients. Grade 2 or worse severe radiation pneumonitis was observed in all three patients that had the volume of lung receiving at least 20 Gy (V20) >30%. The results of this study indicate that no further investigation is warranted into nab-PTX and CBDCA with concurrent thoracic radiation for Stage III NSCLC with V20 > 30% due to severe toxicity. PMID:26442970

Development and validation of cell-based luciferase reporter gene assays for measuring neutralizing anti-drug antibodies against interferon beta.

PubMed

Hermanrud, Christina; Ryner, Malin; Luft, Thomas; Jensen, Poul Erik; Ingenhoven, Kathleen; Rat, Dorothea; Deisenhammer, Florian; Sørensen, Per Soelberg; Pallardy, Marc; Sikkema, Dan; Bertotti, Elisa; Kramer, Daniel; Creeke, Paul; Fogdell-Hahn, Anna

2016-03-01

Neutralizing anti-drug antibodies (NAbs) against therapeutic interferon beta (IFNβ) in people with multiple sclerosis (MS) are measured with cell-based bioassays. The aim of this study was to redevelop and validate two luciferase reporter-gene bioassays, LUC and iLite, using a cut-point approach to identify NAb positive samples. Such an approach is favored by the pharmaceutical industry and governmental regulatory agencies as it has a clear statistical basis and overcomes the limitations of the current assays based on the Kawade principle. The work was conducted following the latest assay guidelines. The assays were re-developed and validated as part of the "Anti-Biopharmaceutical Immunization: Prediction and analysis of clinical relevance to minimize the risk" (ABIRISK) consortium and involved a joint collaboration between four academic laboratories and two pharmaceutical companies. The LUC assay was validated at Innsbruck Medical University (LUCIMU) and at Rigshospitalet (LUCRH) Copenhagen, and the iLite assay at Karolinska Institutet, Stockholm. For both assays, the optimal serum sample concentration in relation to sensitivity and recovery was 2.5% (v/v) in assay media. A Shapiro-Wilk test indicated a normal distribution for the majority of runs, allowing a parametric approach for cut-point calculation to be used, where NAb positive samples could be identified with 95% confidence. An analysis of means and variances indicated that a floating cut-point should be used for all assays. The assays demonstrated acceptable sensitivity for being cell-based assays, with a confirmed limit of detection in neat serum of 1519 ng/mL for LUCIMU, 814 ng/mL for LUCRH, and 320 ng/mL for iLite. Use of the validated cut-point assay, in comparison with the previously used Kawade method, identified 14% more NAb positive samples. In conclusion, implementation of the cut-point design resulted in increased sensitivity to detect NAbs. However, the clinical significance of these low

A randomized phase II study of weekly nab-paclitaxel plus gemcitabine or simplified LV5FU2 as first-line therapy in patients with metastatic pancreatic cancer: the AFUGEM GERCOR trial.

PubMed

Bachet, Jean-Baptiste; Chibaudel, Benoist; Bonnetain, Franck; Validire, Pierre; Hammel, Pascal; André, Thierry; Louvet, Christophe

2015-10-06

Metastatic pancreatic adenocarcinoma (PAC) prognosis remains dismal and gemcitabine monotherapy has been the standard treatment over the last decade. Currently, two first-line regimens are used in this setting: FOLFIRINOX and nab-paclitaxel plus gemcitabine. Increasing translational data on the predictive value of hENT1 for determining gemcitabine efficacy suggest that a non-gemcitabine-based regimen is favored in about 60 % of patients with PAC due to high resistance of PAC to this cytotoxic drug. This study aims to evaluate the efficacy of weekly nab-paclitaxel combined with gemcitabine or a simplified (s) LV5FU2 regimen in patients with previously untreated metastatic PAC. AFUGEM is a two-stage, open-label, randomized, multicenter, phase II trial. Patients with PAC who meet the inclusion criteria and provide written informed consent will be randomized in a 1:2 ratio to either nab-paclitaxel (125 mg/m(2)) plus gemcitabine (1000 mg/m(2)) given on days 1, 8, and 15 every 28 days or nab-paclitaxel (125 mg/m(2)) plus sLV5FU2 (leucovorin 400 mg/m(2) followed by bolus 400 mg/m(2) 5-fluorouracil and by 5-fluorouracil 2400 mg/m(2) as an 46-h intravenous infusion) given on days 1 and 15 every 28 days. A total of 114 patients will be randomized to one of the treatment arms. The primary endpoint is progression-free survival at 4 months. Secondary outcomes are rate and duration of response, disease control, overall survival, safety, and quality of life. Potential biomarkers of gemcitabine (hENT1, dCK) and 5-fluorouracil (TS) efficacy will be assessed. The AFUGEM trial is designed to provide valuable information regarding efficacy and tolerability of nab-paclitaxel plus gemcitabine and nab-paclitaxel plus sLV5FU2 regimens. Identification of potential predictive biomarkers of gemcitabine and 5-fluorouracil is likely to drive therapeutic decisions in patients with metastatic PAC. AFUGEM is registered at Clinicaltrials.gov: NCT01964534 , October 15, 2013.

A phase II study of nab-paclitaxel plus carboplatin in combination with thoracic radiation in patients with locally advanced non-small-cell lung cancer.

PubMed

Hasegawa, Takaaki; Futamura, Yohei; Horiba, Akane; Yoshida, Tsutomu; Suzuki, Toshitaka; Kato, Tatsuo; Kaito, Daizo; Ohno, Yasuhi; Iida, Takayoshi; Hayashi, Shinya; Sawa, Toshiyuki

2016-01-01

We investigated the efficacy and safety of albumin-bound paclitaxel (nab-PTX) and carboplatin (CBDCA) with concurrent radiotherapy for unresectable locally advanced non-small-cell lung cancer (NSCLC). Patients with Stage III NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Concurrent chemoradiotherapy consisted of weekly administration of nab-PTX (40 mg/m(2)) plus CBDCA (area under the plasma concentration time curve (AUC) 2) and thoracic radiotherapy (60 Gy/30 fractions) for a total of 6 weeks. After concurrent chemoradiotherapy, patients received an additional two cycles of consolidation phase chemotherapy that consisted of 4-week cycles of nab-PTX (100 mg/m(2) on Days 1, 8 and 15)/CBDCA (AUC 5 mg/ml/min on Day 1). Response was evaluated in accordance with the Response Evaluation Criteria in Solid Tumors. Progression-free survival and overall survival were estimated using the Kaplan-Meier method. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events. A total of 10 patients were enrolled in this trial between September 2013 and January 2014 from three institutes. The overall response rate was 40.0% and the median progression-free survival was 6.7 months. Treatment-related death occurred in two patients. Grade 2 or worse severe radiation pneumonitis was observed in all three patients that had the volume of lung receiving at least 20 Gy (V20) >30%. The results of this study indicate that no further investigation is warranted into nab-PTX and CBDCA with concurrent thoracic radiation for Stage III NSCLC with V20 > 30% due to severe toxicity. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

Application of meandering centreline migration modelling and object-based approach of Long Nab member

NASA Astrophysics Data System (ADS)

Saadi, Saad

2017-04-01

Characterizing the complexity and heterogeneity of the geometries and deposits in meandering river system is an important concern for the reservoir modelling of fluvial environments. Re-examination of the Long Nab member in the Scalby formation of the Ravenscar Group (Yorkshire, UK), integrating digital outcrop data and forward modelling approaches, will lead to a geologically realistic numerical model of the meandering river geometry. The methodology is based on extracting geostatistics from modern analogous, meandering rivers that exemplify both the confined and non-confined meandering point bars deposits and morphodynamics of Long Nab member. The parameters derived from the modern systems (i.e. channel width, amplitude, radius of curvature, sinuosity, wavelength, channel length and migration rate) are used as a statistical control for the forward simulation and resulting object oriented channel models. The statistical data derived from the modern analogues is multi-dimensional in nature, making analysis difficult. We apply data mining techniques such as parallel coordinates to investigate and identify the important relationships within the modern analogue data, which can then be used drive the development of, and as input to the forward model. This work will increase our understanding of meandering river morphodynamics, planform architecture and stratigraphic signature of various fluvial deposits and features. We will then use these forward modelling based channel objects to build reservoir models, and compare the behaviour of the forward modelled channels with traditional object modelling in hydrocarbon flow simulations.

Age-related commonalities and differences in the relationship between executive functions and intelligence: Analysis of the NAB executive functions module and WAIS-IV scores.

PubMed

Buczylowska, Dorota; Petermann, Franz

2017-01-01

Data from five subtests of the Executive Functions Module of the German Neuropsychological Assessment Battery (NAB) and all ten core subtests of the German Wechsler Adult Intelligence Scale - Fourth Edition (WAIS-IV) were used to examine the relationship between executive functions and intelligence in a comparison of two age groups: individuals aged 18-59 years and individuals aged 60-88 years. The NAB subtests Categories and Word Generation demonstrated a consistent correlation pattern for both age groups. However, the NAB Judgment subtest correlated more strongly with three WAIS-IV indices, the Full Scale IQ (FSIQ), and the General Ability Index (GAI) in the older adult group than in the younger group. Additionally, in the 60-88 age group, the Executive Functions Index (EFI) was more strongly correlated with the Verbal Comprehension Index (VCI) than with the Perceptual Reasoning Index (PRI). Both age groups demonstrated a strong association of the EFI with the FSIQ and the Working Memory Index (WMI). The results imply the potential diagnostic utility of the Judgment subtest and a significant relationship between executive functioning and crystallized intelligence at older ages. Furthermore, it may be concluded that there is a considerable age-independent overlap between the EFI and general intelligence, as well as between the EFI and working memory.

The measure and significance of Bateman's principles

PubMed Central

Collet, Julie M.; Dean, Rebecca F.; Worley, Kirsty; Richardson, David S.; Pizzari, Tommaso

2014-01-01

Bateman's principles explain sex roles and sexual dimorphism through sex-specific variance in mating success, reproductive success and their relationships within sexes (Bateman gradients). Empirical tests of these principles, however, have come under intense scrutiny. Here, we experimentally show that in replicate groups of red junglefowl, Gallus gallus, mating and reproductive successes were more variable in males than in females, resulting in a steeper male Bateman gradient, consistent with Bateman's principles. However, we use novel quantitative techniques to reveal that current methods typically overestimate Bateman's principles because they (i) infer mating success indirectly from offspring parentage, and thus miss matings that fail to result in fertilization, and (ii) measure Bateman gradients through the univariate regression of reproductive over mating success, without considering the substantial influence of other components of male reproductive success, namely female fecundity and paternity share. We also find a significant female Bateman gradient but show that this likely emerges as spurious consequences of male preference for fecund females, emphasizing the need for experimental approaches to establish the causal relationship between reproductive and mating success. While providing qualitative support for Bateman's principles, our study demonstrates how current approaches can generate a misleading view of sex differences and roles. PMID:24648220

A phase 1/1B trial of ADI-PEG 20 plus nab-paclitaxel and gemcitabine in patients with advanced pancreatic adenocarcinoma.

PubMed

Lowery, Maeve A; Yu, Kenneth H; Kelsen, David Paul; Harding, James J; Bomalaski, John S; Glassman, Danielle C; Covington, Christina M; Brenner, Robin; Hollywood, Ellen; Barba, Adalberto; Johnston, Amanda; Liu, Kay Chia-Wei; Feng, Xiaoxing; Capanu, Marinela; Abou-Alfa, Ghassan K; O'Reilly, Eileen M

2017-12-01

ADI-PEG 20 is a pegylated form of the arginine-depleting enzyme arginine deiminase. Normal cells synthesize arginine with the enzyme argininosuccinate synthetase (ASS1); ADI-PEG 20 selectively targets malignant cells, which lack ASS1. A single-arm, nonrandomized, open-label, phase 1/1B, standard 3 + 3 dose escalation with an expansion cohort of 9 patients at the recommended phase 2 dose (RP2D) was conducted. Patients who had metastatic pancreatic cancer, up to 1 line of prior treatment (the dose-escalation cohort) or no prior treatment (the expansion cohort), and an Eastern Cooperative Oncology Group performance status of 0 to 1 were included. Patients received both gemcitabine (1000 mg/m 2 ) and nab-paclitaxel (125 mg/m 2 ) for 3 of 4 weeks and intramuscular ADI-PEG 20 at 18 mg/m 2 weekly (cohort 1) or at 36 mg/m 2 weekly (cohort 2 and the expansion cohort).The primary endpoint was to determine the maximum tolerated dose and RP2D of ADI-PEG 20 in combination with nab-paclitaxel and gemcitabine. Eighteen patients were enrolled. No dose-limiting toxicities (DLTs) were observed in cohort 1; cohort 2 was expanded to 6 patients because of 1 DLT occurrence (a grade 3 elevation in bilirubin, aspartate aminotransferase, and alanine aminotransferase). The most frequent adverse events (AEs) of any grade were neutropenia, thrombocytopenia, leukopenia, anemia, peripheral neuropathy, and fatigue; all 18 patients experienced grade 3/4 AEs. The most frequent grade 3/4 toxicities, regardless of the relation with any drugs, included neutropenia (12 patients or 67%), leukopenia (10 patients or 56%), anemia (8 patients or 44%), and lymphopenia (6 patients or 33%). The RP2D for ADI-PEG 20 was 36 mg/m 2 weekly in combination with standard-dose gemcitabine and nab-paclitaxel. The overall response rate among patients treated at the RP2D in the first-line setting was 45.5% (5 of 11).The median progression-free survival time for these patients treated at the RP2D was 6.1 months (95

Application of the coplanar principle to dynamic epidural pressure measurements.

PubMed

Beck, J; Schettini, A; Salton, R

1984-10-01

The application of the coplanar principle to dynamic epidural pressure measurements was investigated in vitro. The authors used a coplanar pressure-displacement transducer, commonly employed to measure the viscoelastic properties of brain tissue in vivo. The present studies were performed using canine dura and a specially constructed fluid-filled chamber. The accuracy of the technique was assessed by comparing the pressure in the chamber recorded by the coplanar transducer to the pressure measured by a transducer directly vented to the chamber. The results show that the coplanar principle remained valid for dynamic measurements with the transducer under a variety of conditions.

Phase II study of neoadjuvant therapy with nab-paclitaxel and cisplatin followed by surgery in patients with locally advanced esophageal squamous cell carcinoma

PubMed Central

Fan, Yun; Jiang, Youhua; Zhou, Xinming; Chen, Qixun; Huang, Zhiyu; Xu, Yanjun; Gong, Lei; Yu, Haifeng; Yang, Haiyan; Liu, Jinshi; Lei, Tao; Zhao, Qiang; Mao, Weimin

2016-01-01

Background We carried out a phase II study to evaluate the efficiency and safety of the combination of nanoparticle albumin bound-paclitaxel (nab-paclitaxel) and cisplatin as preoperative chemotherapy for locally advanced esophageal squamous cell carcinoma (ESCC) Results From Oct 2011 to Dec 2012, 35 patients were enrolled and received neoadjuvant chemotherapy. Thirty patients underwent surgery and achieved a 100% R0 resection. Pathological complete response (pCR) rate was 13.3% and near pCR rate was 6.7%. Down-staging was achieved in 19 patients. With median follow-up of 37.8 months, 16 patients were still alive. One-, 2- and 3- year overall survival (OS) rate was 90.0%, 70.0% and 43.3%, respectively. This treatment resulted in a median disease-free survival (DFS) of 34.7 months and a median OS of 37.8 months. Median DFS and OS of down-staged patients were significantly longer than those of non-downstaged patients. The grade 4 toxicities during neoadjuvant chemotherapy were limited to neutropenia (2.9%) and vomiting (2.9%). Methods Patients with locally advanced ESCC (stage IIA to IIIC) and performance status 0-1 were enrolled and received two cycles of nab-paclitaxel (100 mg/m2) on day 1, 8, 22 and 29, and cisplatin (75 mg/m2) on day 1 and 22, followed by resection. Two cycles of adjuvant chemotherapy with the same regimen were given. Postoperative radiotherapy was permitted and decided by radiation therapist. Conclusion Weekly nab-paclitaxel with three-weekly cisplatin seems effective and safe as a neoadjuvant chemotherapy strategy for locally advanced ESCC. Down-staged patients have favorable outcome. ClinicalTrials.gov Identifier NCT01258192 PMID:27244882

Adventitial nab-rapamycin injection reduces porcine femoral artery luminal stenosis induced by balloon angioplasty via inhibition of medial proliferation and adventitial inflammation.

PubMed

Gasper, Warren J; Jimenez, Cynthia A; Walker, Joy; Conte, Michael S; Seward, Kirk; Owens, Christopher D

2013-12-01

Endovascular interventions on peripheral arteries are limited by high rates of restenosis. Our hypothesis was that adventitial injection of rapamycin nanoparticles would be safe and reduce luminal stenosis in a porcine femoral artery balloon angioplasty model. Eighteen juvenile male crossbred swine were included. Single-injury (40%-60% femoral artery balloon overstretch injury; n=2) and double-injury models (endothelial denudation injury 2 weeks before a 20%-30% overstretch injury; n=2) were compared. The double-injury model produced significantly more luminal stenosis at 28 days, P=0.002, and no difference in medial fibrosis or inflammation. Four pigs were randomized to the double-injury model and adventitial injection of saline (n=2) or 500 μg of nanoparticle albumin-bound rapamycin (nab-rapamycin; n=2) with an endovascular microinfusion catheter. There was 100% procedural success and no difference in endothelial regeneration. At 28 days, nab-rapamycin led to significant reductions in luminal stenosis, 17% (interquartile range, 12%-35%) versus 10% (interquartile range, 8.3%-14%), P=0.001, medial cell proliferation, P<0.001, and fibrosis, P<0.001. There were significantly fewer adventitial leukocytes at 3 days, P<0.001, but no difference at 28 days. Pharmacokinetic analysis (single-injury model) found rapamycin concentrations 1500× higher in perivascular tissues than in blood at 1 hour. Perivascular rapamycin persisted ≥8 days and was not detectable at 28 days. Adventitial nab-rapamycin injection was safe and significantly reduced luminal stenosis in a porcine femoral artery balloon angioplasty model. Observed reductions in early adventitial leukocyte infiltration and late medial cell proliferation and fibrosis suggest an immunosuppressive and antiproliferative mechanism. An intraluminal microinfusion catheter for adventitial injection represents an alternative to stent- or balloon-based local drug delivery.

Nab-paclitaxel plus either gemcitabine or simplified leucovorin and fluorouracil as first-line therapy for metastatic pancreatic adenocarcinoma (AFUGEM GERCOR): a non-comparative, multicentre, open-label, randomised phase 2 trial.

PubMed

Bachet, Jean-Baptiste; Hammel, Pascal; Desramé, Jérôme; Meurisse, Aurélia; Chibaudel, Benoist; André, Thierry; Debourdeau, Philippe; Dauba, Jérome; Lecomte, Thierry; Seitz, Jean-François; Tournigand, Christophe; Aparicio, Thomas; Meyer, Véronique Guerin; Taieb, Julien; Volet, Julien; Monier, Amandine; Bonnetain, Franck; Louvet, Christophe

2017-05-01

Nab-paclitaxel plus gemcitabine has become a standard treatment regimen in patients with metastatic pancreatic adenocarcinoma; however, retrospective data suggest that gemcitabine might be inefficient in 50-60% of patients and thus not an optimum regimen in combination with nab-paclitaxel. We did a phase 2 trial to assess the activity and safety of a new regimen of nab-paclitaxel plus simplified leucovorin and fluorouracil. We did a non-comparative, multicentre, open-label, randomised phase 2 trial in 15 hospitals and institutions in France. Eligible participants were previously untreated patients with metastatic pancreatic adenocarcinoma (previous adjuvant chemotherapy after curative intent resection was allowed if the interval between the end of chemotherapy and relapse was more than 12 months). Patients had to have at least one measurable lesion assessed by CT scan or MRI and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. We randomly assigned participants (1:2) centrally to 28-day cycles of either gemcitabine plus nab-paclitaxel or simplified leucovorin and fluorouracil plus nab-paclitaxel. The randomisation was by minimisation, stratified by centre and ECOG performance status. Drugs were administered in each cycle as follows: nab-paclitaxel (125 mg/m 2 ) and gemcitabine (1000 mg/m 2 ) as 30-min intravenous infusions on days 1, 8, and 15; leucovorin (400 mg/m 2 ) as a 120-min intravenous infusion on days 1 and 15; and fluorouracil (400 mg/m 2 ) as a 5-min bolus intravenous infusion followed by a 46-h continuous intravenous infusion of 2400 mg/m 2 on days 1 and 15. Patients continued treatment until unacceptable toxicity, disease progression, or patient withdrawal. The primary endpoint was progression-free survival at 4 months in the first 72 assessable patients in the leucovorin and fluorouracil group, with a target of 50% for the regimen to be deemed sufficiently active to warrant further study. We did the primary analysis on the

Recombinant HPA-1a antibody therapy for treatment of fetomaternal alloimmune thrombocytopenia: proof of principle in human volunteers

PubMed Central

Herbert, Nina; Hawkins, Louise; Grehan, Nicola; Cookson, Philip; Garner, Steve F.; Crisp-Hihn, Abigail; Lloyd-Evans, Paul; Evans, Amanda; Balan, Kottekkattu; Ouwehand, Willem H.; Armour, Kathryn L.; Clark, Mike R.; Williamson, Lorna M.

2013-01-01

Fetomaternal alloimmune thrombocytopenia, caused by the maternal generation of antibodies against fetal human platelet antigen-1a (HPA-1a), can result in intracranial hemorrhage and intrauterine death. We have developed a therapeutic human recombinant high-affinity HPA-1a antibody (B2G1Δnab) that competes for binding to the HPA-1a epitope but carries a modified constant region that does not bind to Fcγ receptors. In vitro studies with a range of clinical anti–HPA-1a sera have shown that B2G1Δnab blocks monocyte chemiluminescence by >75%. In this first-in-man study, we demonstrate that HPA-1a1b autologous platelets (matching fetal phenotype) sensitized with B2G1Δnab have the same intravascular survival as unsensitized platelets (190 hours), while platelets sensitized with a destructive immunoglobulin G1 version of the antibody (B2G1) are cleared from the circulation in 2 hours. Mimicking the situation in fetuses receiving B2G1Δnab as therapy, we show that platelets sensitized with a combination of B2G1 (representing destructive HPA-1a antibody) and B2G1Δnab survive 3 times as long in circulation compared with platelets sensitized with B2G1 alone. This confirms the therapeutic potential of B2G1Δnab. The efficient clearance of platelets sensitized with B2G1 also opens up the opportunity to carry out studies of prophylaxis to prevent alloimmunization in HPA-1a–negative mothers. PMID:23656729

Recombinant HPA-1a antibody therapy for treatment of fetomaternal alloimmune thrombocytopenia: proof of principle in human volunteers.

PubMed

Ghevaert, Cedric; Herbert, Nina; Hawkins, Louise; Grehan, Nicola; Cookson, Philip; Garner, Steve F; Crisp-Hihn, Abigail; Lloyd-Evans, Paul; Evans, Amanda; Balan, Kottekkattu; Ouwehand, Willem H; Armour, Kathryn L; Clark, Mike R; Williamson, Lorna M

2013-07-18

Fetomaternal alloimmune thrombocytopenia, caused by the maternal generation of antibodies against fetal human platelet antigen-1a (HPA-1a), can result in intracranial hemorrhage and intrauterine death. We have developed a therapeutic human recombinant high-affinity HPA-1a antibody (B2G1Δnab) that competes for binding to the HPA-1a epitope but carries a modified constant region that does not bind to Fcγ receptors. In vitro studies with a range of clinical anti-HPA-1a sera have shown that B2G1Δnab blocks monocyte chemiluminescence by >75%. In this first-in-man study, we demonstrate that HPA-1a1b autologous platelets (matching fetal phenotype) sensitized with B2G1Δnab have the same intravascular survival as unsensitized platelets (190 hours), while platelets sensitized with a destructive immunoglobulin G1 version of the antibody (B2G1) are cleared from the circulation in 2 hours. Mimicking the situation in fetuses receiving B2G1Δnab as therapy, we show that platelets sensitized with a combination of B2G1 (representing destructive HPA-1a antibody) and B2G1Δnab survive 3 times as long in circulation compared with platelets sensitized with B2G1 alone. This confirms the therapeutic potential of B2G1Δnab. The efficient clearance of platelets sensitized with B2G1 also opens up the opportunity to carry out studies of prophylaxis to prevent alloimmunization in HPA-1a-negative mothers.

Continuous quantum measurements and the action uncertainty principle

NASA Astrophysics Data System (ADS)

Mensky, Michael B.

1992-09-01

The path-integral approach to quantum theory of continuous measurements has been developed in preceding works of the author. According to this approach the measurement amplitude determining probabilities of different outputs of the measurement can be evaluated in the form of a restricted path integral (a path integral “in finite limits”). With the help of the measurement amplitude, maximum deviation of measurement outputs from the classical one can be easily determined. The aim of the present paper is to express this variance in a simpler and transparent form of a specific uncertainty principle (called the action uncertainty principle, AUP). The most simple (but weak) form of AUP is δ S≳ℏ, where S is the action functional. It can be applied for simple derivation of the Bohr-Rosenfeld inequality for measurability of gravitational field. A stronger (and having wider application) form of AUP (for ideal measurements performed in the quantum regime) is |∫{/' t″ }(δ S[ q]/δ q( t))Δ q( t) dt|≃ℏ, where the paths [ q] and [Δ q] stand correspondingly for the measurement output and for the measurement error. It can also be presented in symbolic form as Δ(Equation) Δ(Path) ≃ ℏ. This means that deviation of the observed (measured) motion from that obeying the classical equation of motion is reciprocally proportional to the uncertainty in a path (the latter uncertainty resulting from the measurement error). The consequence of AUP is that improving the measurement precision beyond the threshold of the quantum regime leads to decreasing information resulting from the measurement.

Measuring liquid density using Archimedes' principle

NASA Astrophysics Data System (ADS)

Hughes, Stephen W.

2006-09-01

A simple technique is described for measuring absolute and relative liquid density based on Archimedes' principle. The technique involves placing a container of the liquid under test on an electronic balance and suspending a probe (e.g. a glass marble) attached to a length of line beneath the surface of the liquid. If the volume of the probe is known, the density of liquid is given by the difference between the balance reading before and after immersion of the probe divided by the volume of the probe. A test showed that the density of water at room temperature could be measured to an accuracy and precision of 0.01 ± 0.1%. The probe technique was also used to measure the relative density of milk, Coca-Cola, fruit juice, olive oil and vinegar.

Raman spectroscopy study and first-principles calculations of the interaction between nucleic acid bases and carbon nanotubes.

PubMed

Stepanian, Stepan G; Karachevtsev, Maksym V; Glamazda, Alexander Yu; Karachevtsev, Victor A; Adamowicz, L

2009-04-16

In this work, we have used Raman spectroscopy and quantum chemical methods (MP2 and DFT) to study the interactions between nucleic acid bases (NABs) and single-walled carbon nanotubes (SWCNT). We found that the appearance of the interaction between the nanotubes and the NABs is accompanied by a spectral shift of the high-frequency component of the SWCNT G band in the Raman spectrum to a lower frequency region. The value of this shift varies from 0.7 to 1.3 cm(-1) for the metallic nanotubes and from 2.1 to 3.2 cm(-1) for the semiconducting nanotubes. Calculations of the interaction energies between the NABs and a fragment of the zigzag(10,0) carbon nanotube performed at the MP2/6-31++G(d,p)[NABs atoms]|6-31G(d)[nanotube atoms] level of theory while accounting for the basis set superposition error during geometry optimization allowed us to order the NABs according to the increasing interaction energy value. The order is: guanine (-67.1 kJ mol(-1)) > adenine (-59.0 kJ mol(-1)) > cytosine (-50.3 kJ mol(-1)) approximately = thymine (-50.2 kJ mol(-1)) > uracil (-44.2 kJ mol(-1)). The MP2 equilibrium structures and the interaction energies were used as reference points in the evaluation of the ability of various functionals in the DFT method to predict those structures and energies. We showed that the M05, MPWB1K, and MPW1B95 density functionals are capable of correctly predicting the SWCNT-NAB geometries but not the interaction energies, while the M05-2X functional is capable of correctly predicting both the geometries and the interaction energies.

New principle for measuring arterial blood oxygenation, enabling motion-robust remote monitoring.

PubMed

van Gastel, Mark; Stuijk, Sander; de Haan, Gerard

2016-12-07

Finger-oximeters are ubiquitously used for patient monitoring in hospitals worldwide. Recently, remote measurement of arterial blood oxygenation (SpO 2 ) with a camera has been demonstrated. Both contact and remote measurements, however, require the subject to remain static for accurate SpO 2 values. This is due to the use of the common ratio-of-ratios measurement principle that measures the relative pulsatility at different wavelengths. Since the amplitudes are small, they are easily corrupted by motion-induced variations. We introduce a new principle that allows accurate remote measurements even during significant subject motion. We demonstrate the main advantage of the principle, i.e. that the optimal signature remains the same even when the SNR of the PPG signal drops significantly due to motion or limited measurement area. The evaluation uses recordings with breath-holding events, which induce hypoxemia in healthy moving subjects. The events lead to clinically relevant SpO 2 levels in the range 80-100%. The new principle is shown to greatly outperform current remote ratio-of-ratios based methods. The mean-absolute SpO 2 -error (MAE) is about 2 percentage-points during head movements, where the benchmark method shows a MAE of 24 percentage-points. Consequently, we claim ours to be the first method to reliably measure SpO 2 remotely during significant subject motion.

Phase I results of a phase I/II study of weekly nab-paclitaxel in paediatric patients with recurrent/refractory solid tumours: A collaboration with innovative therapies for children with cancer.

PubMed

Moreno, Lucas; Casanova, Michela; Chisholm, Julia C; Berlanga, Pablo; Chastagner, Pascal B; Baruchel, Sylvain; Amoroso, Loredana; Melcón, Soledad Gallego; Gerber, Nicolas U; Bisogno, Gianni; Fagioli, Franca; Geoerger, Birgit; Glade Bender, Julia L; Aerts, Isabelle; Bergeron, Christophe; Hingorani, Pooja; Elias, Ileana; Simcock, Mathew; Ferrara, Stefano; Le Bruchec, Yvan; Slepetis, Ruta; Chen, Nianhang; Vassal, Gilles

2018-06-21

nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients with recurrent/refractory solid tumours treated with nab-paclitaxel are reported. Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m 2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m 2 and grade 4 neutropenia >7 days at 270 mg/m 2 . The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m 2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1-2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases [high-grade, malignant] and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m 2 . Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST. nab-Paclitaxel 240 mg/m 2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. CLINICALTRIALS.GOV: NCT01962103. 2013-000144-26. Copyright © 2018 Elsevier Ltd. All rights reserved.

Phase II study of nab-paclitaxel in refractory small bowel adenocarcinoma and CpG island methylator phenotype (CIMP)-high colorectal cancer.

PubMed

Overman, M J; Adam, L; Raghav, K; Wang, J; Kee, B; Fogelman, D; Eng, C; Vilar, E; Shroff, R; Dasari, A; Wolff, R; Morris, J; Karunasena, E; Pisanic, R; Azad, N; Kopetz, S

2018-01-01

Hypermethylation of promoter CpG islands [CpG island methylator phenotype (CIMP)] represents a unique pathway for the development of colorectal cancer (CRC), characterized by lack of chromosomal instability and a low rate of adenomatous polyposis coli (APC) mutations, which have both been correlated with taxane resistance. Similarly, small bowel adenocarcinoma (SBA), a rare tumor, also has a low rate of APC mutations. This phase II study evaluated taxane sensitivity in SBA and CIMP-high CRC. The primary objective was Response Evaluation Criteria in Solid Tumors version 1.1 response rate. Eligibility included Eastern Cooperative Oncology Group performance status 0/1, refractory disease, and SBA or CIMP-high metastatic CRC. Nab-paclitaxel was initially administered at a dose of 260 mg/m2 every 3 weeks but was reduced to 220 mg/m2 owing to toxicity. A total of 21 patients with CIMP-high CRC and 13 with SBA were enrolled from November 2012 to October 2014. The efficacy-assessable population (patients who received at least three doses of the treatment) comprised 15 CIMP-high CRC patients and 10 SBA patients. Common grade 3 or 4 toxicities were fatigue (12%), neutropenia (9%), febrile neutropenia (9%), dehydration (6%), and thrombocytopenia (6%). No responses were seen in the CIMP-high CRC cohort and two partial responses were seen in the SBA cohort. Median progression-free survival was significantly greater in the SBA cohort than in the CIMP-high CRC cohort (3.2 months compared with 2.1 months, P = 0.03). Neither APC mutation status nor CHFR methylation status correlated with efficacy in the CIMP-high CRC cohort. In vivo testing of paclitaxel in an SBA patient-derived xenograft validated the activity of taxanes in this disease type. Although preclinical studies suggested taxane sensitivity was associated with chromosomal stability and wild-type APC, we found that nab-paclitaxel was inactive in CIMP-high metastatic CRC. Nab-paclitaxel may represent a novel

The Baby Care Questionnaire: A measure of parenting principles and practices during infancy☆

PubMed Central

Winstanley, Alice; Gattis, Merideth

2013-01-01

The current report provides a new framework to explore the role of parenting practices and principles during infancy. We identify structure and attunement as key parenting principles during infancy. Structure represents reliance on regularity and routines in daily life. Attunement represents reliance on infant cues and close physical contact. We suggest parents’ relative endorsement of these parenting principles is related to their choices about practices such as feeding, holding and night-time sleeping. We designed the Baby Care Questionnaire to measure parents’ endorsement of structure and attunement, as well as their daily parenting practices. We report data demonstrating the factor structure, reliability and validity of the BCQ. The BCQ, to our knowledge, is the first comprehensive measure of parenting practices and principles during infancy. We conclude with a discussion of future directions for the measure. PMID:24050932

Introductory review on `Flying Triangulation': a motion-robust optical 3D measurement principle

NASA Astrophysics Data System (ADS)

Ettl, Svenja

2015-04-01

'Flying Triangulation' (FlyTri) is a recently developed principle which allows for a motion-robust optical 3D measurement of rough surfaces. It combines a simple sensor with sophisticated algorithms: a single-shot sensor acquires 2D camera images. From each camera image, a 3D profile is generated. The series of 3D profiles generated are aligned to one another by algorithms, without relying on any external tracking device. It delivers real-time feedback of the measurement process which enables an all-around measurement of objects. The principle has great potential for small-space acquisition environments, such as the measurement of the interior of a car, and motion-sensitive measurement tasks, such as the intraoral measurement of teeth. This article gives an overview of the basic ideas and applications of FlyTri. The main challenges and their solutions are discussed. Measurement examples are also given to demonstrate the potential of the measurement principle.

First-principles definition and measurement of planetary electromagnetic-energy budget.

PubMed

Mishchenko, Michael I; Lock, James A; Lacis, Andrew A; Travis, Larry D; Cairns, Brian

2016-06-01

The imperative to quantify the Earth's electromagnetic-energy budget with an extremely high accuracy has been widely recognized but has never been formulated in the framework of fundamental physics. In this paper we give a first-principles definition of the planetary electromagnetic-energy budget using the Poynting-vector formalism and discuss how it can, in principle, be measured. Our derivation is based on an absolute minimum of theoretical assumptions, is free of outdated notions of phenomenological radiometry, and naturally leads to the conceptual formulation of an instrument called the double hemispherical cavity radiometer (DHCR). The practical measurement of the planetary energy budget would require flying a constellation of several dozen planet-orbiting satellites hosting identical well-calibrated DHCRs.

First-principles definition and measurement of planetary electromagnetic-energy budget

NASA Astrophysics Data System (ADS)

Mishchenko, M. I.; James, L.; Lacis, A. A.; Travis, L. D.; Cairns, B.

2016-12-01

The imperative to quantify the Earth's electromagnetic-energy budget with an extremely high accuracy has been widely recognized but has never been formulated in the framework of fundamental physics. In this talk we give a first-principles definition of the planetary electromagnetic-energy budget using the Poynting-vector formalism and discuss how it can, in principle, be measured. Our derivation is based on an absolute minimum of theoretical assumptions, is free of outdated concepts of phenomenological radiometry, and naturally leads to the conceptual formulation of an instrument called the double hemispherical cavity radiometer (DHCR). The practical measurement of the planetary energy budget would require flying a constellation of several dozen planet-orbiting satellites hosting identical well-calibrated DHCRs.

First-Principles Definition and Measurement of Planetary Electromagnetic-Energy Budget

NASA Technical Reports Server (NTRS)

Mishchenko, Michael I.; Lock, James A.; Lacis, Andrew A.; Travis, Larry D.; Cairns, Brian

2016-01-01

The imperative to quantify the Earths electromagnetic-energy budget with an extremely high accuracy has been widely recognized but has never been formulated in the framework of fundamental physics. In this paper we give a first-principles definition of the planetary electromagnetic-energy budget using the Poynting- vector formalism and discuss how it can, in principle, be measured. Our derivation is based on an absolute minimum of theoretical assumptions, is free of outdated notions of phenomenological radiometry, and naturally leads to the conceptual formulation of an instrument called the double hemispherical cavity radiometer (DHCR). The practical measurement of the planetary energy budget would require flying a constellation of several dozen planet-orbiting satellites hosting identical well-calibrated DHCRs.

The action uncertainty principle for continuous measurements

NASA Astrophysics Data System (ADS)

Mensky, Michael B.

1996-02-01

The action uncertainty principle (AUP) for the specification of the most probable readouts of continuous quantum measurements is proved, formulated in different forms and analyzed (for nonlinear as well as linear systems). Continuous monitoring of an observable A(p,q,t) with resolution Δa( t) is considered. The influence of the measurement process on the evolution of the measured system (quantum measurement noise) is presented by an additional term δ F(t)A(p,q,t) in the Hamiltonian where the function δ F (generalized fictitious force) is restricted by the AUP ∫|δ F(t)| Δa( t) d t ≲ and arbitrary otherwise. Quantum-nondemolition (QND) measurements are analyzed with the help of the AUP. A simple uncertainty relation for continuous quantum measurements is derived. It states that the area of a certain band in the phase space should be of the order of. The width of the band depends on the measurement resolution while its length is determined by the deviation of the system, due to the measurement, from classical behavior.

The four principles: Can they be measured and do they predict ethical decision making?

PubMed Central

2012-01-01

Background The four principles of Beauchamp and Childress - autonomy, non-maleficence, beneficence and justice - have been extremely influential in the field of medical ethics, and are fundamental for understanding the current approach to ethical assessment in health care. This study tests whether these principles can be quantitatively measured on an individual level, and then subsequently if they are used in the decision making process when individuals are faced with ethical dilemmas. Methods The Analytic Hierarchy Process was used as a tool for the measurement of the principles. Four scenarios, which involved conflicts between the medical ethical principles, were presented to participants who then made judgments about the ethicality of the action in the scenario, and their intentions to act in the same manner if they were in the situation. Results Individual preferences for these medical ethical principles can be measured using the Analytic Hierarchy Process. This technique provides a useful tool in which to highlight individual medical ethical values. On average, individuals have a significant preference for non-maleficence over the other principles, however, and perhaps counter-intuitively, this preference does not seem to relate to applied ethical judgements in specific ethical dilemmas. Conclusions People state they value these medical ethical principles but they do not actually seem to use them directly in the decision making process. The reasons for this are explained through the lack of a behavioural model to account for the relevant situational factors not captured by the principles. The limitations of the principles in predicting ethical decision making are discussed. PMID:22606995

The four principles: can they be measured and do they predict ethical decision making?

PubMed

Page, Katie

2012-05-20

The four principles of Beauchamp and Childress--autonomy, non-maleficence, beneficence and justice--have been extremely influential in the field of medical ethics, and are fundamental for understanding the current approach to ethical assessment in health care. This study tests whether these principles can be quantitatively measured on an individual level, and then subsequently if they are used in the decision making process when individuals are faced with ethical dilemmas. The Analytic Hierarchy Process was used as a tool for the measurement of the principles. Four scenarios, which involved conflicts between the medical ethical principles, were presented to participants who then made judgments about the ethicality of the action in the scenario, and their intentions to act in the same manner if they were in the situation. Individual preferences for these medical ethical principles can be measured using the Analytic Hierarchy Process. This technique provides a useful tool in which to highlight individual medical ethical values. On average, individuals have a significant preference for non-maleficence over the other principles, however, and perhaps counter-intuitively, this preference does not seem to relate to applied ethical judgements in specific ethical dilemmas. People state they value these medical ethical principles but they do not actually seem to use them directly in the decision making process. The reasons for this are explained through the lack of a behavioural model to account for the relevant situational factors not captured by the principles. The limitations of the principles in predicting ethical decision making are discussed.

A Phase I Study of Hepatic Arterial Infusion of Nab-Paclitaxel in Combination with Intravenous Gemcitabine and Bevacizumab for Patients with Advanced Cancers and Predominant Liver Metastases

PubMed Central

Tsimberidou, Apostolia M.; Ye, Yang; Wheler, Jennifer; Naing, Aung; Hong, David; Nwosu, Uchechi; Hess, Kenneth R.; Wolff, Robert A.

2014-01-01

PURPOSE We conducted a Phase I clinical trial for patients with advanced cancer and predominant liver disease. EXPERIMENTAL DESIGN Patients were treated with HAI nab-paclitaxel (120-210 mg/m2; day 1); intravenous bevacizumab (10 mg/kg; day 1); and intravenous gemcitabine (600-800 mg/m2; days 1 and 8). A conventional “3 + 3” study design was used. RESULTS Fifty patients with advanced cancer and predominant liver metastases were treated (median age, 58 years; 27 women, 23 men; median number of prior therapies, 3 [range, 0-12]). The most common cancers were breast (n=9) and pancreatic (n=9). Overall, 264 cycles were administered (median/patient, 4; range, 1-17). No dose-limiting toxicities were noted during the escalation phase. On dose level 4, 3 patients were unable to receive gemcitabine on day 8 because of severe thrombocytopenia. Dose level 3 was selected as the maximum tolerated dose (HAI nab-paclitaxel 180 mg/m2 and intravenous gemcitabine 800 mg/m2 and bevacizumab 10 mg/kg); Thirty-two patients were treated in the expansion phase. The most common treatment-related toxicities were thrombocytopenia (n=17), neutropenia (n=10), and fatigue (n=12). Of 46 patients evaluable for response, 9 (20%) had a partial response [1] and 9 (20%) had stable disease for {greater than or equal to} 6 months. The median overall survival duration was 7.0 months (95% CI: 4, 22 months) and the median progression-free survival duration was 4.2 months (95% CI: 2.7, 8.6 months). CONCLUSIONS HAI nab-paclitaxel in combination with gemcitabine and bevacizumab was well tolerated and had antitumor activity in selected patients with advanced cancer and liver metastases. PMID:23377373

Comparison of bone density measurement techniques: DXA and Archimedes' principle.

PubMed

Keenan, M J; Hegsted, M; Jones, K L; Delany, J P; Kime, J C; Melancon, L E; Tulley, R T; Hong, K D

1997-11-01

The standard method for determination of density (g/cm3) of bones from small animals has been the application of Archimedes' principle. A recent development has been software for the determination of "density" (g/cm2) of small animal bones with dual-energy X-ray absorptiometry (DXA). We compared Archimedes' principle and DXA (Hologic QDR-2000) in the measurement of the densities of whole and hollowed femurs of 5- to 6-month-old retired female breeder rats. In an attempt to ensure detectable treatment differences, rats were used from a low-vitamin D Holtzman and a supplemental-vitamin D Sprague-Dawley colony. Whole femur densities were higher for supplemental-vitamin D colony rats than for low vitamin D rats using both techniques (Archimedes' principle, p < 0.002; DXA, p < 0.005), and the densities from the two techniques were highly correlated (r = 0.82, p < 0.0001). Actual density values were higher for Archimedes' principle than for DXA. Other variables such as femur ash weight and calcium content were also highly correlated to densities with both techniques. Hollowed femur density values were higher than whole femur values with Archimedes' principle but lower with DXA. Colony effects for hollowed femur densities were diminished with Archimedes' principle (p < 0.03) and eliminated with DXA (p < 0.53). Investigation of whole bones is more biologically relevant, and both techniques were effective in detecting differences between whole femurs from low-vitamin D and supplemental-vitamin D colony rats.

THE DEVELOPMENT OF AN INSTRUMENT FOR MEASURING THE UNDERSTANDING OF PROFIT-MAXIMIZING PRINCIPLES.

ERIC Educational Resources Information Center

MCCORMICK, FLOYD G.

THE PURPOSE OF THE STUDY WAS TO DEVELOP AN INSTRUMENT FOR MEASURING PROFIT-MAXIMIZING PRINCIPLES IN FARM MANAGEMENT WITH IMPLICATIONS FOR VOCATIONAL AGRICULTURE. PRINCIPLES WERE IDENTIFIED FROM LITERATURE SELECTED BY AGRICULTURAL ECONOMISTS. FORTY-FIVE MULTIPLE-CHOICE QUESTIONS WERE REFINED ON THE BASIS OF RESULTS OF THREE PRETESTS AND…

High natural antibody titers of indigenous chickens are related with increased hazard in confinement

PubMed Central

Wondmeneh, E.; Van Arendonk, J. A. M.; Van der Waaij, E. H.; Ducro, B. J.; Parmentier, H. K.

2015-01-01

Natural antibody (NAb) levels and survival rates were evaluated in 4 breeds of laying hens in Ethiopia: indigenous, improved indigenous, exotic layer, and crossbred. Titers of NAb isotypes IgG and IgM binding keyhole limpet hemocyanin (KLH) in serum were measured at 20, 26, 35, and 45 wk age. Repeated-measure ANOVA showed that IgG and IgM levels vary with time within each breed (P < 0.05). Indigenous chickens had significantly (P < 0.05) higher NAb levels at all ages. The Cox proportional hazard analysis showed increased hazard with increased levels of NAbs in the exotic layers (P < 0.05). However, the reduced hazards with increased levels of NAbs were not significant in the improved indigenous and crossbred chickens. Indigenous chickens showed increased hazard with increasing levels of NAb (P > 0.05). We concluded that not only the NAb levels but also the effect of Nabs on survival vary between indigenous and improved breeds. The results indicate that NAb levels are associated with survival in elite (improved) breeds, but are associated with increased hazard in indigenous chickens. PMID:25910906

Multi-fiber strains measured by micro-Raman spectroscopy: Principles and experiments

NASA Astrophysics Data System (ADS)

Lei, Zhenkun; Wang, Yunfeng; Qin, Fuyong; Qiu, Wei; Bai, Ruixiang; Chen, Xiaogang

2016-02-01

Based on widely used axial strain measurement method of Kevlar single fiber, an original theoretical model and measurement principle of application of micro-Raman spectroscopy to multi-fiber strains in a fiber bundle were established. The relationship between the nominal Raman shift of fiber bundle and the multi-fiber strains was deduced. The proposed principle for multi-fiber strains measurement is consistent with two special cases: single fiber deformation and multi-fiber deformation under equal strain. It is found experimentally that the distribution of Raman scattering intensity of a Kevlar 49 fiber as a function of distance between a fiber and the laser spot center follows a Gaussian function. Combining the Raman-shift/strain relationship of the Kevlar 49 single fiber and the uniaxial tension measured by micro-Raman spectroscopy, the Raman shift as a function of strain was obtained. Then the Raman peak at 1610 cm-1 for the Kevlar 49 fiber was fitted to a Lorentzian function and the FWHM showed a quadratic increase with the fiber strain. Finally, a dual-fiber tensile experiment was performed to verify the adequacy of the Raman technique for the measurement of multi-fiber strains.

High natural antibody titers of indigenous chickens are related with increased hazard in confinement.

PubMed

Wondmeneh, E; Van Arendonk, J A M; Van der Waaij, E H; Ducro, B J; Parmentier, H K

2015-07-01

Natural antibody (NAb) levels and survival rates were evaluated in 4 breeds of laying hens in Ethiopia: indigenous, improved indigenous, exotic layer, and crossbred. Titers of NAb isotypes IgG and IgM binding keyhole limpet hemocyanin (KLH) in serum were measured at 20, 26, 35, and 45 wk age. Repeated-measure ANOVA showed that IgG and IgM levels vary with time within each breed (P < 0.05). Indigenous chickens had significantly (P < 0.05) higher NAb levels at all ages. The Cox proportional hazard analysis showed increased hazard with increased levels of NAbs in the exotic layers (P < 0.05). However, the reduced hazards with increased levels of NAbs were not significant in the improved indigenous and crossbred chickens. Indigenous chickens showed increased hazard with increasing levels of NAb (P > 0.05). We concluded that not only the NAb levels but also the effect of Nabs on survival vary between indigenous and improved breeds. The results indicate that NAb levels are associated with survival in elite (improved) breeds, but are associated with increased hazard in indigenous chickens. © The Author 2015. Published by Oxford University Press on behalf of Poultry Science Association.

Quality of Life and its Measurement: Important Principles and Guidelines

ERIC Educational Resources Information Center

Verdugo, M. A.; Schalock, R. L.; Keith, K. D.; Stancliffe, R. J.

2005-01-01

Background: The importance of the valid assessment of quality of life (QOL) is heightened with the increased use of the QOL construct as a basis for policies and practices in the field of intellectual disability (ID). Method: This article discusses the principles that should guide the measurement process, the major interrogatories (i.e. who, what,…

Sodium butyrate epigenetically modulates high-fat diet-induced skeletal muscle mitochondrial adaptation, obesity and insulin resistance through nucleosome positioning

PubMed Central

Henagan, Tara M; Stefanska, Barbara; Fang, Zhide; Navard, Alexandra M; Ye, Jianping; Lenard, Natalie R; Devarshi, Prasad P

2015-01-01

Background and Purpose Sodium butyrate (NaB), an epigenetic modifier, is effective in promoting insulin sensitivity. The specific genomic loci and mechanisms underlying epigenetically induced obesity and insulin resistance and the targets of NaB are not fully understood. Experimental Approach The anti-diabetic and anti-obesity effects of NaB treatment were measured by comparing phenotypes and physiologies of C57BL/6J mice fed a low-fat diet (LF), high-fat diet (HF) or high-fat diet plus NaB (HF + NaB) for 10 weeks. We determined a possible mechanism of NaB action through induction of beneficial skeletal muscle mitochondrial adaptations and applied microccocal nuclease digestion with sequencing (MNase-seq) to assess whole genome differences in nucleosome occupancy or positioning and to identify associated epigenetic targets of NaB. Key Results NaB prevented HF diet-induced increases in body weight and adiposity without altering food intake or energy expenditure, improved insulin sensitivity as measured by glucose and insulin tolerance tests, and decreased respiratory exchange ratio. In skeletal muscle, NaB increased the percentage of type 1 fibres, improved acylcarnitine profiles as measured by metabolomics and produced a chromatin structure, determined by MNase-seq, similar to that seen in LF. Targeted analysis of representative nuclear-encoded mitochondrial genes showed specific repositioning of the −1 nucleosome in association with altered gene expression. Conclusions and Implications NaB treatment may be an effective pharmacological approach for type 2 diabetes and obesity by inducing −1 nucleosome repositioning within nuclear-encoded mitochondrial genes, causing skeletal muscle mitochondrial adaptations that result in more complete β-oxidation and a lean, insulin sensitive phenotype. PMID:25559882

40 CFR Appendix C to Part 50 - Measurement Principle and Calibration Procedure for the Measurement of Carbon Monoxide in the...

Code of Federal Regulations, 2013 CFR

2013-07-01

... measurement interference from water vapor, carbon dioxide (CO2), or other species. Also, various schemes may....0Interferences 3.1The NDIR measurement principle is potentially susceptible to interference from water vapor and...

Ecological validity of the screening module and the Daily Living tests of the Neuropsychological Assessment Battery using the Mayo-Portland Adaptability Inventory-4 in postacute brain injury rehabilitation.

PubMed

Zgaljardic, Dennis J; Yancy, Sybil; Temple, Richard O; Watford, Monica F; Miller, Rebekah

2011-11-01

The assessment of ecological validity of neuropsychological measures is an area of growing interest, particularly in the postacute brain injury rehabilitation (PABIR) setting, as there is an increasing demand for clinicians to address functional and real-world outcomes. In the current study, we assessed the predictive value of the Screening module and the Daily Living tests of the Neuropsychological Assessment Battery (NAB) using clinician ratings from the Mayo-Portland Adaptability Inventory-4 (MPAI-4) in patients with moderate to severe traumatic brain injury. Forty-seven individuals were each administered the NAB Screening module (NAB-SM) and the NAB Daily Living (NAB-DL) tests following admission to a residential PABIR program. MPAI-4 ratings were also obtained at admission. Linear regression analysis was used to examine the association between these functional and neuropsychological assessment measures. We replicated prior work (Temple at al., 2009) and expanded evidence for the ecological validity of the NAB-SM. Furthermore, our findings support the ecological validity of the NAB-DL Bill Payment, Judgment, and Map Reading tests with regards to functional skills and real-world activities. The current study supports prior work from our lab assessing the predictive value of the NAB-SM, as well as provides evidence for the ecological validity for select NAB-DL tests in patients with moderate to severe traumatic brain injury admitted to a residential PABIR program.

PULSED EDDY CURRENT THICKNESS MEASUREMENT OF SELECTIVE PHASE CORROSION ON NICKEL ALUMINUM BRONZE VALVES

DOE Office of Scientific and Technical Information (OSTI.GOV)

Krause, T. W.; Harlley, D.; Babbar, V. K.

Nickel Aluminum Bronze (NAB) is a material with marine environment applications that under certain conditions can undergo selective phase corrosion (SPC). SPC involves the removal of minority elements while leaving behind a copper matrix. Pulsed eddy current (PEC) was evaluated for determination of SPC thickness on a NAB valve section with access from the surface corroded side. A primarily linear response of PEC amplitude, up to the maximum available SPC thickness of 4 mm was observed. The combination of reduced conductivity and permeability in the SPC phase relative to the base NAB was used to explain the observed sensitivity ofmore » PEC to SPC thickness variations.« less

The measurement of principled morality by the Kohlberg Moral Dilemma Questionnaire.

PubMed

Heilbrun, A B; Georges, M

1990-01-01

The four stages preceding the postconventional level in the Kohlberg (1958, 1971, 1976) system of moral development are described as involving moral judgments that conform to external conditions of punishment, reward, social expectation, and conformity to the law. No special level of self-control seems necessary to behave in keeping with these conditions of external reinforcement. In contrast, the two stages of postconventional (principled) mortality involve defiance of majority opinion and defiance of the law--actions that would seem to require greater self-control. This study was concerned with whether postconventional moral reasoning, as measured by the Kohlberg Moral Dilemma Questionnaire (MDQ), can be associated with higher self-control. If so, prediction of principled moral behavior from the MDQ would be based not only on postconventional moral reasoning but bolstered by the necessary level of self-control as well. College students who came the closest to postconventional moral reasoning showed better self-control than college students who were more conventional or preconventional in their moral judgments. These results support the validity of the MDQ for predicting principled moral behavior.

Developing recombinant HPA-1a–specific antibodies with abrogated Fcγ receptor binding for the treatment of fetomaternal alloimmune thrombocytopenia

PubMed Central

Ghevaert, Cedric; Wilcox, David A.; Fang, Juan; Armour, Kathryn L.; Clark, Mike R.; Ouwehand, Willem H.; Williamson, Lorna M.

2008-01-01

Fetomaternal alloimmune thrombocytopenia (FMAIT) is caused by maternal generation of antibodies specific for paternal platelet antigens and can lead to fetal intracranial hemorrhage. A SNP in the gene encoding integrin β3 causes a clinically important maternal-paternal antigenic difference; Leu33 generates the human platelet antigen 1a (HPA-1a), whereas Pro33 generates HPA-1b. As a potential treatment to prevent fetal intracranial hemorrhage in HPA-1a alloimmunized pregnancies, we generated an antibody that blocks the binding of maternal HPA-1a–specific antibodies to fetal HPA-1a1b platelets by combining a high-affinity human HPA-1a–specific scFv (B2) with an IgG1 constant region modified to minimize Fcγ receptor–dependent platelet destruction (G1Δnab). B2G1Δnab saturated HPA-1a+ platelets and substantially inhibited binding of clinical HPA-1a–specific sera to HPA-1a+ platelets. The response of monocytes to B2G1Δnab-sensitized platelets was substantially less than their response to unmodified B2G1, as measured by chemiluminescence. In addition, B2G1Δnab inhibited chemiluminescence induced by B2G1 and HPA-1a–specific sera. In a chimeric mouse model, B2G1 and polyclonal Ig preparations from clinical HPA-1a–specific sera reduced circulating HPA-1a+ platelets, concomitant with transient thrombocytopenia. As the Δnab constant region is uninformative in mice, F(ab′)2 B2G1 was used as a proof of principle blocking antibody and prevented the in vivo platelet destruction seen with B2G1 and polyclonal HPA-1a–specific antibodies. These results provide rationale for human clinical studies. PMID:18654666

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer patients: prospective evaluation of activity, safety, and quality of life.

PubMed

Palumbo, Raffaella; Sottotetti, Federico; Trifirò, Giuseppe; Piazza, Elena; Ferzi, Antonella; Gambaro, Anna; Spinapolice, Elena Giulia; Pozzi, Emma; Tagliaferri, Barbara; Teragni, Cristina; Bernardo, Antonio

2015-01-01

A prospective, multicenter trial was undertaken to assess the activity, safety, and quality of life of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as second-line chemotherapy in HER2-negative, taxane-pretreated metastatic breast cancer (MBC). Fifty-two women with HER2-negative MBC who were candidates for second-line chemotherapy for the metastatic disease were enrolled and treated at three centers in Northern Italy. All patients had previously received taxane-based chemotherapy in the adjuvant or first-line metastatic setting. Single-agent nab-paclitaxel was given at the dose of 260 mg/m(2) as a 30-minute intravenous infusion on day 1 each treatment cycle, which lasted 3 weeks, in the outpatient setting. No steroid or antihistamine premedication was provided. Treatment was stopped for documented disease progression, unacceptable toxicity, or patient refusal. All of the enrolled patients were evaluable for the study endpoints. The objective response rate was 48% (95% CI, 31.5%-61.3%) and included complete responses from 13.5%. Disease stabilization was obtained in 19 patients and lasted >6 months in 15 of them; the overall clinical benefit rate was 77%. The median time to response was 70 days (range 52-86 days). The median progression-free survival time was 8.9 months (95% CI, 8.0-11.6 months, range 5-21+ months). The median overall survival point has not yet been reached. Toxicities were expected and manageable with good patient compliance and preserved quality of life in patients given long-term treatment. Our results showed that single-agent nab-paclitaxel 260 mg/m(2) every 3 weeks is an effective and well tolerated regimen as second-line chemotherapy in HER2-negative, taxane-pretreated MBC patients, and that it produced interesting values of objective response rate and progression-free survival without the concern of significant toxicity. Specifically, the present study shows that such a regimen is a valid therapeutic option for that 'difficult to

Commercially available immunoglobulins contain virus neutralizing antibodies against all major genotypes of polyomavirus BK.

PubMed

Randhawa, P; Pastrana, D V; Zeng, G; Huang, Y; Shapiro, R; Sood, P; Puttarajappa, C; Berger, M; Hariharan, S; Buck, C B

2015-04-01

Neutralizing antibodies (NAbs) form the basis of immunotherapeutic strategies against many important human viral infections. Accordingly, we studied the prevalence, titer, genotype-specificity, and mechanism of action of anti-polyomavirus BK (BKV) NAbs in commercially available human immune globulin (IG) preparations designed for intravenous (IV) use. Pseudovirions (PsV) of genotypes Ia, Ib2, Ic, II, III, and IV were generated by co-transfecting a reporter plasmid encoding luciferase and expression plasmids containing synthetic codon-modified VP1, VP2, and VP3 capsid protein genes into 293TT cells. NAbs were measured using luminometry. All IG preparations neutralized all BKV genotypes, with mean EC50 titers as high as 254 899 for genotype Ia and 6,666 for genotype IV. Neutralizing titers against genotypes II and III were higher than expected, adding to growing evidence that infections with these genotypes are more common than currently appreciated. Batch to batch variation in different lots of IG was within the limits of experimental error. Antibody mediated virus neutralizing was dose dependent, modestly enhanced by complement, genotype-specific, and achieved without effect on viral aggregation, capsid morphology, elution, or host cell release. IG contains potent NAbs capable of neutralizing all major BKV genotypes. Clinical trials based on sound pharmacokinetic principles are needed to explore prophylactic and therapeutic applications of these anti-viral effects, until effective small molecule inhibitors of BKV replication can be developed. © Copyright 2015 The American Society of Transplantation and the American Society of Transplant Surgeons.

Genetic variation of natural antibodies in milk of Dutch Holstein-Friesian cows.

PubMed

Ploegaert, T C W; Wijga, S; Tijhaar, E; van der Poel, J J; Lam, T J G M; Savelkoul, H F J; Parmentier, H K; van Arendonk, J A M

2010-11-01

Defense mechanisms of dairy cows against diseases partly rest on their naturally present disease resistance capacity. Natural antibodies (NAb) form a soluble part of the innate immune system, being defined as antibodies circulating in animals without prior intentional antigenic stimulation. Genetic selection on NAb titers in milk, therefore, might improve disease resistance. We estimated genetic parameters of NAb titers binding lipopolysaccharide, lipoteichoic acid (LTA), peptidoglycan, and keyhole limpet hemocyanin, and titers of the NAb isotypes IgG1, IgM, and IgA binding LTA in milk of Dutch Holstein-Friesian heifers. Natural antibody titers were measured in 1 milk sample from each of 1,939 Holstein-Friesian heifers and used for estimating genetic parameters of NAb titers. The data show that phenotypic variation exists among heifers in NAb titers binding lipopolysaccharide, LTA, peptidoglycan, and keyhole limpet hemocyanin, and the NAb isotypes IgG1, IgM, and IgA binding LTA in milk. High genetic correlations among NAb (ranging from 0.45 to 0.99) indicated a common genetic basis for the levels of different NAb in bovine milk. Intra-herd heritability estimates for NAb ranged from 0.10 to 0.53. The results indicated that NAb levels have potential for genetic selection. Copyright © 2010 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

A New Principle in Physiscs: the Principle "Finiteness", and Some Consequences

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abraham Sternlieb

2010-06-25

In this paper I propose a new principle in physics: the principle of "finiteness". It stems from the definition of physics as a science that deals (among other things) with measurable dimensional physical quantities. Since measurement results, including their errors, are always finite, the principle of finiteness postulates that the mathematical formulation of "legitimate" laws of physics should prevent exactly zero or infinite solutions. Some consequences of the principle of finiteness are discussed, in general, and then more specifically in the fields of special relativity, quantum mechanics, and quantum gravity. The consequences are derived independently of any other theory ormore » principle in physics. I propose "finiteness" as a postulate (like the constancy of the speed of light in vacuum, "c"), as opposed to a notion whose validity has to be corroborated by, or derived theoretically or experimentally from other facts, theories, or principles.« less

Serum IFN neutralizing antibodies and neopterin levels in a cross-section of MS patients.

PubMed

Cook, S D; Quinless, J R; Jotkowitz, A; Beaton, P

2001-09-25

To determine levels of serum interferon beta (IFNbeta) neutralizing antibody (NAb) and neopterin-an IFN biologic response marker-in patients with MS treated with Betaseron or Avonex. Controversy exists over the relative immunogenicity of IFNbeta-1a and IFNbeta-1b and the reasons for any such difference. To determine the role of patient profile and test methodology in IFNbeta, NAb levels need to be measured blindly and simultaneously in a predefined closely matched MS patient cohort. Serum NAb and neopterin levels were measured in closely matched patients on Avonex (n = 98) or Betaseron (n = 64). NAb were determined by Athena Diagnostics and serum neopterin levels by Covance Laboratories using a competitive binding radioimmunoassay. More patients taking Betaseron (22%) than Avonex (7%) had elevated titers of NAb (p = 0.008). Mean serum neopterin levels were lower in patients with high as compared to low NAb titers (p = 0.0002). No difference in mean neopterin levels was found comparing the total Betaseron group to the Avonex group; however, in the subset of patients with low NAb titers, mean neopterin levels were higher in the Betaseron than in the Avonex group (p = 0.027). A random cross-sectional sampling of patients on Avonex showed a decrease in neopterin levels over time between weekly doses. NAb are more commonly found with Betaseron than Avonex. More studies are needed to determine the correlation among serum neopterin levels, other biologic response markers, NAb, and disease activity in patients with MS being treated with IFNbeta.

Psychometric Principles in Measurement for Geoscience Education Research: A Climate Change Example

NASA Astrophysics Data System (ADS)

Libarkin, J. C.; Gold, A. U.; Harris, S. E.; McNeal, K.; Bowles, R.

2015-12-01

Understanding learning in geoscience classrooms requires that we use valid and reliable instruments aligned with intended learning outcomes. Nearly one hundred instruments assessing conceptual understanding in undergraduate science and engineering classrooms (often called concept inventories) have been published and are actively being used to investigate learning. The techniques used to develop these instruments vary widely, often with little attention to psychometric principles of measurement. This paper will discuss the importance of using psychometric principles to design, evaluate, and revise research instruments, with particular attention to the validity and reliability steps that must be undertaken to ensure that research instruments are providing meaningful measurement. An example from a climate change inventory developed by the authors will be used to exemplify the importance of validity and reliability, including the value of item response theory for instrument development. A 24-item instrument was developed based on published items, conceptions research, and instructor experience. Rasch analysis of over 1000 responses provided evidence for the removal of 5 items for misfit and one item for potential bias as measured via differential item functioning. The resulting 18-item instrument can be considered a valid and reliable measure based on pre- and post-implementation metrics. Consideration of the relationship between respondent demographics and concept inventory scores provides unique insight into the relationship between gender, religiosity, values and climate change understanding.

Effects of Sodium Butyrate on Methamphetamine-Sensitized Locomotor Activity

PubMed Central

Harkness, John H.; Hitzemann, Robert J.; Edmunds, Stephanie; Phillips, Tamara J.

2012-01-01

Neuroadaptations associated with behavioral sensitization induced by repeated exposure to methamphetamine (MA) appear to be involved in compulsive drug pursuit and use. Increased histone acetylation, an epigenetic effect resulting in altered gene expression, may promote sensitized responses to psychostimulants. The role of histone acetylation in the expression and acquisition of MA-induced locomotor sensitization was examined by measuring the effect of histone deacetylase inhibition by sodium butyrate (NaB). For the effect on expression, vehicle or NaB (630 mg/kg, intraperitoneally) was administered 30 min prior to MA challenge in mice treated repeatedly with MA (10 days of 2 mg/kg MA) or saline (10 days), and then locomotor response to MA challenge was measured. NaB treatment increased the locomotor response to MA in both acutely MA treated and sensitized animals. For acquisition, NaB was administered 30 min prior to each MA exposure (10 days of 1 or 2 mg/kg), but not prior to the MA challenge test. Treatment with NaB during the sensitization acquisition period significantly increased locomotor activation by MA in sensitized mice only. NaB alone did not significantly alter locomotor activity. Acute NaB or MA, but not the combination, appeared to increase striatal acetylation at histone H4. Repeated treatment with MA, but not NaB or MA plus NaB, increased striatal acetylation at histone H3. Although increased histone acetylation may alter the expression of genes involved in acute locomotor response to MA and in the acquisition of MA-induced sensitization, results for acetylation at H3 and H4 showed little correspondence with behavior. PMID:23137698

A blood-based predictor for neocortical Aβ burden in Alzheimer's disease: results from the AIBL study.

PubMed

Burnham, S C; Faux, N G; Wilson, W; Laws, S M; Ames, D; Bedo, J; Bush, A I; Doecke, J D; Ellis, K A; Head, R; Jones, G; Kiiveri, H; Martins, R N; Rembach, A; Rowe, C C; Salvado, O; Macaulay, S L; Masters, C L; Villemagne, V L

2014-04-01

Dementia is a global epidemic with Alzheimer's disease (AD) being the leading cause. Early identification of patients at risk of developing AD is now becoming an international priority. Neocortical Aβ (extracellular β-amyloid) burden (NAB), as assessed by positron emission tomography (PET), represents one such marker for early identification. These scans are expensive and are not widely available, thus, there is a need for cheaper and more widely accessible alternatives. Addressing this need, a blood biomarker-based signature having efficacy for the prediction of NAB and which can be easily adapted for population screening is described. Blood data (176 analytes measured in plasma) and Pittsburgh Compound B (PiB)-PET measurements from 273 participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study were utilised. Univariate analysis was conducted to assess the difference of plasma measures between high and low NAB groups, and cross-validated machine-learning models were generated for predicting NAB. These models were applied to 817 non-imaged AIBL subjects and 82 subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) for validation. Five analytes showed significant difference between subjects with high compared to low NAB. A machine-learning model (based on nine markers) achieved sensitivity and specificity of 80 and 82%, respectively, for predicting NAB. Validation using the ADNI cohort yielded similar results (sensitivity 79% and specificity 76%). These results show that a panel of blood-based biomarkers is able to accurately predict NAB, supporting the hypothesis for a relationship between a blood-based signature and Aβ accumulation, therefore, providing a platform for developing a population-based screen.

Assessing Visuospatial Skills in Parkinson's: Comparison of Neuropsychological Assessment Battery Visual Discrimination to the Judgment of Line Orientation.

PubMed

Renfroe, Jenna B; Turner, Travis H; Hinson, Vanessa K

2017-02-01

Judgment of Line Orientation (JOLO) test is widely used in assessing visuospatial deficits in Parkinson's disease (PD). The neuropsychological assessment battery (NAB) offers the Visual Discrimination test, with age and education correction, parallel forms, and co-normed standardization sample for comparisons within and between domains. However, NAB Visual Discrimination has not been validated in PD, and may not measure the same construct as JOLO. A heterogeneous sample of 47 PD patients completed the JOLO and NAB Visual Discrimination within a broader neuropsychological evaluation. Pearson correlations assessed relationships between JOLO and NAB Visual Discrimination performances. Raw and demographically corrected scores from JOLO and Visual Discrimination were only weakly correlated. NAB Visual Discrimination subtest was moderately correlated with overall cognitive functioning, whereas the JOLO was not. Despite apparent virtues, results do not support NAB Visual Discrimination as an alternative to JOLO in assessing visuospatial functioning in PD. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Study on Measuring the Viscosity of Lubricating Oil by Viscometer Based on Hele - Shaw Principle

NASA Astrophysics Data System (ADS)

Li, Longfei

2017-12-01

In order to explore the method of accurately measuring the viscosity value of oil samples using the viscometer based on Hele-Shaw principle, three different measurement methods are designed in the laboratory, and the statistical characteristics of the measured values are compared, in order to get the best measurement method. The results show that the oil sample to be measured is placed in the magnetic field formed by the magnet, and the oil sample can be sucked from the same distance from the magnet. The viscosity value of the sample can be measured accurately.

A novel cell-based assay for measuring neutralizing autoantibodies against type I interferons in patients with autoimmune polyendocrine syndrome type 1.

PubMed

Breivik, Lars; Oftedal, Bergithe E V; Bøe Wolff, Anette S; Bratland, Eirik; Orlova, Elizaveta M; Husebye, Eystein S

2014-07-01

An important characteristic of autoimmune polyendocrine syndrome type 1 (APS 1) is the existence of neutralizing autoantibodies (nAbs) against the type I interferons (IFN) -α2 and -ω at frequencies close to 100%. Type 1 IFN autoantibodies are detected by antiviral neutralizing assays (AVA), binding assays with radiolabelled antigens (RLBA), enzyme-linked immunosorbent assay (ELISA), or by reporter-based cell assays. We here present a simple and reliable version of the latter utilizing a commercially available cell line (HEK-Blue IFN-α/β). All 67 APS 1 patients were positive for IFN-ω nAbs, while 90% were positive for IFN-α2 nAbs, a 100% and 96% correlation with RLBA, respectively. All blood donors and non-APS 1 patients were negative. The dilution titer required to reduce the effect of IFN-ω nAbs correlated with the RLBA index. This cell-based autoantibody assay (CBAA) is easy to perform, suitable for high throughput, while providing high specificity and sensitivity. Copyright © 2014 Elsevier Inc. All rights reserved.

CD4/CD8 Ratio and KT Ratio Predict Yellow Fever Vaccine Immunogenicity in HIV-Infected Patients.

PubMed

Avelino-Silva, Vivian I; Miyaji, Karina T; Hunt, Peter W; Huang, Yong; Simoes, Marisol; Lima, Sheila B; Freire, Marcos S; Caiaffa-Filho, Helio H; Hong, Marisa A; Costa, Dayane Alves; Dias, Juliana Zanatta C; Cerqueira, Natalia B; Nishiya, Anna Shoko; Sabino, Ester Cerdeira; Sartori, Ana M; Kallas, Esper G

2016-12-01

HIV-infected individuals have deficient responses to Yellow Fever vaccine (YFV) and may be at higher risk for adverse events (AE). Chronic immune activation-characterized by low CD4/CD8 ratio or high indoleamine 2,3-dioxygenase-1 (IDO) activity-may influence vaccine response in this population. We prospectively assessed AE, viremia by the YFV virus and YF-specific neutralizing antibodies (NAb) in HIV-infected (CD4>350) and -uninfected adults through 1 year after vaccination. The effect of HIV status on initial antibody response to YFV was measured during the first 3 months following vaccination, while the effect on persistence of antibody response was measured one year following vaccination. We explored CD4/CD8 ratio, IDO activity (plasma kynurenine/tryptophan [KT] ratio) and viremia by Human Pegivirus as potential predictors of NAb response to YFV among HIV-infected participants with linear mixed models. 12 HIV-infected and 45-uninfected participants were included in the final analysis. HIV was not significantly associated with AE, YFV viremia or NAb titers through the first 3 months following vaccination. However, HIV-infected participants had 0.32 times the NAb titers observed for HIV-uninfected participants at 1 year following YFV (95% CI 0.13 to 0.83, p = 0.021), independent of sex, age and prior vaccination. In HIV-infected participants, each 10% increase in CD4/CD8 ratio predicted a mean 21% higher post-baseline YFV Nab titer (p = 0.024). Similarly, each 10% increase in KT ratio predicted a mean 21% lower post-baseline YFV Nab titer (p = 0.009). Viremia by Human Pegivirus was not significantly associated with NAb titers. HIV infection appears to decrease the durability of NAb responses to YFV, an effect that may be predicted by lower CD4/CD8 ratio or higher KT ratio.

CD4/CD8 Ratio and KT Ratio Predict Yellow Fever Vaccine Immunogenicity in HIV-Infected Patients

PubMed Central

Hunt, Peter W.; Huang, Yong; Simoes, Marisol; Lima, Sheila B.; Freire, Marcos S.; Caiaffa-Filho, Helio H.; Hong, Marisa A.; Costa, Dayane Alves; Dias, Juliana Zanatta C.; Cerqueira, Natalia B.; Nishiya, Anna Shoko; Sabino, Ester Cerdeira; Sartori, Ana M.; Kallas, Esper G.

2016-01-01

Background HIV-infected individuals have deficient responses to Yellow Fever vaccine (YFV) and may be at higher risk for adverse events (AE). Chronic immune activation–characterized by low CD4/CD8 ratio or high indoleamine 2,3-dioxygenase-1 (IDO) activity—may influence vaccine response in this population. Methods We prospectively assessed AE, viremia by the YFV virus and YF-specific neutralizing antibodies (NAb) in HIV-infected (CD4>350) and -uninfected adults through 1 year after vaccination. The effect of HIV status on initial antibody response to YFV was measured during the first 3 months following vaccination, while the effect on persistence of antibody response was measured one year following vaccination. We explored CD4/CD8 ratio, IDO activity (plasma kynurenine/tryptophan [KT] ratio) and viremia by Human Pegivirus as potential predictors of NAb response to YFV among HIV-infected participants with linear mixed models. Results 12 HIV-infected and 45-uninfected participants were included in the final analysis. HIV was not significantly associated with AE, YFV viremia or NAb titers through the first 3 months following vaccination. However, HIV–infected participants had 0.32 times the NAb titers observed for HIV-uninfected participants at 1 year following YFV (95% CI 0.13 to 0.83, p = 0.021), independent of sex, age and prior vaccination. In HIV-infected participants, each 10% increase in CD4/CD8 ratio predicted a mean 21% higher post-baseline YFV Nab titer (p = 0.024). Similarly, each 10% increase in KT ratio predicted a mean 21% lower post-baseline YFV Nab titer (p = 0.009). Viremia by Human Pegivirus was not significantly associated with NAb titers. Conclusions HIV infection appears to decrease the durability of NAb responses to YFV, an effect that may be predicted by lower CD4/CD8 ratio or higher KT ratio. PMID:27941965

Design of internal screw thread measuring device based on the Three-Line method principle

NASA Astrophysics Data System (ADS)

Hu, Dachao; Chen, Jianguo

2010-08-01

In accordance with the principle of Three-Line, this paper analyze the correlation of every main parameter of internal screw thread, and then designed a device to measure the main parameters of internal screw thread. Internal thread parameters, such as the pitch diameter, thread angle and screw-pitch of common screw thread, terraced screw thread, zigzag screw thread were obtained through calculation and measurement. The practical applications have proved that this device is convenience to use, and the measurements have a high accuracy. Meanwhile, the application for the patent of invention has been accepted by the Patent Office (Filing number: 200710044081.5).

Are electrostatic potentials between regions of different chemical composition measurable? The Gibbs-Guggenheim Principle reconsidered, extended and its consequences revisited.

PubMed

Pethica, Brian A

2007-12-21

As indicated by Gibbs and made explicit by Guggenheim, the electrical potential difference between two regions of different chemical composition cannot be measured. The Gibbs-Guggenheim Principle restricts the use of classical electrostatics in electrochemical theories as thermodynamically unsound with some few approximate exceptions, notably for dilute electrolyte solutions and concomitant low potentials where the linear limit for the exponential of the relevant Boltzmann distribution applies. The Principle invalidates the widespread use of forms of the Poisson-Boltzmann equation which do not include the non-electrostatic components of the chemical potentials of the ions. From a thermodynamic analysis of the parallel plate electrical condenser, employing only measurable electrical quantities and taking into account the chemical potentials of the components of the dielectric and their adsorption at the surfaces of the condenser plates, an experimental procedure to provide exceptions to the Principle has been proposed. This procedure is now reconsidered and rejected. No other related experimental procedures circumvent the Principle. Widely-used theoretical descriptions of electrolyte solutions, charged surfaces and colloid dispersions which neglect the Principle are briefly discussed. MD methods avoid the limitations of the Poisson-Bolzmann equation. Theoretical models which include the non-electrostatic components of the inter-ion and ion-surface interactions in solutions and colloid systems assume the additivity of dispersion and electrostatic forces. An experimental procedure to test this assumption is identified from the thermodynamics of condensers at microscopic plate separations. The available experimental data from Kelvin probe studies are preliminary, but tend against additivity. A corollary to the Gibbs-Guggenheim Principle is enunciated, and the Principle is restated that for any charged species, neither the difference in electrostatic potential nor the

Extra-epitopic hepatitis C virus polymorphisms confer resistance to broadly neutralizing antibodies by modulating binding to scavenger receptor B1.

PubMed

El-Diwany, Ramy; Cohen, Valerie J; Mankowski, Madeleine C; Wasilewski, Lisa N; Brady, Jillian K; Snider, Anna E; Osburn, William O; Murrell, Ben; Ray, Stuart C; Bailey, Justin R

2017-02-01

Broadly-neutralizing monoclonal antibodies (bNAbs) may guide vaccine development for highly variable viruses including hepatitis C virus (HCV), since they target conserved viral epitopes that could serve as vaccine antigens. However, HCV resistance to bNAbs could reduce the efficacy of a vaccine. HC33.4 and AR4A are two of the most potent anti-HCV human bNAbs characterized to date, binding to highly conserved epitopes near the amino- and carboxy-terminus of HCV envelope (E2) protein, respectively. Given their distinct epitopes, it was surprising that these bNAbs showed similar neutralization profiles across a panel of natural HCV isolates, suggesting that some viral polymorphisms may confer resistance to both bNAbs. To investigate this resistance, we developed a large, diverse panel of natural HCV envelope variants and a novel computational method to identify bNAb resistance polymorphisms in envelope proteins (E1 and E2). By measuring neutralization of a panel of HCV pseudoparticles by 10 μg/mL of each bNAb, we identified E1E2 variants with resistance to one or both bNAbs, despite 100% conservation of the AR4A binding epitope across the panel. We discovered polymorphisms outside of either binding epitope that modulate resistance to both bNAbs by altering E2 binding to the HCV co-receptor, scavenger receptor B1 (SR-B1). This study is focused on a mode of neutralization escape not addressed by conventional analysis of epitope conservation, highlighting the contribution of extra-epitopic polymorphisms to bNAb resistance and presenting a novel mechanism by which HCV might persist even in the face of an antibody response targeting multiple conserved epitopes.

Development and characterization of a pre-treatment procedure to eliminate human monoclonal antibody therapeutic drug and matrix interference in cell-based functional neutralizing antibody assays.

PubMed

Xu, Weifeng; Jiang, Hao; Titsch, Craig; Haulenbeek, Jonathan R; Pillutla, Renuka C; Aubry, Anne-Françoise; DeSilva, Binodh S; Arnold, Mark E; Zeng, Jianing; Dodge, Robert W

2015-01-01

Biological therapeutics can induce an undesirable immune response resulting in the formation of anti-drug antibodies (ADA), including neutralizing antibodies (NAbs). Functional (usually cell-based) NAb assays are preferred to determine NAb presence in patient serum, but are often subject to interferences from numerous serum factors, such as growth factors and disease-related cytokines. Many functional cell-based NAb assays are essentially drug concentration assays that imply the presence of NAbs by the detection of small changes in functional drug concentration. Any drug contained in the test sample will increase the total amount of drug in the assay, thus reducing the sensitivity of NAb detection. Biotin-drug Extraction with Acid Dissociation (BEAD) has been successfully applied to extract ADA, thereby removing drug and other interfering factors from human serum samples. However, to date there has been no report to estimate the residual drug level after BEAD treatment when the drug itself is a human monoclonal antibody; mainly due to the limitation of traditional ligand-binding assays. Here we describe a universal BEAD optimization procedure for human monoclonal antibody (mAb) drugs by using a LC-MS/MS method to simultaneously measure drug (a mutant human IgG4), NAb positive control (a mouse IgG), and endogenous human IgGs as an indicator of nonspecific carry-over in the BEAD eluate. This is the first report demonstrating that residual human mAb drug level in clinical sample can be measured after BEAD pre-treatment, which is critical for further BEAD procedure optimization and downstream immunogenicity testing. Copyright © 2014 Elsevier B.V. All rights reserved.

The balance principle in scientific research.

PubMed

Hu, Liang-ping; Bao, Xiao-lei; Wang, Qi

2012-05-01

The principles of balance, randomization, control and repetition, which are closely related, constitute the four principles of scientific research. The balance principle is the kernel of the four principles which runs through the other three. However, in scientific research, the balance principle is always overlooked. If the balance principle is not well performed, the research conclusion is easy to be denied, which may lead to the failure of the whole research. Therefore, it is essential to have a good command of the balance principle in scientific research. This article stresses the definition and function of the balance principle, the strategies and detailed measures to improve balance in scientific research, and the analysis of the common mistakes involving the use of the balance principle in scientific research.

How quantitative measures unravel design principles in multi-stage phosphorylation cascades.

PubMed

Frey, Simone; Millat, Thomas; Hohmann, Stefan; Wolkenhauer, Olaf

2008-09-07

We investigate design principles of linear multi-stage phosphorylation cascades by using quantitative measures for signaling time, signal duration and signal amplitude. We compare alternative pathway structures by varying the number of phosphorylations and the length of the cascade. We show that a model for a weakly activated pathway does not reflect the biological context well, unless it is restricted to certain parameter combinations. Focusing therefore on a more general model, we compare alternative structures with respect to a multivariate optimization criterion. We test the hypothesis that the structure of a linear multi-stage phosphorylation cascade is the result of an optimization process aiming for a fast response, defined by the minimum of the product of signaling time and signal duration. It is then shown that certain pathway structures minimize this criterion. Several popular models of MAPK cascades form the basis of our study. These models represent different levels of approximation, which we compare and discuss with respect to the quantitative measures.

The Subpolar North Atlantic Spring Bloom - What Did We Learn from the NAB 2008 Autonomous Experiment?

NASA Astrophysics Data System (ADS)

Perry, M. J.

2015-12-01

The subpolar North Atlantic bloom is one of the most remarkable features on the planet, with almost explosive 'greening' of the oceans. Over decades, investigators from countries bordering the North Atlantic have caught snippets of the bloom from research vessels or merchant ships transiting between continents. On 4 April 2008, Eric D'Asaro, Craig Lee, and I began a comprehensive study of the initiation and demise of the spring bloom using 2 types of autonomous platforms - a patch-following Lagrangian mixed-layer float and 4 float-following gliders. The 3 mo autonomous experiment integrated measurements from the float, gliders and ships, observations from satellites, and analyses from models. The diatom-dominated bloom began in mid April when the water column stabilized, not by solar warming, but rather by eddy-driven slumping of horizontal density gradients. The resulting bloom was patchy in both biomass and phytoplankton diversity, despite high, non-limiting concentrations of macronutrients. Magnitudes and relative proportions of net community productivity (NCP; determined from autonomous budgets of O2 and NO3) and net phytoplankton productivity (NPP; computed from ship-based photosynthetic parameters and float-based biomass and light) diverged as the bloom evolved, with higher fractions of particulate organic carbon (POC) consumed within the mixed layer as the bloom aged. Export productivity (EP; derived as the difference between NCP and accumulation rate of POC) was of similar magnitude during the May diatom bloom and the June picophytoplankton bloom. When silicic acid dropped to 1 μM, diatoms aggregated and sank; the deep flux event was dominated by resting spores of Chaetoceros. Although a short-lived event, it was ubiquitously observed by the 4 gliders and ship. An eddy-driven subduction event was likewise observed, indicating transport of otherwise non-sinking POC along isopycnals to depths of > 200 m. These striking export events reinforce the value of a

Development of a micro hole measuring system based on the capacitance principle

NASA Astrophysics Data System (ADS)

Chang, Ting-Yen; Liao, Yunn-Shiuan; Liu, Wei-Cheng

2009-10-01

A new 3D micro hole measuring system has been developed in this paper. The system is mainly composed of a probe, a rotary stage and a program which can convert data points to a 3D profile. The principle of capacitance is adopted and a device to sense the variation of capacitance when the probe touches the workpiece is designed and implemented. With the aid of rotation stage, positions around the contour are measured. The measured coordinates are calculated by an algorithm proposed in this paper. The developed system is capable of measuring the interior profile of a high aspect ratio micro hole and calculating its roundness. A grade A gauge block is used to verify the developed system. It is found that the repeatability error of the system is within ±0.78 µm. The linearity error can approach 1 µm and the maximum measuring depth is 15 mm. Finally, a micro hole of 1.0 mm in diameter and 10 mm in depth is successfully measured and the 3D profile is constructed accordingly. The roundness of each layer spacing 1 mm apart and the inclination of the axis of the micro hole are calculated as well.

Subpixelic measurement of large 1D displacements: principle, processing algorithms, performances and software.

PubMed

Guelpa, Valérian; Laurent, Guillaume J; Sandoz, Patrick; Zea, July Galeano; Clévy, Cédric

2014-03-12

This paper presents a visual measurement method able to sense 1D rigid body displacements with very high resolutions, large ranges and high processing rates. Sub-pixelic resolution is obtained thanks to a structured pattern placed on the target. The pattern is made of twin periodic grids with slightly different periods. The periodic frames are suited for Fourier-like phase calculations-leading to high resolution-while the period difference allows the removal of phase ambiguity and thus a high range-to-resolution ratio. The paper presents the measurement principle as well as the processing algorithms (source files are provided as supplementary materials). The theoretical and experimental performances are also discussed. The processing time is around 3 µs for a line of 780 pixels, which means that the measurement rate is mostly limited by the image acquisition frame rate. A 3-σ repeatability of 5 nm is experimentally demonstrated which has to be compared with the 168 µm measurement range.

Subpixelic Measurement of Large 1D Displacements: Principle, Processing Algorithms, Performances and Software

PubMed Central

Guelpa, Valérian; Laurent, Guillaume J.; Sandoz, Patrick; Zea, July Galeano; Clévy, Cédric

2014-01-01

This paper presents a visual measurement method able to sense 1D rigid body displacements with very high resolutions, large ranges and high processing rates. Sub-pixelic resolution is obtained thanks to a structured pattern placed on the target. The pattern is made of twin periodic grids with slightly different periods. The periodic frames are suited for Fourier-like phase calculations—leading to high resolution—while the period difference allows the removal of phase ambiguity and thus a high range-to-resolution ratio. The paper presents the measurement principle as well as the processing algorithms (source files are provided as supplementary materials). The theoretical and experimental performances are also discussed. The processing time is around 3 μs for a line of 780 pixels, which means that the measurement rate is mostly limited by the image acquisition frame rate. A 3-σ repeatability of 5 nm is experimentally demonstrated which has to be compared with the 168 μm measurement range. PMID:24625736

Uninfected Bystander Cells Impact the Measurement of HIV-Specific Antibody-Dependent Cellular Cytotoxicity Responses.

PubMed

Richard, Jonathan; Prévost, Jérémie; Baxter, Amy E; von Bredow, Benjamin; Ding, Shilei; Medjahed, Halima; Delgado, Gloria G; Brassard, Nathalie; Stürzel, Christina M; Kirchhoff, Frank; Hahn, Beatrice H; Parsons, Matthew S; Kaufmann, Daniel E; Evans, David T; Finzi, Andrés

2018-03-20

The conformation of the HIV-1 envelope glycoprotein (Env) substantially impacts antibody recognition and antibody-dependent cellular cytotoxicity (ADCC) responses. In the absence of the CD4 receptor at the cell surface, primary Envs sample a "closed" conformation that occludes CD4-induced (CD4i) epitopes. The virus controls CD4 expression through the actions of Nef and Vpu accessory proteins, thus protecting infected cells from ADCC responses. However, gp120 shed from infected cells can bind to CD4 present on uninfected bystander cells, sensitizing them to ADCC mediated by CD4i antibodies (Abs). Therefore, we hypothesized that these bystander cells could impact the interpretation of ADCC measurements. To investigate this, we evaluated the ability of antibodies to CD4i epitopes and broadly neutralizing Abs (bNAbs) to mediate ADCC measured by five ADCC assays commonly used in the field. Our results indicate that the uninfected bystander cells coated with gp120 are efficiently recognized by the CD4i ligands but not the bNabs. Consequently, the uninfected bystander cells substantially affect in vitro measurements made with ADCC assays that fail to identify responses against infected versus uninfected cells. Moreover, using an mRNA flow technique that detects productively infected cells, we found that the vast majority of HIV-1-infected cells in in vitro cultures or ex vivo samples from HIV-1-infected individuals are CD4 negative and therefore do not expose significant levels of CD4i epitopes. Altogether, our results indicate that ADCC assays unable to differentiate responses against infected versus uninfected cells overestimate responses mediated by CD4i ligands. IMPORTANCE Emerging evidence supports a role for antibody-dependent cellular cytotoxicity (ADCC) in protection against HIV-1 transmission and disease progression. However, there are conflicting reports regarding the ability of nonneutralizing antibodies targeting CD4-inducible (CD4i) Env epitopes to mediate

Disturbance, the uncertainty principle and quantum optics

NASA Technical Reports Server (NTRS)

Martens, Hans; Demuynck, Willem M.

1993-01-01

It is shown how a disturbance-type uncertainty principle can be derived from an uncertainty principle for joint measurements. To achieve this, we first clarify the meaning of 'inaccuracy' and 'disturbance' in quantum mechanical measurements. The case of photon number and phase is treated as an example, and it is applied to a quantum non-demolition measurement using the optical Kerr effect.

The precautionary principle.

PubMed

Hayes, A Wallace

2005-06-01

The Precautionary Principle in its simplest form states: "When an activity raises threats of harm to human health or the environment, precautionary measures should be taken even if some cause-and-effect relationships are not fully established scientifically". This Principle is the basis for European environmental law, and plays an increasing role in developing environmental health policies as well. It also is used in environmental decision-making in Canada and in several European countries, especially in Denmark, Sweden, and Germany. The Precautionary Principle has been used in the environmental decision-making process and in regulating drugs and other consumer products in the United States. The Precautionary Principle enhances the collection of risk information for, among other items, high production volume chemicals and risk-based analyses in general. It does not eliminate the need for good science or for science-based risk assessments. Public participation is encouraged in both the review process and the decision-making process. The Precautionary Principle encourages, and in some cases may require, transparency of the risk assessment process on health risk of chemicals both for public health and the environment. A debate continues on whether the Principle should embrace the "polluter pays" directive and place the responsibility for providing risk assessment on industry. The best elements of a precautionary approach demand good science and challenge the scientific community to improve methods used for risk assessment.

A technique for fast and accurate measurement of hand volumes using Archimedes' principle.

PubMed

Hughes, S; Lau, J

2008-03-01

A new technique for measuring hand volumes using Archimedes principle is described. The technique involves the immersion of a hand in a water container placed on an electronic balance. The volume is given by the change in weight divided by the density of water. This technique was compared with the more conventional technique of immersing an object in a container with an overflow spout and collecting and weighing the volume of overflow water. The hand volume of two subjects was measured. Hand volumes were 494 +/- 6 ml and 312 +/- 7 ml for the immersion method and 476 +/- 14 ml and 302 +/- 8 ml for the overflow method for the two subjects respectively. Using plastic test objects, the mean difference between the actual and measured volume was -0.3% and 2.0% for the immersion and overflow techniques respectively. This study shows that hand volumes can be obtained more quickly than the overflow method. The technique could find an application in clinics where frequent hand volumes are required.

Age-, sex-, and education-specific norms for an extended CERAD Neuropsychological Assessment Battery-Results from the population-based LIFE-Adult-Study.

PubMed

Luck, Tobias; Pabst, Alexander; Rodriguez, Francisca S; Schroeter, Matthias L; Witte, Veronica; Hinz, Andreas; Mehnert, Anja; Engel, Christoph; Loeffler, Markus; Thiery, Joachim; Villringer, Arno; Riedel-Heller, Steffi G

2018-05-01

To provide new age-, sex-, and education-specific reference values for an extended version of the well-established Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Assessment Battery (CERAD-NAB) that additionally includes the Trail Making Test and the Verbal Fluency Test-S-Words. Norms were calculated based on the cognitive performances of n = 1,888 dementia-free participants (60-79 years) from the population-based German LIFE-Adult-Study. Multiple regressions were used to examine the association of the CERAD-NAB scores with age, sex, and education. In order to calculate the norms, quantile and censored quantile regression analyses were performed estimating marginal means of the test scores at 2.28, 6.68, 10, 15.87, 25, 50, 75, and 90 percentiles for age-, sex-, and education-specific subgroups. Multiple regression analyses revealed that younger age was significantly associated with better cognitive performance in 15 CERAD-NAB measures and higher education with better cognitive performance in all 17 measures. Women performed significantly better than men in 12 measures and men than women in four measures. The determined norms indicate ceiling effects for the cognitive performances in the Boston Naming, Word List Recognition, Constructional Praxis Copying, and Constructional Praxis Recall tests. The new norms for the extended CERAD-NAB will be useful for evaluating dementia-free German-speaking adults in a broad variety of relevant cognitive domains. The extended CERAD-NAB follows more closely the criteria for the new DSM-5 Mild and Major Neurocognitive Disorder. Additionally, it could be further developed to include a test for social cognition. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Anti-Interferon Alpha Antibodies in Patients with High-Risk BCR/ABL-Negative Myeloproliferative Neoplasms Treated with Recombinant Human Interferon-α

PubMed Central

Li, Limei

2018-01-01

Background The objective of this study was to characterize the incidence and impact of immunogenicity to interferon-α (IFN-α-2a, IFN-α-2b, and Peg-IFN-α-2a) over a period of 12 months in patients with BCR/ABL-negative myeloproliferative neoplasms (MPNs). Material/Methods A total of 131 patients from an observational prospective cohort were selected. Antidrug antibodies, in serial serum samples obtained monthly after initiation of therapy, were measured by ELISA and WISH/VSV CPE assays. The association between antidrug antibodies and treatment response and adverse effects was evaluated. Results Among patients who completed 12 months of follow-up, binding antibodies (BAbs) were detected in 53% of those receiving IFN-α (69 of 131) and neutralizing antibodies (NAbs) were detected in 19% (25 of 131). NAbs-positivity was correlated with poorer clinical response, and Bab-positivity was associated with more adverse events. Almost all BAbs and NAbs appeared within 8 months after treatment began (≥95%). Complete remission (CR) rate was 62% for patients who were BAbs-positive and 69% for patients who were BAbs-negative; however, the CR rate of patients with NAbs(+) (24%) was obviously lower than in patients with NAbs(−) (75%). Patients with BAbs(+) had more immune adverse effects (including fever, myalgia, skin reaction, and stomatitis) than BAbs(−) patients, and NAbs to IFN-α had no obvious influence on the adverse effects rate. Conclusions The development of BAbs and NAbs can adversely affect IFN-α treatment in patients with MPN. PMID:29693647

Anti-Interferon Alpha Antibodies in Patients with High-Risk BCR/ABL-Negative Myeloproliferative Neoplasms Treated with Recombinant Human Interferon-α.

PubMed

Aruna; Li, Limei

2018-04-17

BACKGROUND The objective of this study was to characterize the incidence and impact of immunogenicity to interferon-a (IFN-α-2a, IFN-α-2b, and Peg-IFN-α-2a) over a period of 12 months in patients with BCR/ABL-negative myeloproliferative neoplasms (MPNs). MATERIAL AND METHODS A total of 131 patients from an observational prospective cohort were selected. Antidrug antibodies, in serial serum samples obtained monthly after initiation of therapy, were measured by ELISA and WISH/VSV CPE assays. The association between antidrug antibodies and treatment response and adverse effects was evaluated. RESULTS Among patients who completed 12 months of follow-up, binding antibodies (BAbs) were detected in 53% of those receiving IFN-α (69 of 131) and neutralizing antibodies (NAbs) were detected in 19% (25 of 131). NAbs-positivity was correlated with poorer clinical response, and Bab-positivity was associated with more adverse events. Almost all BAbs and NAbs appeared within 8 months after treatment began (≥95%). Complete remission (CR) rate was 62% for patients who were BAbs-positive and 69% for patients who were BAbs-negative; however, the CR rate of patients with NAbs(+) (24%) was obviously lower than in patients with NAbs(-) (75%). Patients with BAbs(+) had more immune adverse effects (including fever, myalgia, skin reaction, and stomatitis) than BAbs(-) patients, and NAbs to IFN-α had no obvious influence on the adverse effects rate. CONCLUSIONS The development of BAbs and NAbs can adversely affect IFN-a treatment in patients with MPN.

Thermographic Phosphors for High Temperature Measurements: Principles, Current State of the Art and Recent Applications

PubMed Central

Khalid, Ashiq Hussain; Kontis, Konstantinos

2008-01-01

This paper reviews the state of phosphor thermometry, focusing on developments in the past 15 years. The fundamental principles and theory are presented, and the various spectral and temporal modes, including the lifetime decay, rise time and intensity ratio, are discussed. The entire phosphor measurement system, including relative advantages to conventional methods, choice of phosphors, bonding techniques, excitation sources and emission detection, is reviewed. Special attention is given to issues that may arise at high temperatures. A number of recent developments and applications are surveyed, with examples including: measurements in engines, hypersonic wind tunnel experiments, pyrolysis studies and droplet/spray/gas temperature determination. They show the technique is flexible and successful in measuring temperatures where conventional methods may prove to be unsuitable. PMID:27873836

Reproducibility of techniques using Archimedes' principle in measuring cancellous bone volume.

PubMed

Zou, L; Bloebaum, R D; Bachus, K N

1997-01-01

Researchers have been interested in developing techniques to accurately and reproducibly measure the volume fraction of cancellous bone. Historically bone researchers have used Archimedes' principle with water to measure the volume fraction of cancellous bone. Preliminary results in our lab suggested that the calibrated water technique did not provide reproducible results. Because of this difficulty, it was decided to compare the conventional water method to a water with surfactant and a helium method using a micropycnometer. The water/surfactant and the helium methods were attempts to improve the fluid penetration into the small voids present in the cancellous bone structure. In order to compare the reproducibility of the new methods with the conventional water method, 16 cancellous bone specimens were obtained from femoral condyles of human and greyhound dog femora. The volume fraction measurements on each specimen were repeated three times with all three techniques. The results showed that the helium displacement method was more than an order of magnitudes more reproducible than the two other water methods (p < 0.05). Statistical analysis also showed that the conventional water method produced the lowest reproducibility (p < 0.05). The data from this study indicate that the helium displacement technique is a very useful, rapid and reproducible tool for quantitatively characterizing anisotropic porous tissue structures such as cancellous bone.

Budding yeast telomerase RNA transcription termination is dictated by the Nrd1/Nab3 non-coding RNA termination pathway

PubMed Central

Noël, Jean-François; Larose, Stéphanie; Abou Elela, Sherif; Wellinger, Raymund J.

2012-01-01

The RNA component of budding yeast telomerase (Tlc1) occurs in two forms, a non-polyadenylated form found in functional telomerase and a rare polyadenylated version with unknown function. Previous work suggested that the functional Tlc1 polyA− RNA is processed from the polyA+ form, but the mechanisms regulating its transcription termination and 3′-end formation remained unclear. Here we examined transcription termination of Tlc1 RNA in the sequences 3′ of the TLC1 gene and relate it to telomere maintenance. Strikingly, disruption of all probable or cryptic polyadenylation signals near the 3′-end blocked the accumulation of the previously reported polyA+ RNA without affecting the level, function or specific 3′ nucleotide of the mature polyA− form. A genetic approach analysing TLC1 3′-end sequences revealed that transcription terminates upstream of the polyadenylation sites. Furthermore, the results also demonstrate that the function of this Tlc1 terminator depends on the Nrd1/Nab3 transcription termination pathway. The data thus show that transcription termination of the budding yeast telomerase RNA occurs as that of snRNAs and Tlc1 functions in telomere maintenance are not strictly dependent on a polyadenylated precursor, even if the polyA+ form can serve as intermediate in a redundant termination/maturation pathway. PMID:22379137

Field testing, comparison, and discussion of five aeolian sand transport measuring devices operating on different measuring principles

NASA Astrophysics Data System (ADS)

Goossens, Dirk; Nolet, Corjan; Etyemezian, Vicken; Duarte-Campos, Leonardo; Bakker, Gerben; Riksen, Michel

2018-06-01

Five types of sediment samplers designed to measure aeolian sand transport were tested during a wind erosion event on the Sand Motor, an area on the west coast of the Netherlands prone to severe wind erosion. Each of the samplers operates on a different principle. The MWAC (Modified Wilson And Cooke) is a passive segmented trap. The modified Leatherman sampler is a passive vertically integrating trap. The Saltiphone is an acoustic sampler that registers grain impacts on a microphone. The Wenglor sampler is an optical sensor that detects particles as they pass through a laser beam. The SANTRI (Standalone AeoliaN Transport Real-time Instrument) detects particles travelling through an infrared beam, but in different channels each associated with a particular grain size spectrum. A procedure is presented to transform the data output, which is different for each sampler, to a common standard so that the samplers can be objectively compared and their relative efficiency calculated. Results show that the efficiency of the samplers is comparable despite the differences in operating principle and the instrumental and environmental uncertainties associated to working with particle samplers in field conditions. The ability of the samplers to register the temporal evolution of a wind erosion event is investigated. The strengths and weaknesses of the samplers are discussed. Some problems inherent to optical sensors are looked at in more detail. Finally, suggestions are made for further improvement of the samplers.

Uninfected Bystander Cells Impact the Measurement of HIV-Specific Antibody-Dependent Cellular Cytotoxicity Responses

PubMed Central

Richard, Jonathan; Prévost, Jérémie; Baxter, Amy E.; Ding, Shilei; Medjahed, Halima; Delgado, Gloria G.; Brassard, Nathalie; Stürzel, Christina M.; Kirchhoff, Frank; Hahn, Beatrice H.; Parsons, Matthew S.; Kaufmann, Daniel E.; Evans, David T.

2018-01-01

ABSTRACT The conformation of the HIV-1 envelope glycoprotein (Env) substantially impacts antibody recognition and antibody-dependent cellular cytotoxicity (ADCC) responses. In the absence of the CD4 receptor at the cell surface, primary Envs sample a “closed” conformation that occludes CD4-induced (CD4i) epitopes. The virus controls CD4 expression through the actions of Nef and Vpu accessory proteins, thus protecting infected cells from ADCC responses. However, gp120 shed from infected cells can bind to CD4 present on uninfected bystander cells, sensitizing them to ADCC mediated by CD4i antibodies (Abs). Therefore, we hypothesized that these bystander cells could impact the interpretation of ADCC measurements. To investigate this, we evaluated the ability of antibodies to CD4i epitopes and broadly neutralizing Abs (bNAbs) to mediate ADCC measured by five ADCC assays commonly used in the field. Our results indicate that the uninfected bystander cells coated with gp120 are efficiently recognized by the CD4i ligands but not the bNabs. Consequently, the uninfected bystander cells substantially affect in vitro measurements made with ADCC assays that fail to identify responses against infected versus uninfected cells. Moreover, using an mRNA flow technique that detects productively infected cells, we found that the vast majority of HIV-1-infected cells in in vitro cultures or ex vivo samples from HIV-1-infected individuals are CD4 negative and therefore do not expose significant levels of CD4i epitopes. Altogether, our results indicate that ADCC assays unable to differentiate responses against infected versus uninfected cells overestimate responses mediated by CD4i ligands. PMID:29559570

Structure design and characteristic analysis of micro-nano probe based on six dimensional micro-force measuring principle

NASA Astrophysics Data System (ADS)

Yang, Hong-tao; Cai, Chun-mei; Fang, Chuan-zhi; Wu, Tian-feng

2013-10-01

In order to develop micro-nano probe having error self-correcting function and good rigidity structure, a new micro-nano probe system was developed based on six-dimensional micro-force measuring principle. The structure and working principle of the probe was introduced in detail. The static nonlinear decoupling method was established with BP neural network to do the static decoupling for the dimension coupling existing in each direction force measurements. The optimal parameters of BP neural network were selected and the decoupling simulation experiments were done. The maximum probe coupling rate after decoupling is 0.039% in X direction, 0.025% in Y direction and 0.027% in Z direction. The static measurement sensitivity of the probe can reach 10.76μɛ / mN in Z direction and 14.55μɛ / mN in X and Y direction. The modal analysis and harmonic response analysis under three dimensional harmonic load of the probe were done by using finite element method. The natural frequencies under different vibration modes were obtained and the working frequency of the probe was determined, which is higher than 10000 Hz . The transient response analysis of the probe was done, which indicates that the response time of the probe can reach 0.4 ms. From the above results, it is shown that the developed micro-nano probe meets triggering requirements of micro-nano probe. Three dimension measuring force can be measured precisely by the developed probe, which can be used to predict and correct the force deformation error and the touch error of the measuring ball and the measuring rod.

Novel view on the mechanism of water-assisted proton transfer in the DNA bases: bulk water hydration.

PubMed

Furmanchuk, Al'ona; Isayev, Olexandr; Gorb, Leonid; Shishkin, Oleg V; Hovorun, Dmytro M; Leszczynski, Jerzy

2011-03-14

In the present work, the conventional static ab initio picture of a water-assisted mechanism of the tautomerization of Nucleic Acid Bases (NABs) in an aqueous environment is enhanced by the classical and Car-Parrinello molecular dynamics simulations. The inclusion of the dynamical contribution is vital because the formation and longevity of the NAB-water bridge complexes represent decisive factors for further tautomerization. The results of both molecular dynamic techniques indicate that the longest time when such complexes exist is significantly shorter than the time required for proton transfer suggested by the static ab initio level of theory. New rate constants of tautomerization corrected for the dynamic effect of environment are proposed based on the first principles molecular dynamics data. Those values are used for the evaluation of a water-assisted mechanism that is feasible in such biological systems as E. coli cell.

The base rate principle and the fairness principle in social judgment

PubMed Central

Cao, Jack; Banaji, Mahzarin R.

2016-01-01

Meet Jonathan and Elizabeth. One person is a doctor and the other is a nurse. Who is the doctor? When nothing else is known, the base rate principle favors Jonathan to be the doctor and the fairness principle favors both individuals equally. However, when individuating facts reveal who is actually the doctor, base rates and fairness become irrelevant, as the facts make the correct answer clear. In three experiments, explicit and implicit beliefs were measured before and after individuating facts were learned. These facts were either stereotypic (e.g., Jonathan is the doctor, Elizabeth is the nurse) or counterstereotypic (e.g., Elizabeth is the doctor, Jonathan is the nurse). Results showed that before individuating facts were learned, explicit beliefs followed the fairness principle, whereas implicit beliefs followed the base rate principle. After individuating facts were learned, explicit beliefs correctly aligned with stereotypic and counterstereotypic facts. Implicit beliefs, however, were immune to counterstereotypic facts and continued to follow the base rate principle. Having established the robustness and generality of these results, a fourth experiment verified that gender stereotypes played a causal role: when both individuals were male, explicit and implicit beliefs alike correctly converged with individuating facts. Taken together, these experiments demonstrate that explicit beliefs uphold fairness and incorporate obvious and relevant facts, but implicit beliefs uphold base rates and appear relatively impervious to counterstereotypic facts. PMID:27325760

The base rate principle and the fairness principle in social judgment.

PubMed

Cao, Jack; Banaji, Mahzarin R

2016-07-05

Meet Jonathan and Elizabeth. One person is a doctor and the other is a nurse. Who is the doctor? When nothing else is known, the base rate principle favors Jonathan to be the doctor and the fairness principle favors both individuals equally. However, when individuating facts reveal who is actually the doctor, base rates and fairness become irrelevant, as the facts make the correct answer clear. In three experiments, explicit and implicit beliefs were measured before and after individuating facts were learned. These facts were either stereotypic (e.g., Jonathan is the doctor, Elizabeth is the nurse) or counterstereotypic (e.g., Elizabeth is the doctor, Jonathan is the nurse). Results showed that before individuating facts were learned, explicit beliefs followed the fairness principle, whereas implicit beliefs followed the base rate principle. After individuating facts were learned, explicit beliefs correctly aligned with stereotypic and counterstereotypic facts. Implicit beliefs, however, were immune to counterstereotypic facts and continued to follow the base rate principle. Having established the robustness and generality of these results, a fourth experiment verified that gender stereotypes played a causal role: when both individuals were male, explicit and implicit beliefs alike correctly converged with individuating facts. Taken together, these experiments demonstrate that explicit beliefs uphold fairness and incorporate obvious and relevant facts, but implicit beliefs uphold base rates and appear relatively impervious to counterstereotypic facts.

Is the Precautionary Principle Really Incoherent?

PubMed

Boyer-Kassem, Thomas

2017-11-01

The Precautionary Principle has been an increasingly important principle in international treaties since the 1980s. Through varying formulations, it states that when an activity can lead to a catastrophe for human health or the environment, measures should be taken to prevent it even if the cause-and-effect relationship is not fully established scientifically. The Precautionary Principle has been critically discussed from many sides. This article concentrates on a theoretical argument by Peterson (2006) according to which the Precautionary Principle is incoherent with other desiderata of rational decision making, and thus cannot be used as a decision rule that selects an action among several ones. I claim here that Peterson's argument fails to establish the incoherence of the Precautionary Principle, by attacking three of its premises. I argue (i) that Peterson's treatment of uncertainties lacks generality, (ii) that his Archimedian condition is problematic for incommensurability reasons, and (iii) that his explication of the Precautionary Principle is not adequate. This leads me to conjecture that the Precautionary Principle can be envisaged as a coherent decision rule, again. © 2017 Society for Risk Analysis.

Eligibility of Metastatic Pancreatic Cancer Patients for First-Line Palliative Intent nab-Paclitaxel Plus Gemcitabine Versus FOLFIRINOX.

PubMed

Peixoto, Renata D; Ho, Maria; Renouf, Daniel J; Lim, Howard J; Gill, Sharlene; Ruan, Jenny Y; Cheung, Winson Y

2017-10-01

The PRODIGE and MPACT trials showed superiority of FOLFIRINOX and nab-paclitaxel plus gemcitabine (NG) over gemcitabine alone, respectively. However, both had strict inclusion criteria. We sought to determine the characteristics of patients with metastatic pancreatic cancer (MPC) which inform the appropriateness of first-line chemotherapy FOLFIRINOX and NG in routine practice. Patients with MPC who initiated palliative chemotherapy with gemcitabine from 2000 to 2011 at the British Columbia Cancer Agency were identified. Clinicopathologic variables and outcomes were retrospectively collected and compared among groups. Eligibility criteria for each regimen were in accordance with the respective pivotal phase III trials. A total of 473 patients were included: 25% of the patients were eligible for FOLFIRINOX versus 45% for NG. Main reasons for FOLFIRINOX ineligibility were Eastern Cooperative Oncology Group (ECOG) performance status (PS)≥2 (56.5%), age older than 75 years (19.0%), and bilirubin>1.5× upper limit of normal (18.6%), whereas those for NG ineligibility were bilirubin > upper limit of normal (24.5%), ECOG PS≥3 (14.6%), and cardiac dysfunction (13.8%). Univariate analyses revealed that FOLFIRINOX and NG-eligible patients had longer median overall survival than their respective ineligible group (8.6 vs. 4.7 mo, P<0.001; 6.7 vs. 4.9 mo, P=0.008, respectively). After accounting for ECOG PS in the multivariate model, however, eligibility for either FOLFIRINOX or NG no longer predicted for better overall survival. The majority of patients with MPC are not candidates to either NG or FOLFIRINOX due to restrictive eligibility requirements. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

Cooperation between Strain-Specific and Broadly Neutralizing Responses Limited Viral Escape and Prolonged the Exposure of the Broadly Neutralizing Epitope

PubMed Central

Anthony, Colin; York, Talita; Bekker, Valerie; Matten, David; Selhorst, Philippe; Ferreria, Roux-Cil; Garrett, Nigel J.; Karim, Salim S. Abdool; Morris, Lynn; Wood, Natasha T.; Moore, Penny L.

2017-01-01

ABSTRACT V3-glycan-targeting broadly neutralizing antibodies (bNAbs) are a focus of HIV-1 vaccine development. Understanding the viral dynamics that stimulate the development of these antibodies can provide insights for immunogen design. We used a deep-sequencing approach, together with neutralization phenotyping, to investigate the rate and complexity of escape from V3-glycan-directed bNAbs compared to overlapping early strain-specific neutralizing antibody (ssNAb) responses to the V3/C3 region in donor CAP177. Escape from the ssNAb response occurred rapidly via an N334-to-N332 glycan switch, which took just 7.5 weeks to reach >50% frequency. In contrast, escape from the bNAbs was mediated via multiple pathways and took longer, with escape first occurring through an increase in V1 loop length, which took 46 weeks to reach 50% frequency, followed by an N332-to-N334 reversion, which took 66 weeks. Importantly, bNAb escape was incomplete, with contemporaneous neutralization observed up to 3 years postinfection. Both the ssNAb response and the bNAb response were modulated by the presence/absence of the N332 glycan, indicating an overlap between the two epitopes. Thus, selective pressure by ssNAbs to maintain the N332 glycan may have constrained the bNAb escape pathway. This slower and incomplete viral escape resulted in prolonged exposure of the bNAb epitope, which may in turn have aided the maturation of the bNAb lineage. IMPORTANCE The development of an HIV-1 vaccine is of paramount importance, and broadly neutralizing antibodies are likely to be a key component of a protective vaccine. The V3-glycan-targeting bNAb responses are among the most promising vaccine targets, as they are commonly elicited during infection. Understanding the interplay between viral evolution and the development of these antibodies provides insights that may guide immunogen design. Our work contrasted the dynamics of the early strain-specific antibodies and the later broadly neutralizing

Neutralization of Virus Infectivity by Antibodies: Old Problems in New Perspectives

PubMed Central

Klasse, P. J.

2016-01-01

Neutralizing antibodies (NAbs) can be both sufficient and necessary for protection against viral infections, although they sometimes act in concert with cellular immunity. Successful vaccines against viruses induce NAbs but vaccine candidates against some major viral pathogens, including HIV-1, have failed to induce potent and effective such responses. Theories of how antibodies neutralize virus infectivity have been formulated and experimentally tested since the 1930s; and controversies about the mechanistic and quantitative bases for neutralization have continually arisen. Soluble versions of native oligomeric viral proteins that mimic the functional targets of neutralizing antibodies now allow the measurement of the relevant affinities of NAbs. Thereby the neutralizing occupancies on virions can be estimated and related to the potency of the NAbs. Furthermore, the kinetics and stoichiometry of NAb binding can be compared with neutralizing efficacy. Recently, the fundamental discovery that the intracellular factor TRIM21 determines the degree of neutralization of adenovirus has provided new mechanistic and quantitative insights. Since TRIM21 resides in the cytoplasm, it would not affect the neutralization of enveloped viruses, but its range of activity against naked viruses will be important to uncover. These developments bring together the old problems of virus neutralization—mechanism, stoichiometry, kinetics, and efficacy—from surprising new angles. PMID:27099867

Analysis of neutralizing antibodies to therapeutic interferon-beta in multiple sclerosis patients: a comparison of three methods in a large Australasian cohort.

PubMed

McKay, Fiona; Schibeci, Stephen; Heard, Robert; Stewart, Graeme; Booth, David

2006-03-20

Persistent high-titre neutralizing antibodies (NAB) to therapeutic interferon-beta(IFNbeta)in multiple sclerosis patients reduce therapeutic efficacy. Difficulties in standardization of cell-based bioactivity assays have hindered interlaboratory comparison of NAB titres and the determination of a clinically relevant definition of seropositivity. We determined NAB status in Australasian multiple sclerosis patients receiving IFNbetausing both the antiviral cytopathic effect (CPE) assay (n = 227) and the more specific ELISA for the type I interferon-inducible MxA protein (n = 350). While the log(10) titres determined in the two assays were highly correlated (p < 0.0001; r = 0.967) with similar distributions, the MxA assay was more sensitive, detecting lower concentrations of NAB than the CPE assay. The range of titres determined in the CPE assay was 10 to >7290; and 9 to 53,700 in the MxA assay, with ranked titre distribution highlighting the arbitrary nature of currently accepted definitions of NAB seropositivity. Bioactivity of injected IFNbetawas significantly reduced in NAB-positive patients (p = 0.006; NAB MxA titres = 184 to 5340) compared to NAB-negative patients as assessed ex vivo using real-time RT-PCR analysis of MxA gene induction. The range of MxA mRNA levels in healthy controls was remarkably consistent with previously published results, regardless of the assay standardization method [Gilli, F., Sala, A., Marnetto, F., Lindberg, R.L., Leppert, D. and Bertolotto, A. (2003) Comparison of IFNbeta bioavailability evaluations by MxA mRNA using two independent quantification methods. Abstract, ECTRIMS Meeting, Milan, Italy; Pachner, A., Narayan, K., Price, N., Hurd, M. and Dail, D. (2003a) MxA Gene Expression Analysis as an Interferon-beta Bioactivity Measurement in Patients with Multiple Sclerosis and the Identification of Antibody-Mediated Decreased Bioactivity. Mol. Diagn. 7, 17-25]. Assessment of IFNbetaresponse ex vivo accounts for both circulating

The precautionary principle within European Union public health policy. The implementation of the principle under conditions of supranationality and citizenship.

PubMed

Antonopoulou, Lila; van Meurs, Philip

2003-11-01

The present study examines the precautionary principle within the parameters of public health policy in the European Union, regarding both its meaning, as it has been shaped by relevant EU institutions and their counterparts within the Member States, and its implementation in practice. In the initial section I concentrate on the methodological question of "scientific uncertainty" concerning the calculation of risk and possible damage. Calculation of risk in many cases justifies the adopting of preventive measures, but, as it is argued, the principle of precaution and its implementation cannot be wholly captured by a logic of calculation; such a principle does not only contain scientific uncertainty-as the preventive principle does-but it itself is generated as a principle by this scientific uncertainty, recognising the need for a society to act. Thus, the implementation of the precautionary principle is also a simultaneous search for justification of its status as a principle. This justification would result in the adoption of precautionary measures against risk although no proof of this principle has been produced based on the "cause-effect" model. The main part of the study is occupied with an examination of three cases from which the stance of the official bodies of the European Union towards the precautionary principle and its implementation emerges: the case of the "mad cows" disease, the case of production and commercialization of genetically modified foodstuffs. The study concludes with the assessment that the effective implementation of the precautionary principle on a European level depends on the emergence of a concerned Europe-wide citizenship and its acting as a mechanism to counteract the material and social conditions that pose risks for human health.

Inhalers and nebulizers: basic principles and preliminary measurements

NASA Astrophysics Data System (ADS)

Misik, Ondrej; Lizal, Frantisek; Asl, Vahid Farhikhteh; Belka, Miloslav; Jedelsky, Jan; Elcner, Jakub; Jicha, Miroslav

2018-06-01

Inhalers are hand-held devices which are used for administration of therapeutic aerosols via inhalation. Nebulizers are larger devices serving for home and hospital care using inhaled medication. This contribution describes the basic principles of dispersion of aerosol particles used in various types of inhalers and nebulizers, and lists the basic physical mechanisms contributing to the deposition of inhaled particles in the human airways. The second part of this article presents experimental setup, methodology and preliminary results of particle size distributions produced by several selected inhalers and nebulizers.

Precision measurement and modeling of superconducting magnetic bearings for the satellite test of the equivalence principle

NASA Astrophysics Data System (ADS)

Sapilewski, Glen Alan

The Satellite Test of the Equivalence Principle (STEP) is a modern version of Galileo's experiment of dropping two objects from the leaning tower of Pisa. The Equivalence Principle states that all objects fall with the same acceleration, independent of their composition. The primary scientific objective of STEP is to measure a possible violation of the Equivalence Principle one million times better than the best ground based tests. This extraordinary sensitivity is made possible by using cryogenic differential accelerometers in the space environment. Critical to the STEP experiment is a sound fundamental understanding of the behavior of the superconducting magnetic linear bearings used in the accelerometers. We have developed a theoretical bearing model and a precision measuring system with which to validate the model. The accelerometers contain two concentric hollow cylindrical test masses, of different materials, each levitated and constrained to axial motion by a superconducting magnetic bearing. Ensuring that the bearings satisfy the stringent mission specifications requires developing new testing apparatus and methods. The bearing is tested using an actively-controlled table which tips it relative to gravity. This balances the magnetic forces from the bearing against a component of gravity. The magnetic force profile of the bearing can be mapped by measuring the tilt necessary to position the test mass at various locations. An operational bearing has been built and is being used to verify the theoretical levitation models. The experimental results obtained from the bearing test apparatus were inconsistent with the previous models used for STEP bearings. This led to the development of a new bearing model that includes the influence of surface current variations in the bearing wires and the effect of the superconducting transformer. The new model, which has been experimentally verified, significantly improves the prediction of levitation current, accurately

The action uncertainty principle and quantum gravity

NASA Astrophysics Data System (ADS)

Mensky, Michael B.

1992-02-01

Results of the path-integral approach to the quantum theory of continuous measurements have been formulated in a preceding paper in the form of an inequality of the type of the uncertainty principle. The new inequality was called the action uncertainty principle, AUP. It was shown that the AUP allows one to find in a simple what outputs of the continuous measurements will occur with high probability. Here a more simple form of the AUP will be formulated, δ S≳ħ. When applied to quantum gravity, it leads in a very simple way to the Rosenfeld inequality for measurability of the average curvature.

BRIDGES: Evolution of basic and applied linkages in benthic science

USGS Publications Warehouse

Aumen, Nicholas G.; Gurtz, Martin E.; Barbour, Michael T.; Moerke, Ashley

2010-01-01

Growing awareness of environmental degradation resulted in stricter environmental regulations and laws for aquatic ecosystems. These regulations were followed by an increase in applied research and monitoring beginning in the early 1970s. The number of applied scientists who were members of the North American Benthological Society grew at a commensurate rate. The editors of J-NABS recognized that, despite these increases, submitted manuscripts mostly addressed basic science. In response, the BRIDGES section of J-NABS was created in 1994 to provide a forum for linking basic ecological principles to applied science problems and issues. We examined the emergence of applied science topics in J-NABS and its predecessor, Freshwater Invertebrate Biology, from their beginning in 1982 to 2009. We classified papers among 11 categories that included a basic/applied science linkage. In the 1980s, applied papers were predominantly on effects of eutrophication/pollution and landuse changes. When BRIDGES was established in 1994, papers were solicited by editors and BRIDGES sections usually included >1 paper on a common theme to express complementary or alternate viewpoints. Forty-two papers appeared in BRIDGES between 1994 and 2009, but the number per issue declined after 2001. The total number of applied science papers in J-NABS has increased since ∼1994. Citation analysis of BRIDGES papers illustrates how information is being cited, but applied papers often are used in ways that might not lead to citations. BRIDGES transitioned to a new format in September 2009 to address new types of complex, multifaceted linkages. All new BRIDGES articles will be open access, and authors will be encouraged to produce lay-language fact sheets and to post them on the web.

In vitro fruiting of Armillaria species.

Treesearch

Jimmy L. Reaves; Michael. McWilliams

1991-01-01

Thirty-three different isolates of various Armillaria species were grown on sterilized orange slices under a controlled temperature and light regime. Nine isolates of A. ostoyae (North American Biological Species I, NABS I), three of NABS VII, one of NABS IX, one of NABS X, and two unidentified isolates formed basidiomes. Most...

Novel principle of contactless gauge block calibration.

PubMed

Buchta, Zdeněk; Reřucha, Simon; Mikel, Břetislav; Cížek, Martin; Lazar, Josef; Cíp, Ondřej

2012-01-01

In this paper, a novel principle of contactless gauge block calibration is presented. The principle of contactless gauge block calibration combines low-coherence interferometry and laser interferometry. An experimental setup combines Dowell interferometer and Michelson interferometer to ensure a gauge block length determination with direct traceability to the primary length standard. By monitoring both gauge block sides with a digital camera gauge block 3D surface measurements are possible too. The principle presented is protected by the Czech national patent No. 302948.

The 4th Thermodynamic Principle?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Montero Garcia, Jose de la Luz; Novoa Blanco, Jesus Francisco

2007-04-28

It should be emphasized that the 4th Principle above formulated is a thermodynamic principle and, at the same time, is mechanical-quantum and relativist, as it should inevitably be and its absence has been one of main the theoretical limitations of the physical theory until today.We show that the theoretical discovery of Dimensional Primitive Octet of Matter, the 4th Thermodynamic Principle, the Quantum Hexet of Matter, the Global Hexagonal Subsystem of Fundamental Constants of Energy and the Measurement or Connected Global Scale or Universal Existential Interval of the Matter is that it is possible to be arrived at a global formulationmore » of the four 'forces' or fundamental interactions of nature. The Einstein's golden dream is possible.« less

Low-affinity FcγR interactions can decide the fate of novel human IgG-sensitised red blood cells and platelets

PubMed Central

Armour, Kathryn L; Smith, Cheryl S; Turner, Craig P; Kirton, Christopher M; Wilkes, Anthony M; Hadley, Andrew G; Ghevaert, Cedric; Williamson, Lorna M; Clark, Michael R

2014-01-01

G1Δnab is a mutant human IgG1 constant region with a lower ability to interact with FcγR than the natural IgG constant regions. Radiolabelled RBCs and platelets sensitised with specific G1Δnab Abs were cleared more slowly from human circulation than IgG1-sensitised counterparts. However, non-destructive splenic retention of G1Δnab-coated RBCs required investigation and plasma radioactivities now suggest this also occurred for platelets sensitised with an IgG1/G1Δnab mixture. In vitro assays with human cells showed that G1Δnab-sensitised RBCs did not cause FcγRI-mediated monocyte activation, FcγRIIIa-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) or macrophage phagocytosis although they did adhere to macrophages. Thus, FcγRII was implicated in the adhesion despite the Δnab mutation reducing the already low-affinity binding to this receptor class. Additional contacts via P-selectin enhance the interaction of sensitised platelets with monocytes and this system provided evidence of FcγRII-dependent activation by G1Δnab. These results emphasise the physiological relevance of low-affinity interactions: It appears that FcγRII interactions of G1Δnab allowed splenic retention of G1Δnab-coated RBCs with inhibitory FcγRIIb binding preventing RBC destruction and that FcγRIIb engagement by G1Δnab on IgG1/G1Δnab-sensitised platelets overcame activation by IgG1. Considering therapeutic blocking Abs, G1Δnab offers lower FcγR binding and a greater bias towards inhibition than IgG2 and IgG4 constant regions. PMID:24285214

Low-affinity FcγR interactions can decide the fate of novel human IgG-sensitised red blood cells and platelets.

PubMed

Armour, Kathryn L; Smith, Cheryl S; Turner, Craig P; Kirton, Christopher M; Wilkes, Anthony M; Hadley, Andrew G; Ghevaert, Cedric; Williamson, Lorna M; Clark, Michael R

2014-03-01

G1Δnab is a mutant human IgG1 constant region with a lower ability to interact with FcγR than the natural IgG constant regions. Radiolabelled RBCs and platelets sensitised with specific G1Δnab Abs were cleared more slowly from human circulation than IgG1-sensitised counterparts. However, non-destructive splenic retention of G1Δnab-coated RBCs required investigation and plasma radioactivities now suggest this also occurred for platelets sensitised with an IgG1/G1Δnab mixture. In vitro assays with human cells showed that G1Δnab-sensitised RBCs did not cause FcγRI-mediated monocyte activation, FcγRIIIa-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) or macrophage phagocytosis although they did adhere to macrophages. Thus, FcγRII was implicated in the adhesion despite the Δnab mutation reducing the already low-affinity binding to this receptor class. Additional contacts via P-selectin enhance the interaction of sensitised platelets with monocytes and this system provided evidence of FcγRII-dependent activation by G1Δnab. These results emphasise the physiological relevance of low-affinity interactions: It appears that FcγRII interactions of G1Δnab allowed splenic retention of G1Δnab-coated RBCs with inhibitory FcγRIIb binding preventing RBC destruction and that FcγRIIb engagement by G1Δnab on IgG1/G1Δnab-sensitised platelets overcame activation by IgG1. Considering therapeutic blocking Abs, G1Δnab offers lower FcγR binding and a greater bias towards inhibition than IgG2 and IgG4 constant regions. © 2013 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Fabricating Superior NiAl Bronze Components through Wire Arc Additive Manufacturing.

PubMed

Ding, Donghong; Pan, Zengxi; van Duin, Stephen; Li, Huijun; Shen, Chen

2016-08-03

Cast nickel aluminum bronze (NAB) alloy is widely used for large engineering components in marine applications due to its excellent mechanical properties and corrosion resistance. Casting porosity, as well as coarse microstructure, however, are accompanied by a decrease in mechanical properties of cast NAB components. Although heat treatment, friction stir processing, and fusion welding were implemented to eliminate porosity, improve mechanical properties, and refine the microstructure of as-cast metal, their applications are limited to either surface modification or component repair. Instead of traditional casting techniques, this study focuses on developing NAB components using recently expanded wire arc additive manufacturing (WAAM). Consumable welding wire is melted and deposited layer-by-layer on substrates producing near-net shaped NAB components. Additively-manufactured NAB components without post-processing are fully dense, and exhibit fine microstructure, as well as comparable mechanical properties, to as-cast NAB alloy. The effects of heat input from the welding process and post-weld-heat-treatment (PWHT) are shown to give uniform NAB alloys with superior mechanical properties revealing potential marine applications of the WAAM technique in NAB production.

Fabricating Superior NiAl Bronze Components through Wire Arc Additive Manufacturing

PubMed Central

Ding, Donghong; Pan, Zengxi; van Duin, Stephen; Li, Huijun; Shen, Chen

2016-01-01

Cast nickel aluminum bronze (NAB) alloy is widely used for large engineering components in marine applications due to its excellent mechanical properties and corrosion resistance. Casting porosity, as well as coarse microstructure, however, are accompanied by a decrease in mechanical properties of cast NAB components. Although heat treatment, friction stir processing, and fusion welding were implemented to eliminate porosity, improve mechanical properties, and refine the microstructure of as-cast metal, their applications are limited to either surface modification or component repair. Instead of traditional casting techniques, this study focuses on developing NAB components using recently expanded wire arc additive manufacturing (WAAM). Consumable welding wire is melted and deposited layer-by-layer on substrates producing near-net shaped NAB components. Additively-manufactured NAB components without post-processing are fully dense, and exhibit fine microstructure, as well as comparable mechanical properties, to as-cast NAB alloy. The effects of heat input from the welding process and post-weld-heat-treatment (PWHT) are shown to give uniform NAB alloys with superior mechanical properties revealing potential marine applications of the WAAM technique in NAB production. PMID:28773774

Novel Principle of Contactless Gauge Block Calibration

PubMed Central

Buchta, Zdeněk; Řeřucha, Šimon; Mikel, Břetislav; Čížek, Martin; Lazar, Josef; Číp, Ondřej

2012-01-01

In this paper, a novel principle of contactless gauge block calibration is presented. The principle of contactless gauge block calibration combines low-coherence interferometry and laser interferometry. An experimental setup combines Dowell interferometer and Michelson interferometer to ensure a gauge block length determination with direct traceability to the primary length standard. By monitoring both gauge block sides with a digital camera gauge block 3D surface measurements are possible too. The principle presented is protected by the Czech national patent No. 302948. PMID:22737012

p21ras independent down-regulation of ras-induced increases in natural antibody binding during tumor progression.

PubMed

Tough, D F; Feng, X; Chow, D A

1995-01-01

Selective outgrowth of v-H-ras-infected 10T1/2 cells based on the cointroduction of a gene for resistance to geneticin (G418), yielded cells which exhibited an increased capacity to bind polyclonal serum natural antibody (NAb). This demonstrated an NAb-susceptible phase of tumor development which would be a basic requirement for NAb-mediated surveillance of tumors. The ras-oncogene dependence of the high-NAb-binding phenotype provided a model for assessing NAb resistance against ras transformants in vivo and for a comparative analysis of phenotypic and genetic alterations contributing to the progression of ras transformants. Variants were developed through in vitro and in vivo models of tumor progression. T24-H-ras and v-H-ras transformants were isolated in vitro through more rigorous growth conditions, focus formation in the presence of untransformed cells with no selecting drug. These clones expressed p21ras but exhibited little or no increase in NAb binding. Variants recovered following growth from intravenous or threshold subcutaneous (s.c.) inocula of high-NAb-binding ras transformants in syngeneic C3H/HeN mice exhibited decreases in NAb binding but no uniform change in p21ras. Concurring inverse correlations between NAb binding and s.c. tumorigenicity were exhibited by the T24-H-ras transformant clones, the ras transformants grown in vivo, and the v-H-ras-transformed clones isolated in the presence versus the absence of untransformed cells. This consistent inverse correlation, together with the reduced NAb binding of the ras transformants grown in vivo, provides strong evidence that NAb participates in the defense against ras-transformed cells in vivo. The lack of any direct correlation between p21ras expression and the reduction in NAb binding or the increase in tumorigenicity of cells generated through progression in vivo suggested the regulatory action of additional genes. Hybridization studies between high- and low-NAb-binding clones implicated the

HIV Neutralizing Antibodies Induced by Native-like Envelope Trimers

PubMed Central

Sanders, Rogier W.; van Gils, Marit J.; Derking, Ronald; Sok, Devin; Ketas, Thomas J.; Burger, Judith A.; Ozorowski, Gabriel; Cupo, Albert; Simonich, Cassandra; Goo, Leslie; Arendt, Heather; Kim, Helen J.; Lee, Jeong Hyun; Pugach, Pavel; Williams, Melissa; Debnath, Gargi; Moldt, Brian; van Breemen, Mariëlle J.; Isik, Gözde; Medina-Ramírez, Max; Back, Jaap Willem; Koff, Wayne; Julien, Jean-Philippe; Rakasz, Eva G.; Seaman, Michael S.; Guttman, Miklos; Lee, Kelly K.; Klasse, Per Johan; LaBranche, Celia; Schief, William R.; Wilson, Ian A.; Overbaugh, Julie; Burton, Dennis R.; Ward, Andrew B.; Montefiori, David C.; Dean, Hansi; Moore, John P.

2015-01-01

A challenge for HIV-1 immunogen design is inducing neutralizing antibodies (NAbs) against neutralization-resistant (Tier-2) viruses that dominate human transmissions. We show that a soluble recombinant HIV-1 envelope glycoprotein trimer that adopts a native conformation (BG505 SOSIP.664) induced NAbs potently against the sequence-matched Tier-2 virus in rabbits and similar but weaker responses in macaques. The trimer also consistently induced cross-reactive NAbs against more sensitive (Tier-1) viruses. Tier-2 NAbs recognized conformational epitopes that differed between animals and in some cases overlapped with those recognized by broadly neutralizing antibodies (bNAbs), whereas Tier-1 responses targeted linear V3 epitopes. A second trimer, B41 SOSIP.664, also induced a strong autologous Tier-2 NAb response in rabbits. Thus, native-like trimers represent a promising starting point for developing HIV-1 vaccines aimed at inducing bNAbs. PMID:26089353

Who has to pay for measures in the field of water management? A proposal for applying the polluter pays principle.

PubMed

Grünebaum, Thomas; Schweder, Heinrich; Weyand, Michael

2009-01-01

There is no doubt about the fact that the implementation of the European Water Framework Directive (WFD) and the pursuit of its goal of good ecological status will give rise to measures in different fields of water management. However, a conclusive and transparent method of financing these measures is still missing up to now. Measures in the water management sector are no mere end in themselves; instead, they serve specific ends directed at human activities or they serve general environment objectives. Following the integrative approach of the WFD on looking upon river basins as a whole and its requirement to observe the polluter pays principle, all different groups within a river basin should contribute to the costs according to their cost-bearer roles as polluters, stakeholders with vested interests or beneficiaries via relevant yardsticks. In order to quantify the financial expenditure of each cost bearer, a special algorithm was developed and tested in the river basin of a small tributary of the Ruhr River. It was proved to be generally practicable with regard to its handling and the comprehension of the results. Therefore, the application of a cost bearer system based on the polluter-pays principle and thus in correspondence with the WFD's requirements should appear possible in order to finance future measures.

Effects of Sodium Benzoate Treatment in Combination with An Extinction Training on the Maintenance of Cocaine-Supported Memory.

PubMed

Tsai, Yi-Ni; Tzeng, Wen-Yu; Cherng, Chianfang G; Liao, Tien You; Wu, Hsin-Hua; Lin, Jie-Kuan; Yu, Lung

2016-02-29

Activation of N-methyl-D-aspartate (NMDA) receptor can facilitate the extinction of various maladaptive memories. Sodium benzoate (NaB) has been known to enhance a naturally occurring full agonist on the glycine binding site of the NMDA receptor. This study aimed to test whether systemic NaB treatment can affect the extinction of a cocaine-supported memory, the cocaine-induced conditioned place preference (CPP). Following the establishment of the cocaine (10 mg/kg/conditioning × 3)-induced CPP, an extinction protocol, consisting of two consecutive extinction training bouts at an 8-h interval, was used. NaB (500 mg/kg) or an equivalent volume of saline was given immediately following each extinction training bout to test the modulating effect of NaB on the maintenance of cocaine-induced CPP. Moreover, NaB was bilaterally micro-infused into the medial prefrontal cortex (mPFC) to validate the involvement of this brain region in mediating systemic NaB treatment-produced effect on cocaine-induced CPP. Systemic (500 mg/kg) and intra-mPFC (10 μg/side) NaB treatment significantly decreased subsequent cocaine-induced CPP magnitude, although the NaB treatment or the extinction training alone did not affect such CPP magnitude. It was of importance to note that systemic or intra-mPFC NaB delivery did not affect mouse locomotor activity in the retests. These results, taken together, suggest that NaB treatment in combination with the extinction training may facilitate the extinction of the cocaine-supported memory. Moreover, systemic NaB treatment exerts such effects, at least in part, via its effect in the mPFC.

Itch Management: General Principles.

PubMed

Misery, Laurent

2016-01-01

Like pain, itch is a challenging condition that needs to be managed. Within this setting, the first principle of itch management is to get an appropriate diagnosis to perform an etiology-oriented therapy. In several cases it is not possible to treat the cause, the etiology is undetermined, there are several causes, or the etiological treatment is not effective enough to alleviate itch completely. This is also why there is need for symptomatic treatment. In all patients, psychological support and associated pragmatic measures might be helpful. General principles and guidelines are required, yet patient-centered individual care remains fundamental. © 2016 S. Karger AG, Basel.

Instantaneous electron beam emittance measurement system based on the optical transition radiation principle

NASA Astrophysics Data System (ADS)

Jiang, Xiao-Guo; Wang, Yuan; Zhang, Kai-Zhi; Yang, Guo-Jun; Shi, Jin-Shui; Deng, Jian-Jun; Li, Jin

2014-01-01

One kind of instantaneous electron beam emittance measurement system based on the optical transition radiation principle and double imaging optical method has been set up. It is mainly adopted in the test for the intense electron-beam produced by a linear induction accelerator. The system features two characteristics. The first one concerns the system synchronization signal triggered by the following edge of the main output waveform from a Blumlein switch. The synchronous precision of about 1 ns between the electron beam and the image capture time can be reached in this way so that the electron beam emittance at the desired time point can be obtained. The other advantage of the system is the ability to obtain the beam spot and beam divergence in one measurement so that the calculated result is the true beam emittance at that time, which can explain the electron beam condition. It provides to be a powerful beam diagnostic method for a 2.5 kA, 18.5 MeV, 90 ns (FWHM) electron beam pulse produced by Dragon I. The ability of the instantaneous measurement is about 3 ns and it can measure the beam emittance at any time point during one beam pulse. A series of beam emittances have been obtained for Dragon I. The typical beam spot is 9.0 mm (FWHM) in diameter and the corresponding beam divergence is about 10.5 mrad.

Fundamental uncertainty limit of optical flow velocimetry according to Heisenberg's uncertainty principle.

PubMed

Fischer, Andreas

2016-11-01

Optical flow velocity measurements are important for understanding the complex behavior of flows. Although a huge variety of methods exist, they are either based on a Doppler or a time-of-flight measurement principle. Doppler velocimetry evaluates the velocity-dependent frequency shift of light scattered at a moving particle, whereas time-of-flight velocimetry evaluates the traveled distance of a scattering particle per time interval. Regarding the aim of achieving a minimal measurement uncertainty, it is unclear if one principle allows to achieve lower uncertainties or if both principles can achieve equal uncertainties. For this reason, the natural, fundamental uncertainty limit according to Heisenberg's uncertainty principle is derived for Doppler and time-of-flight measurement principles, respectively. The obtained limits of the velocity uncertainty are qualitatively identical showing, e.g., a direct proportionality for the absolute value of the velocity to the power of 32 and an indirect proportionality to the square root of the scattered light power. Hence, both measurement principles have identical potentials regarding the fundamental uncertainty limit due to the quantum mechanical behavior of photons. This fundamental limit can be attained (at least asymptotically) in reality either with Doppler or time-of-flight methods, because the respective Cramér-Rao bounds for dominating photon shot noise, which is modeled as white Poissonian noise, are identical with the conclusions from Heisenberg's uncertainty principle.

Bernoulli's Principle

ERIC Educational Resources Information Center

Hewitt, Paul G.

2004-01-01

Some teachers have difficulty understanding Bernoulli's principle particularly when the principle is applied to the aerodynamic lift. Some teachers favor using Newton's laws instead of Bernoulli's principle to explain the physics behind lift. Some also consider Bernoulli's principle too difficult to explain to students and avoid teaching it…

Development and Optimization of a High-Throughput Assay To Measure Neutralizing Antibodies against Clostridium difficile Binary Toxin

PubMed Central

Xie, Jinfu; Horton, Melanie; Zorman, Julie; Antonello, Joseph M.; Zhang, Yuhua; Arnold, Beth A.; Secore, Susan; Xoconostle, Rachel; Miezeiewski, Matthew; Wang, Su; Price, Colleen E.; Thiriot, David; Goerke, Aaron; Gentile, Marie-Pierre; Skinner, Julie M.

2014-01-01

Clostridium difficile strains producing binary toxin, in addition to toxin A (TcdA) and toxin B (TcdB), have been associated with more severe disease and increased recurrence of C. difficile infection in recent outbreaks. Binary toxin comprises two subunits (CDTa and CDTb) and catalyzes the ADP-ribosylation of globular actin (G-actin), which leads to the depolymerization of filamentous actin (F-actin) filaments. A robust assay is highly desirable for detecting the cytotoxic effect of the toxin and the presence of neutralizing antibodies in animal and human sera to evaluate vaccine efficacy. We describe here the optimization, using design-of-experiment (DOE) methodology, of a high-throughput assay to measure the toxin potency and neutralizing antibodies (NAb) against binary toxin. Vero cells were chosen from a panel of cells screened for sensitivity and specificity. We have successfully optimized the CDTa-to-CDTb molar ratio, toxin concentration, cell-seeding density, and sera-toxin preincubation time in the NAb assay using DOE methodology. This assay is robust, produces linear results across serial dilutions of hyperimmune serum, and can be used to quantify neutralizing antibodies in sera from hamsters and monkeys immunized with C. difficile binary toxin-containing vaccines. The assay will be useful for C. difficile diagnosis, for epidemiology studies, and for selecting and optimizing vaccine candidates. PMID:24623624

Direct optical sensors: principles and selected applications.

PubMed

Gauglitz, Guenter

2005-01-01

In the field of bio and chemosensors a large number of detection principles has been published within the last decade. These detection principles are based either on the observation of fluorescence-labelled systems or on direct optical detection in the heterogeneous phase. Direct optical detection can be measured by remission (absorption of reflected radiation, opt(r)odes), by measuring micro-refractivity, or measuring interference. In the last case either Mach-Zehnder interferometers or measurement of changes in the physical thickness of the layer (measuring micro-reflectivity) caused, e.g., by swelling effects in polymers (due to interaction with analytes) or in bioassays (due to affinity reactions) also play an important role. Here, an overview of methods of microrefractometric and microreflectometric principles is given and benefits and drawbacks of the various approaches are demonstrated using samples from the chemo and biosensor field. The quality of sensors does not just depend on transduction principles but on the total sensor system defined by this transduction, the sensitive layer, data acquisition electronics, and evaluation software. The intention of this article is, therefore, to demonstrate the essentials of the interaction of these parts within the system, and the focus is on optical sensing using planar transducers, because fibre optical sensors have been reviewed in this journal only recently. Lack of selectivity of chemosensors can be compensated either by the use of sensor arrays or by evaluating time-resolved measurements of analyte/sensitive layer interaction. In both cases chemometrics enables the quantification of analyte mixtures. These data-processing methods have also been successfully applied to antibody/antigen interactions even using cross-reactive antibodies. Because miniaturisation and parallelisation are essential approaches in recent years, some aspects and current trends, especially for bio-applications, will be discussed

A Special Connection between γδ T Cells and Natural Antibodies?

PubMed Central

Born, Willi K.; Huang, Yafei; Zeng, Wanjiang; Torres, Raul M.; O’Brien, Rebecca L.

2017-01-01

Natural antibodies (NAbs) play an important role in early host defense, autophagy and tissue remodeling, and in immune regulation. They arise spontaneously (without specific immunization), and are already present at birth. NAbs are produced by B1 B cells, MZ B cells and other B cell types. They include all major Ig subclasses but IgM antibodies are prevalent, especially early in development. NAbs may be poly-specific, recognize particular auto-antigens, or detect neo-determinants such as those exposed during apoptosis or generated by oxidation. NAbs do not require cognate T cell help but depend on soluble mediators produced by T cells. Our recent studies suggest that γδ T cells may have a special relationship with NAbs, and play a prominent role in their regulation, in part through the fine-tuning of IL-4-levels. The spontaneously activated state of these cells likely enables their cytokine production and other functions in the absence of external stimulation. Ontogenetically, the earlier arising γδ T cells are better positioned than αβ T cells to shape the developing repertoire of NAbs. Intriguingly, ligand specificities of NAbs and γδ T cell receptors appear to be overlapping, perhaps allowing γδ cognate help for certain NAb specificities. Via NAbs, γδ T cells could exert a regulatory influence on numerous processes in health and disease. PMID:27235134

A Special Connection between γδ T Cells and Natural Antibodies?

PubMed

Born, Willi K; Huang, Yafei; Zeng, Wanjiang; Torres, Raul M; O'Brien, Rebecca L

2016-12-01

Natural antibodies (NAbs) play an important role in early host defense, autophagy and tissue remodeling, and in immune regulation. They arise spontaneously (without specific immunization), and are already present at birth. NAbs are produced by B1 B cells, MZ B cells and other B cell types. They include all major Ig subclasses but IgM antibodies are prevalent, especially early in development. NAbs may be poly-specific, recognize particular auto-antigens, or detect neo-determinants such as those exposed during apoptosis or generated by oxidation. NAbs do not require cognate T cell help but depend on soluble mediators produced by T cells. Our recent studies suggest that γδ T cells may have a special relationship with NAbs, and play a prominent role in their regulation, in part through the fine-tuning of IL-4 levels. The spontaneously activated state of these cells likely enables their cytokine production and other functions in the absence of external stimulation. Ontogenetically, the earlier arising γδ T cells are better positioned than αβ T cells to shape the developing repertoire of NAbs. Intriguingly, ligand specificities of NAbs and γδ T cell receptors appear to be overlapping, perhaps allowing γδ cognate help for certain NAb specificities. Via NAbs, γδ T cells could exert a regulatory influence on numerous processes in health and disease.

Dynamic principle for ensemble control tools.

PubMed

Samoletov, A; Vasiev, B

2017-11-28

Dynamical equations describing physical systems in contact with a thermal bath are commonly extended by mathematical tools called "thermostats." These tools are designed for sampling ensembles in statistical mechanics. Here we propose a dynamic principle underlying a range of thermostats which is derived using fundamental laws of statistical physics and ensures invariance of the canonical measure. The principle covers both stochastic and deterministic thermostat schemes. Our method has a clear advantage over a range of proposed and widely used thermostat schemes that are based on formal mathematical reasoning. Following the derivation of the proposed principle, we show its generality and illustrate its applications including design of temperature control tools that differ from the Nosé-Hoover-Langevin scheme.

Dark matter and the equivalence principle

NASA Technical Reports Server (NTRS)

Frieman, Joshua A.; Gradwohl, Ben-Ami

1993-01-01

A survey is presented of the current understanding of dark matter invoked by astrophysical theory and cosmology. Einstein's equivalence principle asserts that local measurements cannot distinguish a system at rest in a gravitational field from one that is in uniform acceleration in empty space. Recent test-methods for the equivalence principle are presently discussed as bases for testing of dark matter scenarios involving the long-range forces between either baryonic or nonbaryonic dark matter and ordinary matter.

High precision test of the equivalence principle

NASA Astrophysics Data System (ADS)

Schlamminger, Stephan; Wagner, Todd; Choi, Ki-Young; Gundlach, Jens; Adelberger, Eric

2007-05-01

The equivalence principle is the underlying foundation of General Relativity. Many modern quantum theories of gravity predict violations of the equivalence principle. We are using a rotating torsion balance to search for a new equivalence principle violating, long range interaction. A sensitive torsion balance is mounted on a turntable rotating with constant angular velocity. On the torsion pendulum beryllium and titanium test bodies are installed in a composition dipole configuration. A violation of the equivalence principle would yield to a differential acceleration of the two materials towards a source mass. I will present measurements with a differential acceleration sensitivity of 3x10-15;m/s^2. To cite this abstract, use the following reference: http://meetings.aps.org/link/BAPS.2007.NWS07.B3.5

Evidence-Based Biosafety: a Review of the Principles and Effectiveness of Microbiological Containment Measures

PubMed Central

Kimman, Tjeerd G.; Smit, Eric; Klein, Michèl R.

2008-01-01

We examined the available evidence on the effectiveness of measures aimed at protecting humans and the environment against the risks of working with genetically modified microorganisms (GMOs) and with non-GMO pathogenic microorganisms. A few principles and methods underlie the current biosafety practice: risk assessment, biological containment, concentration and enclosure, exposure minimization, physical containment, and hazard minimization. Many of the current practices are based on experience and expert judgment. The effectiveness of biosafety measures may be evaluated at the level of single containment equipment items and procedures, at the level of the laboratory as a whole, or at the clinical-epidemiological level. Data on the containment effectiveness of equipment and laboratories are scarce and fragmented. Laboratory-acquired infections (LAIs) are therefore important for evaluating the effectiveness of biosafety. For the majority of LAIs there appears to be no direct cause, suggesting that failures of biosafety were not noticed or that containment may have been insufficient. The number of reported laboratory accidents associated with GMOs is substantially lower than that of those associated with non-GMOs. It is unknown to what extent specific measures contribute to the overall level of biosafety. We therefore recommend that the evidence base of biosafety practice be strengthened. PMID:18625678

Evidence-based biosafety: a review of the principles and effectiveness of microbiological containment measures.

PubMed

Kimman, Tjeerd G; Smit, Eric; Klein, Michèl R

2008-07-01

We examined the available evidence on the effectiveness of measures aimed at protecting humans and the environment against the risks of working with genetically modified microorganisms (GMOs) and with non-GMO pathogenic microorganisms. A few principles and methods underlie the current biosafety practice: risk assessment, biological containment, concentration and enclosure, exposure minimization, physical containment, and hazard minimization. Many of the current practices are based on experience and expert judgment. The effectiveness of biosafety measures may be evaluated at the level of single containment equipment items and procedures, at the level of the laboratory as a whole, or at the clinical-epidemiological level. Data on the containment effectiveness of equipment and laboratories are scarce and fragmented. Laboratory-acquired infections (LAIs) are therefore important for evaluating the effectiveness of biosafety. For the majority of LAIs there appears to be no direct cause, suggesting that failures of biosafety were not noticed or that containment may have been insufficient. The number of reported laboratory accidents associated with GMOs is substantially lower than that of those associated with non-GMOs. It is unknown to what extent specific measures contribute to the overall level of biosafety. We therefore recommend that the evidence base of biosafety practice be strengthened.

Prediction of HIV-1 sensitivity to broadly neutralizing antibodies shows a trend towards resistance over time.

PubMed

Hake, Anna; Pfeifer, Nico

2017-10-01

Treatment with broadly neutralizing antibodies (bNAbs) has proven effective against HIV-1 infections in humanized mice, non-human primates, and humans. Due to the high mutation rate of HIV-1, resistance testing of the patient's viral strains to the bNAbs is still inevitable. So far, bNAb resistance can only be tested in expensive and time-consuming neutralization experiments. Here, we introduce well-performing computational models that predict the neutralization response of HIV-1 to bNAbs given only the envelope sequence of the virus. Using non-linear support vector machines based on a string kernel, the models learnt even the important binding sites of bNAbs with more complex epitopes, i.e., the CD4 binding site targeting bNAbs, proving thereby the biological relevance of the models. To increase the interpretability of the models, we additionally provide a new kind of motif logo for each query sequence, visualizing those residues of the test sequence that influenced the prediction outcome the most. Moreover, we predicted the neutralization sensitivity of around 34,000 HIV-1 samples from different time points to a broad range of bNAbs, enabling the first analysis of HIV resistance to bNAbs on a global scale. The analysis showed for many of the bNAbs a trend towards antibody resistance over time, which had previously only been discovered for a small non-representative subset of the global HIV-1 population.

Prediction of HIV-1 sensitivity to broadly neutralizing antibodies shows a trend towards resistance over time

PubMed Central

2017-01-01

Treatment with broadly neutralizing antibodies (bNAbs) has proven effective against HIV-1 infections in humanized mice, non-human primates, and humans. Due to the high mutation rate of HIV-1, resistance testing of the patient’s viral strains to the bNAbs is still inevitable. So far, bNAb resistance can only be tested in expensive and time-consuming neutralization experiments. Here, we introduce well-performing computational models that predict the neutralization response of HIV-1 to bNAbs given only the envelope sequence of the virus. Using non-linear support vector machines based on a string kernel, the models learnt even the important binding sites of bNAbs with more complex epitopes, i.e., the CD4 binding site targeting bNAbs, proving thereby the biological relevance of the models. To increase the interpretability of the models, we additionally provide a new kind of motif logo for each query sequence, visualizing those residues of the test sequence that influenced the prediction outcome the most. Moreover, we predicted the neutralization sensitivity of around 34,000 HIV-1 samples from different time points to a broad range of bNAbs, enabling the first analysis of HIV resistance to bNAbs on a global scale. The analysis showed for many of the bNAbs a trend towards antibody resistance over time, which had previously only been discovered for a small non-representative subset of the global HIV-1 population. PMID:29065122

Hexon and fiber of adenovirus type 14 and 55 are major targets of neutralizing antibody but only fiber-specific antibody contributes to cross-neutralizing activity.

PubMed

Feng, Ying; Sun, Xikui; Ye, Xianmiao; Feng, Yupeng; Wang, Jinlin; Zheng, Xuehua; Liu, Xinglong; Yi, Changhua; Hao, Mingli; Wang, Qian; Li, Feng; Xu, Wei; Li, Liang; Li, Chufang; Zhou, Rong; Chen, Ling; Feng, Liqiang

2018-05-01

Re-emerging human adenoviruses type 14 (HAdV14) and 55 (HAdV55) represent two highly virulent adenoviruses. The neutralizing antibody (nAb) responses elicited by infection or immunization remain largely unknown. Herein, we generated hexon-chimeric HAdV14 viruses harboring each single or entire hexon hyper-variable-regions (HVR) from HAdV55, and determined the neutralizing epitopes of human and mouse nAbs. In human sera, hexon-targeting nAbs are type-specific and mainly recognize HVR2, 5, and 7. Fiber-targeting nAbs are only detectable in sera cross-neutralizing HAdV14 and HAdV55 and contribute substantially to cross-neutralization. Penton-binding antibodies, however, show no significant neutralizing activities. In mice immunized with HAdV14 or HAdV55, a single immunization mainly elicited hexon-specific nAbs, which recognized HAdV14 HVR1, 2, and 7 and HAdV55 HVR1 and 2, respectively. After a booster immunization, cross-neutralizing fiber-specific nAbs became detectable. These results indicated that hexon elicits type-specific nAbs whereas fiber induces cross-neutralizing nAbs to HAdV14 and HAdV55, which are of significance in vaccine development. Copyright © 2018 Elsevier Inc. All rights reserved.

Pharmacokinetic and Pharmacodynamic Interaction of Andrographolide and Standardized Extract of Andrographis paniculata (Nees) with Nabumetone in Wistar Rats.

PubMed

Balap, Aishwarya; Lohidasan, Sathiyanarayanan; Sinnathambi, Arulmozhi; Mahadik, Kakasaheb

2017-01-01

The aim of the study was to investigate the herb-drug interaction of Andrographis paniculata Nees (Acanthaceae) and Andrographolide (AN) with nabumetone (NAB) in wistar rats. Pharmacokinetic and pharmacodynamic interactions were studied after co-administration of APE and AN with NAB in Wistar rats. In pharmacokinetic studies, significant decrease in Cmax, AUC 0-t and AUC 0-∞ of 6-MNA after co-administration with pure AN and APE has been observed. T max of 6-MNA has been increased to 2 h from 1.5 h in AN + NAB treated group. Changes in mean residential time, clearance and volume of distribution of 6-MNA in APE + NAB treated group and AN + NAB treated group indicated interference of other components of APE other than AN. In pharmacodynamic study, significant decrease in antiarthritic activity of NAB on concomitant administration with APE and AN has been observed. The study concludes that NAB exhibits pharmacokinetic and pharmacodynamic interactions with APE and AN in rats thus alarms the concomitant use of herbal preparations containing APE and AN with NAB. Further study is needed to understand the mechanism and predict the herb-drug interaction in humans. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Nanoparticle albumin-bound paclitaxel: a novel Cremphor-EL-free formulation of paclitaxel.

PubMed

Stinchcombe, Thomas E

2007-08-01

Standard formulation paclitaxel requires the use of solvents, such as Cremphor-EL, which contribute to some of the toxicities commonly associated with paclitaxel-based therapy. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is a novel solvent-free formulation of paclitaxel. The formulation is prepared by high-pressure homogenization of paclitaxel in the presence of serum albumin into a nanoparticle colloidal suspension. The human albumin-stabilized paclitaxel particles have an average size of 130 nm. Nab-paclitaxel has several practical advantages over Cremphor-EL-paclitaxel, including a shorter infusion time (30 min) and no need for premedications for hypersensitivity reactions. The nab-paclitaxel formulation eliminates the impact of Cremphor-EL on paclitaxel pharmacokinetics and utilizes the endogenous albumin transport mechanisms to concentrate nab-paclitaxel within the tumor. A recent Phase III trial compared nab- and Cremphor-EL-paclitaxel in patients with metastatic breast cancer. Patients treated with nab-paclitaxel experienced a higher response, longer time to tumor progression and, in patients receiving second-line or greater therapy, a longer median survival. Patients treated with nab-paclitaxel had a significantly lower rate of severe neutropenia and a higher rate of sensory neuropathy. The preclinical and clinical data indicate that the nab-paclitaxel formulation has significant advantages over Cremphor-EL-paclitaxel.

Efficacy of severe acute respiratory syndrome vaccine based on a nonhuman primate adenovirus in the presence of immunity against human adenovirus.

PubMed

Zhi, Yan; Figueredo, Joanita; Kobinger, Gary P; Hagan, Heather; Calcedo, Roberto; Miller, James R; Gao, Guangping; Wilson, James M

2006-05-01

Replication-deficient human adenovirus type 5 (AdH5) vectors can induce strong transgene product-specific cellular and humoral responses. However, many adult humans have neutralizing antibodies (NAbs) against AdH5 as a result of natural infection with this virus. Therefore, a chimpanzee adenovirus C7 (AdC7) vector was developed to circumvent interference by preexisting immunity to AdH5. This study evaluated the impact of preexisting immunity to human adenovirus on the efficacy of adenovirus-based vaccines against the coronavirus that causes severe acute respiratory syndrome (SARS-CoV). Efficacy was assessed after intramuscular injection of the vector into mice and was measured as the frequency of SARS-CoV-specific T cells and NAbs against SARS-CoV. Immunogenicity of the AdH5-based vaccine was significantly attenuated or completely abolished when the preexisting anti-AdH5 NAb titer was higher than 40. Because 27% of human serum samples from the United States tested so far have an anti-AdH5 NAb titer higher than 40, our results suggested that a significant percentage of humans with preexisting anti-AdH5 immunity would not be candidates for vaccination with an AdH5-based genetic vaccine. In contrast, preexisting anti-AdH5 NAbs have a minimal effect on the potency of the AdC7-based genetic vaccine. Taken together, our studies warrant the further development of AdC7 as a vaccine carrier for human trials.

[Application criteria of the precautionary principle].

PubMed

Moccaldi, R

2011-01-01

The precautionary principle, according to the European Commission (February 2, 2000) must be applied when there is a possibility of a danger to humans, animals and/or environment health, i.e. when the potential harmful effects have been identified by a scientific and objective evaluation, but this evaluation does not allow the risk to be determined with sufficient certainty. However this principle has been invoked, without the identification, even partial, of harmful effects, to justify preventive and protective measures deemed necessary by policy maker mainly due to a high (but unjustified) risk perception by the population. We analyze the examples of the limits imposed by Italian legislation for the protection from EMF, and measures of "prudent avoidance" in the use of mobile phones.

Attitude measurement: Principles and sensors

NASA Technical Reports Server (NTRS)

Duchon, P.; Vermande, M. P.

1981-01-01

Tools used in the measurement of satellite attitude are described. Attention is given to the elements that characterize an attitude sensor, the references employed (stars, moon, Sun, Earth, magnetic fields, etc.), and the detectors (optical, magnetic, and inertial). Several examples of attitude sensors are described, including sun sensors, star sensors, earth sensors, triaxial magnetometers, and gyrometers. Finally, sensor combinations that make it possible to determine a complete attitude are considered; the SPOT attitude measurement system and a combined CCD star sensor-gyrometer system are discussed.

Seroprevalence of Neutralizing Antibodies against Human Adenovirus Type-5 and Chimpanzee Adenovirus Type-68 in Cancer Patients.

PubMed

Zhao, Hua; Xu, Can; Luo, Xiaoli; Wei, Feng; Wang, Ning; Shi, Huiying; Ren, Xiubao

2018-01-01

Since the preclinical results about chimpanzee adenovirus serotype-68 (AdC68)-based vaccine showed an encouraging results, it reminded us that AdC68 may be a suitable cancer vaccine vector. Previous study indicated that the seroprevalence of neutralizing antibodies (NAbs) against adenovirus was different between cancer patients and healthy volunteers. Knowledge regarding the prevalence rates of AdC68 NAbs for cancer patients is lacking. Therefore, assessing the preexistence of NAbs against AdC68 in cancer patients could provide useful insights for developing future AdC68-based cancer vaccines. In this study, 440 patients with different pathological types of tumors and 204 healthy adult volunteers were enrolled to evaluate the NAbs against AdC68 and human adenovirus serotype-5 (AdHu5). The seroprevalence of NAbs against AdC68 was much lower than that against AdHu5 in cancer subjects (43.64 vs. 67.05%, P  < 0.01). The seroprevalence rates of NAbs to AdC68 in the cancer subjects were statistically higher than those detected in the healthy adult volunteers (43.64 vs. 23.53%, P  = 0.000). The seroprevalence rates of AdC68 NAbs were much lower in lung, laryngeal, esophageal, and cervical cancer patients compared with oropharyngeal, colon, and rectal cancer patients. Furthermore, the seroprevalence rates of AdC68 NAbs were much lower in lung adenocarcinoma patients than in lung squamous cell carcinoma patients (35.00 vs. 70.00%, P  < 0.05). No significant difference in the AdC68 NAbs among patients with different clinical stages of cancer was detected. The percentage of NAbs against AdC68 was significantly lower than that against AdHu5 ( P  < 0.05) in stage-I, -II, and -III cancer patients. No significant difference between the percentage of NAbs against AdC68 and AdHu5 in the subjects with stage-IV cancer was detected. The study also demonstrated the distribution of AdHu5 and AdC68 NAb titers for the positive samples. It showed that very low NAb titers

Seroprevalence of Neutralizing Antibodies against Human Adenovirus Type-5 and Chimpanzee Adenovirus Type-68 in Cancer Patients

PubMed Central

Zhao, Hua; Xu, Can; Luo, Xiaoli; Wei, Feng; Wang, Ning; Shi, Huiying; Ren, Xiubao

2018-01-01

Since the preclinical results about chimpanzee adenovirus serotype-68 (AdC68)-based vaccine showed an encouraging results, it reminded us that AdC68 may be a suitable cancer vaccine vector. Previous study indicated that the seroprevalence of neutralizing antibodies (NAbs) against adenovirus was different between cancer patients and healthy volunteers. Knowledge regarding the prevalence rates of AdC68 NAbs for cancer patients is lacking. Therefore, assessing the preexistence of NAbs against AdC68 in cancer patients could provide useful insights for developing future AdC68-based cancer vaccines. In this study, 440 patients with different pathological types of tumors and 204 healthy adult volunteers were enrolled to evaluate the NAbs against AdC68 and human adenovirus serotype-5 (AdHu5). The seroprevalence of NAbs against AdC68 was much lower than that against AdHu5 in cancer subjects (43.64 vs. 67.05%, P < 0.01). The seroprevalence rates of NAbs to AdC68 in the cancer subjects were statistically higher than those detected in the healthy adult volunteers (43.64 vs. 23.53%, P = 0.000). The seroprevalence rates of AdC68 NAbs were much lower in lung, laryngeal, esophageal, and cervical cancer patients compared with oropharyngeal, colon, and rectal cancer patients. Furthermore, the seroprevalence rates of AdC68 NAbs were much lower in lung adenocarcinoma patients than in lung squamous cell carcinoma patients (35.00 vs. 70.00%, P < 0.05). No significant difference in the AdC68 NAbs among patients with different clinical stages of cancer was detected. The percentage of NAbs against AdC68 was significantly lower than that against AdHu5 (P < 0.05) in stage-I, -II, and -III cancer patients. No significant difference between the percentage of NAbs against AdC68 and AdHu5 in the subjects with stage-IV cancer was detected. The study also demonstrated the distribution of AdHu5 and AdC68 NAb titers for the positive samples. It showed that very low NAb titers against

Unifying decoherence and the Heisenberg Principle

NASA Astrophysics Data System (ADS)

Janssens, Bas

2017-08-01

We exhibit three inequalities involving quantum measurement, all of which are sharp and state independent. The first inequality bounds the performance of joint measurement. The second quantifies the trade-off between the measurement quality and the disturbance caused on the measured system. Finally, the third inequality provides a sharp lower bound on the amount of decoherence in terms of the measurement quality. This gives a unified description of both the Heisenberg uncertainty principle and the collapse of the wave function.

Intrasubtype B HIV-1 Superinfection Correlates with Delayed Neutralizing Antibody Response

PubMed Central

Landais, Elise; Caballero, Gemma; Phung, Pham; Kosakovsky Pond, Sergei L.; Poignard, Pascal; Richman, Douglas D.; Little, Susan J.; Smith, Davey M.

2017-01-01

ABSTRACT Understanding whether the neutralizing antibody (NAb) response impacts HIV-1 superinfection and how superinfection subsequently modulates the NAb response can help clarify correlates of protection from HIV exposures and better delineate pathways of NAb development. We examined associations between the development of NAb and the occurrence of superinfection in a well-characterized, antiretroviral therapy (ART)-naive, primary infection cohort of men who have sex with men. Deep sequencing was applied to blood plasma samples from the cohort to detect cases of superinfection. We compared the NAb activity against autologous and heterologous viruses between 10 participants with intrasubtype B superinfection and 19 monoinfected controls, matched to duration of infection and risk behavior. Three to 6 months after primary infection, individuals who would later become superinfected had significantly weaker NAb activity against tier 1 subtype B viruses (P = 0.003 for SF-162 and P = 0.017 for NL4-3) and marginally against autologous virus (P = 0.054). Lower presuperinfection NAb responses correlated with weaker gp120 binding and lower plasma total IgG titers. Soon after superinfection, the NAb response remained lower, but between 2 and 3 years after primary infection, NAb levels strengthened and reached those of controls. Superinfecting viruses were typically not susceptible to neutralization by presuperinfection plasma. These observations suggest that recently infected individuals with a delayed NAb response against primary infecting and tier 1 subtype B viruses are more susceptible to superinfection. IMPORTANCE Our findings suggest that within the first year after HIV infection, a relatively weak neutralizing antibody response against primary and subtype-specific neutralization-sensitive viruses increases susceptibility to superinfection in the face of repeated exposures. As natural infection progresses, the immune response strengthens significantly in some

Ventricular assist device elicits serum natural IgG that correlates with the development of primary graft dysfunction following heart transplantation.

PubMed

See, Sarah B; Clerkin, Kevin J; Kennel, Peter J; Zhang, Feifan; Weber, Matthew P; Rogers, Kortney J; Chatterjee, Debanjana; Vasilescu, Elena R; Vlad, George; Naka, Yoshifumi; Restaino, Susan W; Farr, Maryjane A; Topkara, Veli K; Colombo, Paolo C; Mancini, Donna M; Schulze, P Christian; Levin, Bruce; Zorn, Emmanuel

2017-08-01

Pre-transplant sensitization is a limiting factor in solid-organ transplantation. In heart transplants, ventricular assist device (VAD) implantation has been associated with sensitization to human leukocyte antigens (HLA). The effect of VAD on non-HLA antibodies is unclear. We have previously shown that polyreactive natural antibodies (Nabs) contribute to pre-sensitization in kidney allograft recipients. Here we assessed generation of Nabs after VAD implantation in pre-transplant sera and examined their contribution to cardiac allograft outcome. IgM and IgG Nabs were tested in pre-transplant serum samples collected from 206 orthotopic heart transplant recipients, including 128 patients with VAD (VAD patients) and 78 patients without VAD (no-VAD patients). Nabs were assessed by testing serum reactivity to apoptotic cells by flow cytometry and to the generic oxidized epitope, malondialdehyde, by enzyme-linked immunosorbent assay. No difference was observed in serum levels of IgM Nabs between VAD and no-VAD patients. However, serum IgG Nabs levels were significantly increased in VAD compared with no-VAD patients. This increase was likely due to the presence of the VAD, as revealed by lower serum IgG Nabs levels before implantation. Elevated pre-transplant IgG Nabs level was associated with development of primary graft dysfunction (PGD). Our study demonstrates that VAD support elicits IgG Nabs reactive to apoptotic cells and oxidized epitopes. These findings further support broad and non-specific B-cell activation by VAD, resulting in IgG sensitization. Moreover, the association of serum IgG Nabs levels with development of PGD suggests a possible role for these antibodies in the inflammatory reaction accompanying this complication. Copyright © 2017 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

Comparison of homologous and heterologous prime-boost vaccine approaches using Modified Vaccinia Ankara and soluble protein to induce neutralizing antibodies by the human cytomegalovirus pentamer complex in mice.

PubMed

Chiuppesi, Flavia; Wussow, Felix; Scharf, Louise; Contreras, Heidi; Gao, Han; Meng, Zhuo; Nguyen, Jenny; Barry, Peter A; Bjorkman, Pamela J; Diamond, Don J

2017-01-01

Since neutralizing antibodies (NAb) targeting the human cytomegalovirus (HCMV) pentamer complex (PC) potently block HCMV host cell entry, anti-PC NAb induction is thought to be important for a vaccine formulation to prevent HCMV infection. By developing a vaccine strategy based on soluble PC protein and using a previously generated Modified Vaccinia Ankara vector co-expressing all five PC subunits (MVA-PC), we compared HCMV NAb induction by homologous immunization using prime-boost vaccine regimen employing only PC protein or MVA-PC and heterologous immunization using prime-boost combinations of PC protein and MVA-PC. Utilizing a recently isolated anti-PC NAb, we produced highly pure soluble PC protein that displayed conformational and linear neutralizing epitopes, interfered with HCMV entry, and was recognized by antibodies induced by HCMV during natural infection. Mice vaccinated by different immunization routes with the purified PC protein in combination with a clinically approved adjuvant formulation elicited high-titer and durable HCMV NAb. While MVA-PC and soluble PC protein either alone or in combination elicited robust HCMV NAb, significantly different potencies of these vaccine approaches were observed in dependence on immunization schedule. Using only two immunizations, vaccination with MVA-PC alone or prime-boost combinations of MVA-PC and PC protein was significantly more effective in stimulating HCMV NAb than immunization with PC protein alone. In contrast, with three immunizations, NAb induced by soluble PC protein either alone or combined with two boosts of MVA-PC increased to levels that exceeded NAb titer stimulated by MVA-PC alone. These results provide insights into the potency of soluble protein and MVA to elicit NAb by the HCMV PC via homologous and heterologous prime-boost immunization, which may contribute to develop clinically deployable vaccine strategies to prevent HCMV infection.

Intrasubtype B HIV-1 Superinfection Correlates with Delayed Neutralizing Antibody Response.

PubMed

Wagner, Gabriel A; Landais, Elise; Caballero, Gemma; Phung, Pham; Kosakovsky Pond, Sergei L; Poignard, Pascal; Richman, Douglas D; Little, Susan J; Smith, Davey M

2017-09-01

Understanding whether the neutralizing antibody (NAb) response impacts HIV-1 superinfection and how superinfection subsequently modulates the NAb response can help clarify correlates of protection from HIV exposures and better delineate pathways of NAb development. We examined associations between the development of NAb and the occurrence of superinfection in a well-characterized, antiretroviral therapy (ART)-naive, primary infection cohort of men who have sex with men. Deep sequencing was applied to blood plasma samples from the cohort to detect cases of superinfection. We compared the NAb activity against autologous and heterologous viruses between 10 participants with intrasubtype B superinfection and 19 monoinfected controls, matched to duration of infection and risk behavior. Three to 6 months after primary infection, individuals who would later become superinfected had significantly weaker NAb activity against tier 1 subtype B viruses ( P = 0.003 for SF-162 and P = 0.017 for NL4-3) and marginally against autologous virus ( P = 0.054). Lower presuperinfection NAb responses correlated with weaker gp120 binding and lower plasma total IgG titers. Soon after superinfection, the NAb response remained lower, but between 2 and 3 years after primary infection, NAb levels strengthened and reached those of controls. Superinfecting viruses were typically not susceptible to neutralization by presuperinfection plasma. These observations suggest that recently infected individuals with a delayed NAb response against primary infecting and tier 1 subtype B viruses are more susceptible to superinfection. IMPORTANCE Our findings suggest that within the first year after HIV infection, a relatively weak neutralizing antibody response against primary and subtype-specific neutralization-sensitive viruses increases susceptibility to superinfection in the face of repeated exposures. As natural infection progresses, the immune response strengthens significantly in some superinfected

Sodium Butyrate Inhibits Colorectal Cancer Cell Migration by Downregulating Bmi-1 Through Enhanced miR-200c Expression.

PubMed

Xu, Zhiyao; Tao, Jingjing; Chen, Ping; Chen, Long; Sharma, Sherven; Wang, Guanyu; Dong, Qinghua

2018-03-01

Short-chain fatty acid sodium butyrate (NaB) is the byproduct of bacterial anaerobic fermentation of dietary fiber in the colon, and has been shown to have an antitumor effect on colorectal cancer (CRC). The miR-200 family is a key regulator of the epithelial-mesenchymal transition (EMT). We investigate the role of miR-200s expression on cell migration in NaB-treated CRC cells. HCT116 and LOVO CRC cells treated with NaB depicted reduced cell proliferation, enhanced apoptosis, and cell cycle arrest. NaB inhibited cell migration in the wound healing and transwell assays, and in spheriod cultures while regulating EMT-related protein expression. NaB reciprocally increased miR-200s but reduced expression of their target genes (Bmi-1, Zeb1, EZH2). Cells transfected with miR-200c shRNA displayed a significant blockade of NaB-induced anti-invasive activity. Upregulation of Bmi-1 expression partially reversed the effect of NaB. In addition to inhibition of tumor growth in vivo, qRT-PCR results showed that NaB increased miR-200c/200b/492 expression in the tumor tissues. Immunohistochemistry and Western blotting results demonstrated that NaB decreased Bmi-1 expression in vivo. NaB inhibits CRC cell migration by enhancing miR-200c expression-mediated downregulation of Bmi-1. These findings support the utility of NaB in colorectal cancer therapy. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Epidemiology and Clinical Research Design, Part 2: Principles.

PubMed

Manja, Veena; Lakshminrusimha, Satyan

This is the third article covering core knowledge in scholarly activities for neonatal physicians. In this article, we discuss various principles of epidemiology and clinical research design. A basic knowledge of these principles is necessary for conducting clinical research and for proper interpretation of studies. This article reviews bias and confounding, causation, incidence and prevalence, decision analysis, cost-effectiveness, sensitivity analysis, and measurement.

Soft magnetic tweezers: a proof of principle.

PubMed

Mosconi, Francesco; Allemand, Jean François; Croquette, Vincent

2011-03-01

We present here the principle of soft magnetic tweezers which improve the traditional magnetic tweezers allowing the simultaneous application and measurement of an arbitrary torque to a deoxyribonucleic acid (DNA) molecule. They take advantage of a nonlinear coupling regime that appears when a fast rotating magnetic field is applied to a superparamagnetic bead immersed in a viscous fluid. In this work, we present the development of the technique and we compare it with other techniques capable of measuring the torque applied to the DNA molecule. In this proof of principle, we use standard electromagnets to achieve our experiments. Despite technical difficulties related to the present implementation of these electromagnets, the agreement of measurements with previous experiments is remarkable. Finally, we propose a simple way to modify the experimental design of electromagnets that should bring the performances of the device to a competitive level.

Perceived barriers to effective job performance among nursing assistants in long-term care.

PubMed

Parmelee, Patricia A; Laszlo, Mary C; Taylor, Jo A

2009-10-01

This research explored perceived barriers to job performance among a national sample of nursing assistants (NAs). Specific objectives were (1) to clarify which of the problems identified by previous research are most troublesome for NAs, (2) to develop a reliable quantitative measure of perceived barriers to job performance, and (3) to test construct validity of the measure vis-à-vis work-related psychological empowerment and job satisfaction. Nursing assistants attending the 2006 national conference of the National Association of Health Care Assistants completed a paper-and-pencil survey including 33 barriers to job performance and standardized measures of empowerment and job satisfaction. The barriers were also rated by a small sample of NAs at a single Georgia nursing home. Factor analysis of barriers items yielded a 30-item Nursing Assistants Barriers Scale (NABS) comprising 6 subscales: Teamwork, Exclusion, Respect, Workload, Work Stress, and New NAs. Lack of teamwork and exclusion from communication processes were rated as most problematic by both samples. The 6 NABS subscales were significantly and independently associated with empowerment and satisfaction; different barriers predicted the 2 constructs. This study is a first step toward quantitative assessment of NAs' perceptions of barriers to doing their jobs. Primary limitations are the select sample and use of a job satisfaction measure that may have artificially inflated correlations with the NABS. Nonetheless, results confirm the validity of the new scale as an operationalization of the barriers construct. The concept of barriers to job performance is a unique construct from work empowerment and satisfaction with one's job. Nursing assistants clearly differentiate various barriers, converging on workload and lack of teamwork as most problematic. Further work is needed to substantiate validity and reliability of the NABS, particularly with respect to NAs' actual job performance, intent to stay on the

Patterns of HIV/SIV Prevention and Control by Passive Antibody Immunization.

PubMed

Yamamoto, Hiroyuki; Matano, Tetsuro

2016-01-01

Neutralizing antibody (NAb) responses are promising immune effectors for control of human immunodeficiency virus (HIV) infection. Protective activity and mechanisms of immunodeficiency virus-specific NAbs have been increasingly scrutinized in animals infected with simian immunodeficiency virus (SIV), chimeric simian/human immunodeficiency virus (SHIV) and related viruses. Studies on such models have unraveled a previously underscored protective potential against in vivo immunodeficiency virus replication. Pre-challenge NAb titers feasibly provide sterile protection from SIV/SHIV infection by purging the earliest onset of viral replication and likely modulate innate immune cell responses. Sufficient sub-sterile NAb titers after established infection also confer dose-dependent reduction of viremia, and in certain earlier time frames augment adaptive immune cell responses and even provide rebound-free viral control. Here, we provide an overview of the obtained patterns of SIV/SHIV protection and viral control by various types of NAb passive immunizations and discuss how these notions may be extrapolated to NAb-based clinical control of HIV infection.

Conformational Plasticity in Broadly Neutralizing HIV-1 Antibodies Triggers Polyreactivity.

PubMed

Prigent, Julie; Jarossay, Annaëlle; Planchais, Cyril; Eden, Caroline; Dufloo, Jérémy; Kök, Ayrin; Lorin, Valérie; Vratskikh, Oxana; Couderc, Thérèse; Bruel, Timothée; Schwartz, Olivier; Seaman, Michael S; Ohlenschläger, Oliver; Dimitrov, Jordan D; Mouquet, Hugo

2018-05-29

Human high-affinity antibodies to pathogens often recognize unrelated ligands. The molecular origin and the role of this polyreactivity are largely unknown. Here, we report that HIV-1 broadly neutralizing antibodies (bNAbs) are frequently polyreactive, cross-reacting with non-HIV-1 molecules, including self-antigens. Mutating bNAb genes to increase HIV-1 binding and neutralization also results in de novo polyreactivity. Unliganded paratopes of polyreactive bNAbs with improved HIV-1 neutralization exhibit a conformational flexibility, which contributes to enhanced affinity of bNAbs to various HIV-1 envelope glycoproteins and non-HIV antigens. Binding adaptation of polyreactive bNAbs to the divergent ligands mainly involves hydrophophic interactions. Plasticity of bNAbs' paratopes may, therefore, facilitate accommodating divergent viral variants, but it simultaneously triggers promiscuous binding to non-HIV-1 antigens. Thus, a certain level of polyreactivity can be a mark of adaptable antibodies displaying optimal pathogens' recognition. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

[The beginning of the first principles: the anthropic principle].

PubMed

González de Posada, Francisco

2004-01-01

The nowadays classical Anthropic Principle is put both in the historical perspective of the traditional problem of "the place of man in the Universe', and in the confluence of several scientific "border" issues, some of which, due to their problematical nature, are also subject of philosophical analysis. On the one hand, the scientific uses of the Principle, related to the initial and constitutional conditions of "our Universe", are enumerated, as they are supposedly necessary for the appearance and consequent development of Life--up to Man--. On the other, an organized collection of the principles of today's Physics is synthetically exhibited. The object of this work is to determine the intrinsic scientific nature of the Anthropic Principle, and the role it plays in the global frame of the principles of Physics (Astrophysics, Astrobiology and Cosmology).

[The General Principles of Suicide Prevention Policy from the perspective of clinical psychiatry].

PubMed

Cho, Yoshinori; Inagaki, Masatoshi

2014-01-01

In view of the fact that the suicide rate in Japan has remained high since 1998, the Basic Act on Suicide Prevention was implemented in 2006 with the objective of comprehensively promoting suicide prevention measures on a national scale. Based on this Basic Act, in 2007, the Japanese government formulated the General Principles of Suicide Prevention Policy as a guideline for recommended suicide prevention measures. These General Principles were revised in 2012 in accordance with the initial plan of holding a review after five years. The Basic Act places an emphasis on the various social factors that underlie suicides and takes the perspective that suicide prevention measures are also social measures. The slogan of the revised General Principles is "Toward Realization of a Society in which Nobody is Driven to Commit Suicide". The General Principles list various measures that are able to be used universally. These contents would be sufficient if the objective of the General Principles were "realization of a society that is easy to live in"; however, the absence of information on the effectiveness and order of priority for each measure may limit the specific effectiveness of the measures in relation to the actual prevention of suicide. In addition, considering that nearly 90% of suicide victims are in a state at the time of committing suicide in which a psychiatric disorder would be diagnosed, it would appear from a psychiatric standpoint that measures related to mental health, including expansion of psychiatric services, should be the top priority in suicide prevention measures. However, this is not the case in the General Principles, in either its original or revised form. Revisions to the General Principles related to clinical psychiatry provide more detailed descriptions of measures for individuals who unsuccessfully attempt suicide and identify newly targeted mental disorders other than depression; however, the overall proportion of contents relating to

Epidemiology and Clinical Research Design, Part 2: Principles

PubMed Central

Manja, Veena; Lakshminrusimha, Satyan

2015-01-01

This is the third article covering core knowledge in scholarly activities for neonatal physicians. In this article, we discuss various principles of epidemiology and clinical research design. A basic knowledge of these principles is necessary for conducting clinical research and for proper interpretation of studies. This article reviews bias and confounding, causation, incidence and prevalence, decision analysis, cost-effectiveness, sensitivity analysis, and measurement. PMID:26236171

Up-regulation of neurotrophic factors by cinnamon and its metabolite sodium benzoate: therapeutic implications for neurodegenerative disorders.

PubMed

Jana, Arundhati; Modi, Khushbu K; Roy, Avik; Anderson, John A; van Breemen, Richard B; Pahan, Kalipada

2013-06-01

This study underlines the importance of cinnamon, a widely-used food spice and flavoring material, and its metabolite sodium benzoate (NaB), a widely-used food preservative and a FDA-approved drug against urea cycle disorders in humans, in increasing the levels of neurotrophic factors [e.g., brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3)] in the CNS. NaB, but not sodium formate (NaFO), dose-dependently induced the expression of BDNF and NT-3 in primary human neurons and astrocytes. Interestingly, oral administration of ground cinnamon increased the level of NaB in serum and brain and upregulated the levels of these neurotrophic factors in vivo in mouse CNS. Accordingly, oral feeding of NaB, but not NaFO, also increased the level of these neurotrophic factors in vivo in the CNS of mice. NaB induced the activation of protein kinase A (PKA), but not protein kinase C (PKC), and H-89, an inhibitor of PKA, abrogated NaB-induced increase in neurotrophic factors. Furthermore, activation of cAMP response element binding (CREB) protein, but not NF-κB, by NaB, abrogation of NaB-induced expression of neurotrophic factors by siRNA knockdown of CREB and the recruitment of CREB and CREB-binding protein to the BDNF promoter by NaB suggest that NaB exerts its neurotrophic effect through the activation of CREB. Accordingly, cinnamon feeding also increased the activity of PKA and the level of phospho-CREB in vivo in the CNS. These results highlight a novel neutrophic property of cinnamon and its metabolite NaB via PKA - CREB pathway, which may be of benefit for various neurodegenerative disorders.

The Uncertainty Principle in the Presence of Quantum Memory

NASA Astrophysics Data System (ADS)

Renes, Joseph M.; Berta, Mario; Christandl, Matthias; Colbeck, Roger; Renner, Renato

2010-03-01

One consequence of Heisenberg's uncertainty principle is that no observer can predict the outcomes of two incompatible measurements performed on a system to arbitrary precision. However, this implication is invalid if the the observer possesses a quantum memory, a distinct possibility in light of recent technological advances. Entanglement between the system and the memory is responsible for the breakdown of the uncertainty principle, as illustrated by the EPR paradox. In this work we present an improved uncertainty principle which takes this entanglement into account. By quantifying uncertainty using entropy, we show that the sum of the entropies associated with incompatible measurements must exceed a quantity which depends on the degree of incompatibility and the amount of entanglement between system and memory. Apart from its foundational significance, the uncertainty principle motivated the first proposals for quantum cryptography, though the possibility of an eavesdropper having a quantum memory rules out using the original version to argue that these proposals are secure. The uncertainty relation introduced here alleviates this problem and paves the way for its widespread use in quantum cryptography.

Evaluation of the Cross-reactivity of Antidrug Antibodies to CT-P13 and Infliximab Reference Product (Remicade): An Analysis Using Immunoassays Tagged with Both Agents.

PubMed

Reinisch, Walter; Jahnsen, Jørgen; Schreiber, Stefan; Danese, Silvio; Panés, Julián; Balsa, Alejandro; Park, Won; Kim, JiSoo; Lee, Jee Un; Yoo, Dae Hyun

2017-06-01

During two pivotal clinical trials of the infliximab biosimilar CT-P13 (PLANETAS and PLANETRA), antidrug antibodies (ADAs) and neutralising antibodies (NAbs) were detected in the sera of patients treated with CT-P13 and the reference product (RP; Remicade). The aim was to assess the comparability of Remicade- and CT-P13-tagged immunoassays for the detection of ADAs and NAbs using data from these trials, in order to determine the cross-reactivity of CT-P13 and RP ADAs. Sera from patients with rheumatoid arthritis and ankylosing spondylitis were analysed using an electrochemiluminescence (ECL) bridging assay or Gyros immunoassay, tagged with Remicade or CT-P13 at screening, weeks 14, 30 and 54, and the end of study visit. NAb titre was compared at screening and weeks 14 and 30. The proportion of cross-reactive samples was determined and an inter-rater agreement analysis performed to assess the concordance of results between assays. In PLANETAS, 93.1% (94/101) of RP ADA-positive samples and 93.0% (93/100) of RP NAb-positive samples cross-reacted with CT-P13; 99.0% (103/104) of CT-P13 ADA-positive and 98.0% (98/100) of CT-P13 NAb-positive samples cross-reacted with the RP. In PLANETRA, 94.7% (426/450) of RP ADA-positive samples and 94.3% (415/440) of RP NAb-positive samples cross-reacted with CT-P13, and 96.6% (458/474) of CT-P13 ADA-positive and 96.4% (452/469) of CT-P13 NAb-positive samples cross-reacted with the RP. In both studies, there was strong agreement in outcome between assays at all post-screening time points (PLANETAS: Cohen's κ 0.89-0.98 for ADA, 0.86-0.98 for NAb; PLANETRA: 0.92-0.94 for both ADA and NAb, all p < 0.001). Significant concordance between assays was observed for NAb titre at weeks 14 and 30 (PLANETAS: Spearman's ρ 0.73 and 0.74, respectively; PLANETRA: 0.61 and 0.72, respectively; all p < 0.001). This study has demonstrated that ADAs and NAbs against CT-P13 and RP are cross-reactive, indicating that CT-P13 and RP share immunodominant

Clinical roundtable monograph: Recent advances in taxanes for the first-line treatment of advanced non-small cell lung cancer.

PubMed

Socinski, Mark A; Govindan, Ramaswamy; Spigel, David

2012-10-01

Treatments for non-small cell lung cancer (NSCLC) are based on the broad categories of squamous or non-squamous histology. Frontline treatment options include pemetrexed and cisplatin, pemetrexed and a taxane, gemcitabine with cisplatin, and the addition of bevacizumab to a taxane and carboplatin. Pemetrexed is used for maintenance therapy for non-squamous NSCLC, whereas patients with squamous NSCLC lack easy options for maintenance therapy. nab-Paclitaxel overcomes the solubility and toxicity issues of solvent-based paclitaxel, and the albumin in nab-paclitaxel improves the concentration of the drug in the tumor. A recent phase III trial in NSCLC compared nab-paclitaxel with carboplatin versus solvent-based paclitaxel with carboplatin, and found improved overall response rates (ORRs) in the nab-paclitaxel arm (33% vs 25%; P=.005). In a subset analysis, NSCLC patients with squamous histology had a higher ORR (41%) with nab-paclitaxel than with solvent-based paclitaxel (24%; P<.001). Another subset analysis found that patients ages 70 years and older had improved overall survival (median 19.9 months) with nab-paclitaxel compared with solvent-based paclitaxel (median 10.4 months; P=.009). Patients in the nab-paclitaxel arm had less neuropathy, less hearing loss, and fewer interruptions in daily living than patients in the solvent-based paclitaxel arm.

Natively glycosylated HIV-1 Env structure reveals new mode for antibody recognition of the CD4-binding site

PubMed Central

West, Anthony P; Schamber, Michael; Gazumyan, Anna; Golijanin, Jovana; Seaman, Michael S; Fätkenheuer, Gerd; Klein, Florian; Nussenzweig, Michel C; Bjorkman, Pamela J

2016-01-01

HIV-1 vaccine design is informed by structural studies elucidating mechanisms by which broadly neutralizing antibodies (bNAbs) recognize and/or accommodate N-glycans on the trimeric envelope glycoprotein (Env). Variability in high-mannose and complex-type Env glycoforms leads to heterogeneity that usually precludes visualization of the native glycan shield. We present 3.5-Å- and 3.9-Å-resolution crystal structures of the HIV-1 Env trimer with fully processed and native glycosylation, revealing a glycan shield of high-mannose and complex-type N-glycans, which we used to define complete epitopes of two bNAbs. Env trimer was complexed with 10-1074 (against the V3-loop) and IOMA, a new CD4-binding site (CD4bs) antibody. Although IOMA derives from VH1-2*02, the germline gene of CD4bs-targeting VRC01-class bNAbs, its light chain lacks the short CDRL3 that defines VRC01-class bNAbs. Thus IOMA resembles 8ANC131-class/VH1-46–derived CD4bs bNAbs, which have normal-length CDRL3s. The existence of bNAbs that combine features of VRC01-class and 8ANC131-class antibodies has implications for immunization strategies targeting VRC01-like bNAbs. PMID:27617431

Genomic Region Containing Toll-Like Receptor Genes Has a Major Impact on Total IgM Antibodies Including KLH-Binding IgM Natural Antibodies in Chickens

PubMed Central

Berghof, Tom V. L.; Visker, Marleen H. P. W.; Arts, Joop A. J.; Parmentier, Henk K.; van der Poel, Jan J.; Vereijken, Addie L. J.; Bovenhuis, Henk

2018-01-01

Natural antibodies (NAb) are antigen binding antibodies present in individuals without a previous exposure to this antigen. Keyhole limpet hemocyanin (KLH)-binding NAb levels were previously associated with survival in chickens. This suggests that selective breeding for KLH-binding NAb may increase survival by means of improved general disease resistance. Genome-wide association studies (GWAS) were performed to identify genes underlying genetic variation in NAb levels. The studied population consisted of 1,628 adolescent layer chickens with observations for titers of KLH-binding NAb of the isotypes IgM, IgA, IgG, the total KLH-binding (IgT) NAb titers, total antibody concentrations of the isotypes IgM, IgA, IgG, and the total antibodies concentration in plasma. GWAS were performed using 57,636 single-nucleotide polymorphisms (SNP). One chromosomal region on chromosome 4 was associated with KLH-binding IgT NAb, and total IgM concentration, and especially with KLH-binding IgM NAb. The region of interest was fine mapped by imputing the region of the study population to whole genome sequence, and subsequently performing an association study using the imputed sequence variants. 16 candidate genes were identified, of which FAM114A1, Toll-like receptor 1 family member B (TLR1B), TLR1A, Krüppel-like factor 3 (KLF3) showed the strongest associations. SNP located in coding regions of the candidate genes were checked for predicted changes in protein functioning. One SNP (at 69,965,939 base pairs) received the maximum impact score from two independent prediction tools, which makes this SNP the most likely causal variant. This SNP is located in TLR1A, which suggests a fundamental role of TLR1A on regulation of IgM levels (i.e., KLH-binding IgM NAb, and total IgM concentration), or B cells biology, or both. This study contributes to increased understanding of (genetic) regulation of KLH-binding NAb levels, and total antibody concentrations. PMID:29375555

Metaphysics of the principle of least action

NASA Astrophysics Data System (ADS)

Terekhovich, Vladislav

2018-05-01

Despite the importance of the variational principles of physics, there have been relatively few attempts to consider them for a realistic framework. In addition to the old teleological question, this paper continues the recent discussion regarding the modal involvement of the principle of least action and its relations with the Humean view of the laws of nature. The reality of possible paths in the principle of least action is examined from the perspectives of the contemporary metaphysics of modality and Leibniz's concept of essences or possibles striving for existence. I elaborate a modal interpretation of the principle of least action that replaces a classical representation of a system's motion along a single history in the actual modality by simultaneous motions along an infinite set of all possible histories in the possible modality. This model is based on an intuition that deep ontological connections exist between the possible paths in the principle of least action and possible quantum histories in the Feynman path integral. I interpret the action as a physical measure of the essence of every possible history. Therefore only one actual history has the highest degree of the essence and minimal action. To address the issue of necessity, I assume that the principle of least action has a general physical necessity and lies between the laws of motion with a limited physical necessity and certain laws with a metaphysical necessity.

A mouse model of high trait anxiety shows reduced heart rate variability that can be reversed by anxiolytic drug treatment.

PubMed

Gaburro, Stefano; Stiedl, Oliver; Giusti, Pietro; Sartori, Simone B; Landgraf, Rainer; Singewald, Nicolas

2011-11-01

Increasing evidence suggests that specific physiological measures may serve as biomarkers for successful treatment to alleviate symptoms of pathological anxiety. Studies of autonomic function investigating parameters such as heart rate (HR), HR variability and blood pressure (BP) indicated that HR variability is consistently reduced in anxious patients, whereas HR and BP data show inconsistent results. Therefore, HR and HR variability were measured under various emotionally challenging conditions in a mouse model of high innate anxiety (high anxiety behaviour; HAB) vs. control normal anxiety-like behaviour (NAB) mice. Baseline HR, HR variability and activity did not differ between mouse lines. However, after cued Pavlovian fear conditioning, both elevated tachycardia and increased fear responses were observed in HAB mice compared to NAB mice upon re-exposure to the conditioning stimulus serving as the emotional stressor. When retention of conditioned fear was tested in the home cage, HAB mice again displayed higher fear responses than NAB mice, while the HR responses were similar. Conversely, in both experimental settings HAB mice consistently exhibited reduced HR variability. Repeated administration of the anxiolytic NK1 receptor antagonist L-822429 lowered the conditioned fear response and shifted HR dynamics in HAB mice to a more regular pattern, similar to that in NAB mice. Additional receiver-operating characteristic (ROC) analysis demonstrated the high specificity and sensitivity of HR variability to distinguish between normal and high anxiety trait. These findings indicate that assessment of autonomic response in addition to freezing might be a useful indicator of the efficacy of novel anxiolytic treatments.

Physical Therapy Principles in Rehabilitation

PubMed Central

Sparto, Patrick J.

2016-01-01

The use of vestibular rehabilitation for persons with balance and vestibular disorders is used to improve function and decrease dizziness symptoms. Principles of a vestibular rehabilitation program are described including common exercises and outcome measures used to report change. A review of negative and positive predictive factors related to recovery is also provided. PMID:22027077

Demonstrating Fermat's Principle in Optics

ERIC Educational Resources Information Center

Paleiov, Orr; Pupko, Ofir; Lipson, S. G.

2011-01-01

We demonstrate Fermat's principle in optics by a simple experiment using reflection from an arbitrarily shaped one-dimensional reflector. We investigated a range of possible light paths from a lamp to a fixed slit by reflection in a curved reflector and showed by direct measurement that the paths along which light is concentrated have either…

Improvement of the boron neutron capture therapy (BNCT) by the previous administration of the histone deacetylase inhibitor sodium butyrate for the treatment of thyroid carcinoma.

PubMed

Perona, M; Rodríguez, C; Carpano, M; Thomasz, L; Nievas, S; Olivera, M; Thorp, S; Curotto, P; Pozzi, E; Kahl, S; Pisarev, M; Juvenal, G; Dagrosa, A

2013-08-01

We have shown that boron neutron capture therapy (BNCT) could be an alternative for the treatment of poorly differentiated thyroid carcinoma (PDTC). Histone deacetylase inhibitors (HDACI) like sodium butyrate (NaB) cause hyperacetylation of histone proteins and show capacity to increase the gamma irradiation effect. The purpose of these studies was to investigate the use of the NaB as a radiosensitizer of the BNCT for PDTC. Follicular thyroid carcinoma cells (WRO) and rat thyroid epithelial cells (FRTL-5) were incubated with 1 mM NaB and then treated with boronophenylalanine ¹⁰BPA (10 μg ¹⁰B ml⁻¹) + neutrons, or with 2, 4-bis (α,β-dihydroxyethyl)-deutero-porphyrin IX ¹⁰BOPP (10 μg ¹⁰B ml⁻¹) + neutrons, or with a neutron beam alone. The cells were irradiated in the thermal column facility of the RA-3 reactor (flux = (1.0 ± 0.1) × 10¹⁰ n cm⁻² s⁻¹). Cell survival decreased as a function of the physical absorbed dose in both cell lines. Moreover, the addition of NaB decreased cell survival (p < 0.05) in WRO cells incubated with both boron compounds. NaB increased the percentage of necrotic and apoptotic cells in both BNCT groups (p < 0.05). An accumulation of cells in G2/M phase at 24 h was observed for all the irradiated groups and the addition of NaB increased this percentage. Biodistribution studies of BPA (350 mg kg⁻¹ body weight) 24 h after NaB injection were performed. The in vivo studies showed that NaB treatment increases the amount of boron in the tumor at 2-h post-BPA injection (p < 0.01). We conclude that NaB could be used as a radiosensitizer for the treatment of thyroid carcinoma by BNCT.

HIV-1 maternal and infant variants show similar sensitivity to broadly neutralizing antibodies, but sensitivity varies by subtype

PubMed Central

Jennifer, Mabuka; Leslie, Goo; Maxwel, Majiwa O.; Ruth, Nduati; Julie, Overbaugh

2014-01-01

Rationale To protect against HIV infection, passively transferred and/or vaccine elicited neutralizing antibodies (NAbs) need to effectively target diverse subtypes that are transmitted globally. These variants are a limited subset of those present during chronic infection and display some unique features. In the case of mother-to-child transmission (MTCT), transmitted variants tend to be resistant to neutralization by maternal autologous NAbs. Method To investigate whether variants transmitted during MTCT are generally resistant to HIV-1 specific NAbs, 107 maternal or infant variants representing the dominant HIV-1 subtypes were tested against six recently identified HIV-1-specific broadly neutralizing monoclonal antibodies (bNAbs), NIH45-46W, VRC01, PGT128, PGT121, PG9, and PGT145. Results Infant and maternal variants did not differ in their neutralization sensitivity to individual bNAbs, nor did viruses from transmitting versus non-transmitting mothers, although there was a trend for viruses from transmitting mothers to be less sensitive overall. No single bNAb neutralized all viruses, but a combination of bNAbs that target distinct epitopes covered 100% of the variants tested. Compared to heterosexually transmitted variants, vertically transmitted variants, were significantly more sensitive to neutralization by PGT128 and PGT121 (p=0.03 in both cases) but there were no differences for the other bNAbs. Overall, subtype A variants were significantly more sensitive to NIH45-46 (p=0.04), VRC01 (p=0.002) and PGT145 (p=0.03) compared to the non-subtype A and less sensitive to PGT121 than subtype Cs (p=0.0001). Conclusion A combination of bNAbs against distinct epitopes may be needed to provide maximum coverage against viruses in different modes of transmission and diverse subtypes. PMID:23856624

Effect of low levels of aflatoxin B₁ on performance, biochemical parameters, and aflatoxin B₁ in broiler liver tissues in the presence of monensin and sodium bentonite.

PubMed

Magnoli, A P; Monge, M P; Miazzo, R D; Cavaglieri, L R; Magnoli, C E; Merkis, C I; Cristofolini, A L; Dalcero, A M; Chiacchiera, S M

2011-01-01

Aflatoxins (AF) are a major problem in broiler production and are significant economic and public health burdens worldwide. A commercial sodium bentonite (Na-B) adsorbent was used to prevent the effect of AF [50 µg of aflatoxin B₁ (AFB₁)/kg of feed] in broiler productivity, biochemical parameters, macroscopic and microscopic liver changes, and AFB₁ liver residues. The influence of Na-B (0.3%) and monensin (MON, 100 mg/kg), alone or in combination, was investigated in depth. The dietary treatments were as follows: treatment (T) 1: basal diet (B); T2: B + MON; T3: B + Na-B; T4: B + Na-B + MON; T5: B + AFB₁; T6: B + AFB₁ + Na-B + MON; T7: B + AFB₁ + MON; T8: B + AFB₁ + Na-B. Birds were fed dietary treatments for 28 d (d 18 to 46). No significant differences (P < 0.05) were observed among treatments with respect to broiler performance, biochemical parameters, or relative liver weights. With the exception of T8, all livers showed histopathological alterations, with accumulation of fat vacuoles. The normal appearance of livers from T8 showed the protective effect of Na-B against aflatoxicosis. The residual AFB₁ levels in livers from T5 to T8 ranged from 0.2 to 1.0 ng/g and were higher in livers from T6 (P < 0.05). Results of this study indicate a competition between AFB₁ and MON for adsorption sites on Na-B when feed contains low levels of the toxin, indicating a nonselective adsorption capacity of this particular Na-B. In addition, significant levels of AFB₁ in livers indicate that this determination is an important technique not only for diagnosis of aflatoxicosis in broilers, but also for quality control of avian products.

Intuitions, principles and consequences

PubMed Central

Shaw, A

2001-01-01

Some approaches to the assessment of moral intuitions are discussed. The controlled ethical trial isolates a moral issue from confounding factors and thereby clarifies what a person's intuition actually is. Casuistic reasoning from situations, where intuitions are clear, suggests or modifies principles, which can then help to make decisions in situations where intuitions are unclear. When intuitions are defended by a supporting principle, that principle can be tested by finding extreme cases, in which it is counterintuitive to follow the principle. An approach to the resolution of conflict between valid moral principles, specifically the utilitarian and justice principles, is considered. It is argued that even those who justify intuitions by a priori principles are often obliged to modify or support their principles by resort to the consideration of consequences. Key Words: Intuitions • principles • consequences • utilitarianism PMID:11233371

Bispecific Anti-HIV-1 Antibodies with Enhanced Breadth and Potency.

PubMed

Bournazos, Stylianos; Gazumyan, Anna; Seaman, Michael S; Nussenzweig, Michel C; Ravetch, Jeffrey V

2016-06-16

Broadly neutralizing antibodies (bNAbs) against the HIV-1 envelope glycoprotein (Env) suppress viremia in animal models of HIV-1 and humans. To achieve potent activity without the emergence of viral escape mutants, co-administration of different bNAbs is necessary to target distinct epitopes essential for viral fitness. Here, we report the development of bispecific anti-Env neutralizing antibodies (biNAbs) with potent activity. Synergistic activity of biNAbs was achieved by combining an engineered hinge domain of IgG3 to increase Fab domain flexibility necessary for hetero-bivalent binding to the Env trimer while retaining the functional properties of the IgG1-Fc. Compared to unmodified biNAbs, hinge domain variants exhibited substantially improved neutralization activity, with particular combinations showing evidence of synergistic neutralization potency in vitro and enhanced in vivo therapeutic activity in HIV-1-infected humanized mice. These findings suggest innovative strategies for generating biNAbs with enhanced neutralization breadth and potency, representing ideal candidate molecules for the control of HIV-1 infection. Copyright © 2016 Elsevier Inc. All rights reserved.

Quantitative analyses reveal distinct sensitivities of the capture of HIV-1 primary viruses and pseudoviruses to broadly neutralizing antibodies.

PubMed

Kim, Jiae; Jobe, Ousman; Peachman, Kristina K; Michael, Nelson L; Robb, Merlin L; Rao, Mangala; Rao, Venigalla B

2017-08-01

Development of vaccines capable of eliciting broadly neutralizing antibodies (bNAbs) is a key goal to controlling the global AIDS epidemic. To be effective, bNAbs must block the capture of HIV-1 to prevent viral acquisition and establishment of reservoirs. However, the role of bNAbs, particularly during initial exposure of primary viruses to host cells, has not been fully examined. Using a sensitive, quantitative, and high-throughput qRT-PCR assay, we found that primary viruses were captured by host cells and converted into a trypsin-resistant form in less than five minutes. We discovered, unexpectedly, that bNAbs did not block primary virus capture, although they inhibited the capture of pseudoviruses/IMCs and production of progeny viruses at 48h. Further, viruses escaped bNAb inhibition unless the bNAbs were present in the initial minutes of exposure of virus to host cells. These findings will have important implications for HIV-1 vaccine design and determination of vaccine efficacy. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Specificity characteristics of 7 commercial creatinine measurement procedures by enzymatic and Jaffe method principles.

PubMed

Greenberg, Neil; Roberts, William L; Bachmann, Lorin M; Wright, Elizabeth C; Dalton, R Neil; Zakowski, Jack J; Miller, W Greg

2012-02-01

Standardized calibration does not change a creatinine measurement procedure's susceptibility to potentially interfering substances. We obtained individual residual serum or plasma samples (n = 365) from patients with 19 different disease categories associated with potentially interfering substances and from healthy controls. Additional sera at 0.9 mg/dL (80 μmol/L) and 3.8 mg/dL (336 μmol/L) creatinine were supplemented with acetoacetate, acetone, ascorbate, and pyruvate. We measured samples by 4 enzymatic and 3 Jaffe commercially available procedures and by a liquid chromatography/isotope dilution/mass spectrometry measurement procedure against which biases were determined. The number of instances when 3 or more results in a disease category had biases greater than the limits of acceptability was 28 of 57 (49%) for Jaffe and 14 of 76 (18%) for enzymatic procedures. For the aggregate group of 59 diabetes samples with increased β-hydroxybutyrate, glucose, or glycosylated hemoglobin (Hb A(1c)), the enzymatic procedures had 10 biased results of 236 (4.2%) compared with 89 of 177 (50.3%) for the Jaffe procedures, and these interferences were highly procedure dependent. For supplemented sera, interferences were observed in 11 of 24 (46%) of groups for Jaffe and 8 of 32 (25%) of groups for enzymatic procedures and were different at low or high creatinine concentrations. There were differences in both magnitude and direction of bias among measurement procedures, whether enzymatic or Jaffe. The influence of interfering substances was less frequent with the enzymatic procedures, but no procedure was unaffected. The details of implementation of a method principle influenced its susceptibility to potential interfering substances.

Measurement of the quality factor of a new low-frequency differential accelerometer for testing the equivalence principle.

PubMed

Iafolla, V; Lefevre, C; Fiorenza, E; Santoli, F; Nozzoli, S; Magnafico, C; Lucente, M; Lucchesi, D; Peron, R; Shapiro, I I; Glashow, S; Lorenzini, E C

2014-01-01

A cryogenic differential accelerometer has been developed to test the weak equivalence principle to a few parts in 10(15) within the framework of the general relativity accuracy test in an Einstein elevator experiment. The prototype sensor was designed to identify, address, and solve the major issues associated with various aspects of the experiment. This paper illustrates the measurements conducted on this prototype sensor to attain a high quality factor (Q ∼ 10(5)) at low frequencies (<20 Hz). Such a value is necessary for reducing the Brownian noise to match the target acceleration noise of 10(-14) g/√Hz, hence providing the desired experimental accuracy.

Seroprevalence of neutralizing antibodies against adenovirus type 14 and 55 in healthy adults in Southern China

PubMed Central

Zheng, Xuehua; Rong, Xia; Feng, Ying; Sun, Xikui; Li, Liang; Wang, Qian; Wang, Min; Liu, Wenkuan; Li, Chufang; Yang, Yiyu; Zhou, Rong; Lu, Jiahai; Feng, Liqiang; Chen, Ling

2017-01-01

Re-emerging human adenovirus types 14 (Ad14) and 55 (Ad55) have caused severe respiratory diseases and even deaths during recent outbreaks. However, the seroprevalence of neutralizing antibodies (nAbs) in healthy adults, which may reflect previous circulation and help to predict potential outbreaks, remains unclear. In this study, we established micro-neutralizing (MN) assays on the basis of recombinant Ad14 and Ad55 reporter viruses, and we investigated serum nAbs in healthy blood donors from Southern China. We found that the overall seropositive rates were 24.8% and 22.4% for Ad14 and Ad55 nAbs, respectively. The seropositive rates were low in individuals younger than 20, and they gradually increased with age. Ad55-seropositive individuals tended to have high nAb titers (>1000), while low (72–200) and moderate (201–1000) nAb levels were frequently observed in Ad14-seropositive ones. Surprisingly, the seropositive rates and nAb levels were associated with the blood type but not the gender of the blood donors, with type AB individuals displaying higher seropositive rates and nAb levels. Interestingly, a significant positive correlation was observed between Ad14 and Ad55 seroprevalence, and higher titers of nAbs were detected in double-positive individuals compared to single-positive ones. These results clarified the human humoral immune responses against Ad14 and Ad55 and revealed a low level of herd immunity in some subpopulations, which emphasized the importance of monitoring these two highly virulent adenoviruses and reinforced the development of prophylactic vaccines. PMID:28588291

Sodium Benzoate, a Food Additive and a Metabolite of Cinnamon, Enriches Regulatory T Cells via STAT6-Mediated Upregulation of TGF-β.

PubMed

Kundu, Madhuchhanda; Mondal, Susanta; Roy, Avik; Martinson, Jeffrey L; Pahan, Kalipada

2016-10-15

Upregulation and/or maintenance of regulatory T cells (Tregs) during autoimmune insults may have therapeutic efficacy in autoimmune diseases. Earlier we have reported that sodium benzoate (NaB), a metabolite of cinnamon and a Food and Drug Administration-approved drug against urea cycle disorders, upregulates Tregs and protects mice from experimental allergic encephalomyelitis, an animal model of multiple sclerosis. However, mechanisms by which NaB increases Tregs are poorly understood. Because TGF-β is an important inducer of Tregs, we examined the effect of NaB on the status of TGF-β. In this study, we demonstrated that NaB induced the expression of TGF-β mRNA and protein in normal as well as proteolipid protein-primed splenocytes. The presence of a consensus STAT6 binding site in the promoter of the TGF-β gene, activation of STAT6 in splenocytes by NaB, recruitment of STAT6 to the TGF-β promoter by NaB, and abrogation of NaB-induced expression of TGF-β in splenocytes by small interfering RNA knockdown of STAT6 suggest that NaB induces the expression of TGF-β via activation of STAT6. Furthermore, we demonstrated that blocking of TGF-β by neutralizing Abs abrogated NaB-mediated protection of Tregs and experimental allergic encephalomyelitis. These studies identify a new function of NaB in upregulating TGF-β via activation of STAT6, which may be beneficial in MS patients. Copyright © 2016 by The American Association of Immunologists, Inc.

Sodium Benzoate, a Metabolite of Cinnamon and a Food Additive, Upregulates Ciliary Neurotrophic Factor in Astrocytes and Oligodendrocytes.

PubMed

Modi, Khushbu K; Jana, Malabendu; Mondal, Susanta; Pahan, Kalipada

2015-11-01

Ciliary neurotrophic factor (CNTF) is a promyelinating trophic factor that plays an important role in multiple sclerosis (MS). However, mechanisms by which CNTF expression could be increased in the brain are poorly understood. Recently we have discovered anti-inflammatory and immunomodulatory activities of sodium benzoate (NaB), a metabolite of cinnamon and a widely-used food additive. Here, we delineate that NaB is also capable of increasing the mRNA and protein expression of CNTF in primary mouse astrocytes and oligodendrocytes and primary human astrocytes. Accordingly, oral administration of NaB and cinnamon led to the upregulation of astroglial and oligodendroglial CNTF in vivo in mouse brain. Induction of experimental allergic encephalomyelitis, an animal model of MS, reduced the level of CNTF in the brain, which was restored by oral administration of cinnamon. While investigating underlying mechanisms, we observed that NaB induced the activation of protein kinase A (PKA) and H-89, an inhibitor of PKA, abrogated NaB-induced expression of CNTF. The activation of cAMP response element binding (CREB) protein by NaB, the recruitment of CREB and CREB-binding protein to the CNTF promoter by NaB and the abrogation of NaB-induced expression of CNTF in astrocytes by siRNA knockdown of CREB suggest that NaB increases the expression of CNTF via the activation of CREB. These results highlight a novel myelinogenic property of NaB and cinnamon, which may be of benefit for MS and other demyelinating disorders.

Principlism and communitarianism

PubMed Central

Callahan, D

2003-01-01

The decline in the interest in ethical theory is first outlined, as a background to the author's discussion of principlism. The author's own stance, that of a communitarian philosopher, is then described, before the subject of principlism itself is addressed. Two problems stand in the way of the author's embracing principlism: its individualistic bias and its capacity to block substantive ethical inquiry. The more serious problem the author finds to be its blocking function. Discussing the four scenarios the author finds that the utility of principlism is shown in the two scenarios about Jehovah's Witnesses but that when it comes to selling kidneys for transplantation and germline enhancement, principlism is of little help. PMID:14519838

Principlism and communitarianism.

PubMed

Callahan, D

2003-10-01

The decline in the interest in ethical theory is first outlined, as a background to the author's discussion of principlism. The author's own stance, that of a communitarian philosopher, is then described, before the subject of principlism itself is addressed. Two problems stand in the way of the author's embracing principlism: its individualistic bias and its capacity to block substantive ethical inquiry. The more serious problem the author finds to be its blocking function. Discussing the four scenarios the author finds that the utility of principlism is shown in the two scenarios about Jehovah's Witnesses but that when it comes to selling kidneys for transplantation and germline enhancement, principlism is of little help.

Dynamic sealing principles

NASA Technical Reports Server (NTRS)

Zuk, J.

1976-01-01

The fundamental principles governing dynamic sealing operation are discussed. Different seals are described in terms of these principles. Despite the large variety of detailed construction, there appear to be some basic principles, or combinations of basic principles, by which all seals function, these are presented and discussed. Theoretical and practical considerations in the application of these principles are discussed. Advantages, disadvantages, limitations, and application examples of various conventional and special seals are presented. Fundamental equations governing liquid and gas flows in thin film seals, which enable leakage calculations to be made, are also presented. Concept of flow functions, application of Reynolds lubrication equation, and nonlubrication equation flow, friction and wear; and seal lubrication regimes are explained.

The principles of measuring forest fire danger

Treesearch

H. T. Gisborne

1936-01-01

Research in fire danger measurement was commenced in 1922 at the Northern Rocky Mountain Forest and Range Experiment Station of the U. S. Forest Service, with headquarters at Missoula, Mont. Since then investigations have been made concerning ( 1) what to measure, (2) how to measure, and ( 3) field use of these measurements. In all cases the laboratory or restricted...

Selected HIV-1 Env Trimeric Formulations Act as Potent Immunogens in a Rabbit Vaccination Model

PubMed Central

Heyndrickx, Leo; Stewart-Jones, Guillaume; Jansson, Marianne; Schuitemaker, Hanneke; Bowles, Emma; Buonaguro, Luigi; Grevstad, Berit; Vinner, Lasse; Vereecken, Katleen; Parker, Joe; Ramaswamy, Meghna; Biswas, Priscilla; Vanham, Guido; Scarlatti, Gabriella; Fomsgaard, Anders

2013-01-01

Background Ten to 30% of HIV-1 infected subjects develop broadly neutralizing antibodies (bNAbs) during chronic infection. We hypothesized that immunizing rabbits with viral envelope glycoproteins (Envs) from these patients may induce bNAbs, when formulated as a trimeric protein and in the presence of an adjuvant. Methods Based on in vitro neutralizing activity in serum, patients with bNAbs were selected for cloning of their HIV-1 Env. Seven stable soluble trimeric gp140 proteins were generated from sequences derived from four adults and two children infected with either clade A or B HIV-1. From one of the clade A Envs both the monomeric and trimeric Env were produced for comparison. Rabbits were immunized with soluble gp120 or trimeric gp140 proteins in combination with the adjuvant dimethyl dioctadecyl ammonium/trehalose dibehenate (CAF01). Env binding in rabbit immune serum was determined using ELISAs based on gp120-IIIB protein. Neutralizing activity of IgG purified from rabbit immune sera was measured with the pseudovirus-TZMbl assay and a PBMC-based neutralization assay for selected experiments. Results It was initially established that gp140 trimers induce better antibody responses over gp120 monomers and that the adjuvant CAF01 was necessary for such strong responses. Gp140 trimers, based on HIV-1 variants from patients with bNAbs, were able to elicit both gp120IIIB specific IgG and NAbs to Tier 1 viruses of different subtypes. Potency of NAbs closely correlated with titers, and an gp120-binding IgG titer above a threshold of 100,000 was predictive of neutralization capability. Finally, peptide inhibition experiments showed that a large fraction of the neutralizing IgG was directed against the gp120 V3 region. Conclusions Our results indicate that the strategy of reverse immunology based on selected Env sequences is promising when immunogens are delivered as stabilized trimers in CAF01 adjuvant and that the rabbit is a valuable model for HIV vaccine studies

Selected HIV-1 Env trimeric formulations act as potent immunogens in a rabbit vaccination model.

PubMed

Heyndrickx, Leo; Stewart-Jones, Guillaume; Jansson, Marianne; Schuitemaker, Hanneke; Bowles, Emma; Buonaguro, Luigi; Grevstad, Berit; Vinner, Lasse; Vereecken, Katleen; Parker, Joe; Ramaswamy, Meghna; Biswas, Priscilla; Vanham, Guido; Scarlatti, Gabriella; Fomsgaard, Anders

2013-01-01

Ten to 30% of HIV-1 infected subjects develop broadly neutralizing antibodies (bNAbs) during chronic infection. We hypothesized that immunizing rabbits with viral envelope glycoproteins (Envs) from these patients may induce bNAbs, when formulated as a trimeric protein and in the presence of an adjuvant. Based on in vitro neutralizing activity in serum, patients with bNAbs were selected for cloning of their HIV-1 Env. Seven stable soluble trimeric gp140 proteins were generated from sequences derived from four adults and two children infected with either clade A or B HIV-1. From one of the clade A Envs both the monomeric and trimeric Env were produced for comparison. Rabbits were immunized with soluble gp120 or trimeric gp140 proteins in combination with the adjuvant dimethyl dioctadecyl ammonium/trehalose dibehenate (CAF01). Env binding in rabbit immune serum was determined using ELISAs based on gp120-IIIB protein. Neutralizing activity of IgG purified from rabbit immune sera was measured with the pseudovirus-TZMbl assay and a PBMC-based neutralization assay for selected experiments. It was initially established that gp140 trimers induce better antibody responses over gp120 monomers and that the adjuvant CAF01 was necessary for such strong responses. Gp140 trimers, based on HIV-1 variants from patients with bNAbs, were able to elicit both gp120IIIB specific IgG and NAbs to Tier 1 viruses of different subtypes. Potency of NAbs closely correlated with titers, and an gp120-binding IgG titer above a threshold of 100,000 was predictive of neutralization capability. Finally, peptide inhibition experiments showed that a large fraction of the neutralizing IgG was directed against the gp120 V3 region. Our results indicate that the strategy of reverse immunology based on selected Env sequences is promising when immunogens are delivered as stabilized trimers in CAF01 adjuvant and that the rabbit is a valuable model for HIV vaccine studies.

Equivalence principles and electromagnetism

NASA Technical Reports Server (NTRS)

Ni, W.-T.

1977-01-01

The implications of the weak equivalence principles are investigated in detail for electromagnetic systems in a general framework. In particular, it is shown that the universality of free-fall trajectories (Galileo weak equivalence principle) does not imply the validity of the Einstein equivalence principle. However, the Galileo principle plus the universality of free-fall rotation states does imply the Einstein principle.

Differential binding of neutralizing and non-neutralizing antibodies to native-like soluble HIV-1 Env trimers, uncleaved Env proteins, and monomeric subunits

PubMed Central

2014-01-01

Background The trimeric envelope glycoproteins (Env) on the surface of HIV-1 virions are the targets for neutralizing antibodies (NAbs). No candidate HIV-1 immunogen has yet induced potent, broadly active NAbs (bNAbs). Part of the explanation may be that previously tested Env proteins inadequately mimic the functional, native Env complex. Trimerization and the proteolytic processing of Env precursors into gp120 and gp41 profoundly alter antigenicity, but soluble cleaved trimers are too unstable to serve as immunogens. By introducing stabilizing mutations (SOSIP), we constructed soluble, cleaved Env trimers derived from the HIV-1 subtype A isolate BG505 that resemble native Env spikes on virions both structurally and antigenically. Results We used surface plasmon resonance (SPR) to quantify antibody binding to different forms of BG505 Env: the proteolytically cleaved SOSIP.664 trimers, cleaved gp120-gp41ECTO protomers, and gp120 monomers. Non-NAbs to the CD4-binding site bound only marginally to the trimers but equally well to gp120-gp41ECTO protomers and gp120 monomers, whereas the bNAb VRC01, directed to the CD4bs, bound to all three forms. In contrast, bNAbs to V1V2 glycan-dependent epitopes bound preferentially (PG9 and PG16) or exclusively (PGT145) to trimers. We also explored the antigenic consequences of three different features of SOSIP.664 gp140 trimers: the engineered inter-subunit disulfide bond, the trimer-stabilizing I559P change in gp41ECTO, and proteolytic cleavage at the gp120-gp41ECTO junction. Each of these three features incrementally promoted native-like trimer antigenicity. We compared Fab and IgG versions of bNAbs and validated a bivalent model of IgG binding. The NAbs showed widely divergent binding kinetics and degrees of binding to native-like BG505 SOSIP.664. High off-rate constants and low stoichiometric estimates of NAb binding were associated with large amounts of residual infectivity after NAb neutralization of the corresponding BG505.T

Silicon Isotopes doping experiments to measure quartz dissolution and precipitation rates at equilibrium and test the principle of detailed balance

NASA Astrophysics Data System (ADS)

Zhu, C.; Rimstidt, J. D.; Liu, Z.; Yuan, H.

2016-12-01

The principle of detailed balance (PDB) has been a cornerstone for irreversible thermodynamics and chemical kinetics for a long time, and its wide application in geochemistry has mostly been implicit and without experimental testing of its applicability. Nevertheless, many extrapolations based on PDB without experimental validation have far reaching impacts on society's mega environmental enterprises. Here we report an isotope doping method that independently measures simultaneous dissolution and precipitation rates and can test this principle. The technique reacts a solution enriched in a rare isotope of an element with a solid having natural isotopic abundances (Beck et al., 1992; Gaillardet, 2008; Gruber et al., 2013). Dissolution and precipitation rates are found from the changing isotopic ratios. Our quartz experiment doped with 29Si showed that the equilibrium dissolution rate remains unchanged at all degrees of undersaturation. We recommend this approach to test the validity of using the detailed balance relationship in rate equations for other substances.

Heisenberg's uncertainty principle for simultaneous measurement of positive-operator-valued measures

NASA Astrophysics Data System (ADS)

Miyadera, Takayuki; Imai, Hideki

2008-11-01

A limitation on simultaneous measurement of two arbitrary positive-operator-valued measures is discussed. In general, simultaneous measurement of two noncommutative observables is only approximately possible. Following Werner’s formulation, we introduce a distance between observables to quantify an accuracy of measurement. We derive an inequality that relates the achievable accuracy with noncommutativity between two observables. As a byproduct a necessary condition for two positive-operator-valued measures to be simultaneously measurable is obtained.

A new principle photosynthesis capacity biosensor based on quantitative measurement of delayed fluorescence in vivo.

PubMed

Wang, Junsheng; Xing, Da; Zhang, Lingrui; Jia, Li

2007-06-15

Delayed fluorescence (DF) is an excellent marker for evaluating plant photosynthesis. Compared with common methods for measuring the photosynthesis rate based on consumption of CO(2), DF technique can quantify the plant photosynthesis capacity more accurately and faster under its physiological status with less interference from the environment. We previously reported a method for measuring photosynthesis using DF of chloroplast [Wang, C.L., Xing, D., Chen, Q., 2004. Biosens. Bioelectron. 20, 454-459]. In the study, a novel fast and portable photosynthesis capacity biosensor system was developed, which was composed of light-emitting diode lattice as excitation light source, Channel Photomultiplier DC-Module to achieve DF, single-chip microcomputer as control center, hermetic dark sample chamber, battery power supply and CO(2), humidity and temperature controller. Compared with our previous work, the system was portable and can directly measure plant photosynthesis capacity in vivo in less than 10s. A database in the software to carry out data acquisition and processing was developed to translate maximal DF intensity to net photosynthesis rate (Pn). In addition, local-control and remote-control mode can be chosen in the system. To demonstrate the utility of the system, it was applied to evaluate maximum Pn of four different plant species samples (Queen Rape Myrtle (var. rubra), soybean (Lu Hei No. 1), maize (Jin Dan No. 39) and rice (Jing Dao No. 21)) in field. The results were compared with that using commercial photosynthesis system LI-6400 and the uncertainty was less than +/-5%. The new principle of photosynthesis measurement is a challenge and breakthrough to conventional method of gas exchange and may be a potential technique of next generation photosynthesis measurement.

Chemical Principles Exemplified

ERIC Educational Resources Information Center

Plumb, Robert C.

1970-01-01

This is the first of a new series of brief ancedotes about materials and phenomena which exemplify chemical principles. Examples include (1) the sea-lab experiment illustrating principles of the kinetic theory of gases, (2) snow-making machines illustrating principles of thermodynamics in gas expansions and phase changes, and (3) sunglasses that…

Stereological studies of the effects of sodium benzoate or ascorbic acid on rats` cerebellum.

PubMed

Noorafshan, Ali; Erfanizadeh, Mahboobeh; Karbalay-Doust, Saied

2014-12-01

To evaluate the cerebellar structure in sodium benzoate (NaB) or ascorbic acid (AA) treated rats. This experimental study was conducted between May and September 2013 in the Laboratory Animal Center of Shiraz University of Medical Sciences, Shiraz, Iran. The rats received distilled either water, NaB (200mg/kg/day), AA (100mg/kg/day), or NaB+AA. The hemispheres were removed after 28 days and underwent quantitative study. The total volume of the cerebellar hemisphere, its cortex, intracerebellar nuclei; the total number of the Purkinje, Bergman, granule, neurons, and glial cells of the molecular layer; and neurons and glial cells of the intracerebellar nuclei reduced by 21-52% in the NaB-treated rats compared with the distilled water group (p=0.004). The total number of the Purkinje, Bergman, Golgi, and granule cells was 29-45% higher in the AA-treated rats compared with the distilled water group (p=0.05). However, these measures reduced by 17-50% in the NaB+AA-treated rats compared with the distilled water group (p=0.004). The NaB+AA group did not induce any significant structural changes in comparison with the NaB group (p>0.05). The NaB exposure with or without AA treatment could alter the cerebellum. Yet, AA could prevent the loss of some cells in the cerebellum. 

Three Principles of Water Flow in Soils

NASA Astrophysics Data System (ADS)

Guo, L.; Lin, H.

2016-12-01

-based dynamics of water flow, and the third principle combines macroscopic and microscopic consideration to explain a mosaic-like flow regime in soils. Integration of above principles can advance flow theory, measurement, and modeling and can improve management of soil and water resources.

In Vitro Effects of Sodium Benzoate on Th1/Th2 Deviation in Patients with Multiple Sclerosis.

PubMed

Rezaei, N; Amirghofran, Z; Nikseresht, A; Ashjazade, N; Zoghi, S; Tahvili, S; Kamali-Sarvestani, E

2016-10-01

Interleukin 4 (IL-4) can improve the clinical manifestations in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Sodium benzoate (NaB) deviates the cytokine profile to Th2 (or IL-4 producing) cells in EAE and thus might be effective in the treatment of MS. Therefore, in this study the effect of different concentrations of NaB on the percentage and mRNA levels of IL-4 and interferon gamma (IFN-γ)-producing peripheral blood mononuclear cells (PBMCs) of 20 Relapsing-remitting multiple sclerosis (RR-MS) patients and eight healthy controls was evaluated in the presence of mitogen (phytohemagglutinin, PHA) or specific antigen (myelin basic protein, MBP). Our results showed that in the patient's group the percentage of CD4(+)IL-4(+) cells was significantly increased in the presence of all concentrations of NaB when PBMCs were stimulated by MBP (p = 0.001) or PHA (p < 0.03). The same results were obtained for normal donors in the highest concentration of NaB, 1000 µg/ml (p = 0.02). Moreover, in the patient's group the percentage of CD4(+)IFN-γ(+) cells was decreased significantly when the PBMCs were stimulated by PHA and NaB (p < 0.004) or by MBP and 1000 µg/ml of NaB (p < 0.03). The effect of NaB on IL-4 and IFN-γ production was also documented at the mRNA levels. In conclusion, our data suggest that NaB is able to induce IL-4 production by human PBMCs and therefore might be a useful candidate for conjunctive therapy in RR-MS.

Behavior Modification: Basic Principles. Third Edition

ERIC Educational Resources Information Center

Lee, David L.; Axelrod, Saul

2005-01-01

This classic book presents the basic principles of behavior emphasizing the use of preventive techniques as well as consequences naturally available in the home, business, or school environment to change important behaviors. This book, and its companion piece, "Measurement of Behavior," represents more than 30 years of research and strategies in…

Children acquire the later-greater principle after the cardinal principle

PubMed Central

Le Corre, Mathieu

2014-01-01

Many have proposed that the acquisition of the cardinal principle is a result of the discovery of the numerical significance of the order of the number words in the count list. However, this need not be the case. Indeed, the cardinal principle does not state anything about the numerical significance of the order of the number words. It only states that the last word of a correct count denotes the numerosity of the counted set. Here we test whether the acquisition of the cardinal principle involves the discovery of the later-greater principle – i.e., that the order of the number words corresponds to the relative size of the numerosities they denote. Specifically, we tested knowledge of verbal numerical comparisons (e.g., Is “ten” more than “six”?) in children who had recently learned the cardinal principle. We find that these children can compare number words between “six” and “ten” only if they have mapped them onto non-verbal representations of numerosity. We suggest that this means that the acquisition of the cardinal principle does not involve the discovery of the correspondence between the order of the number words and the relative size of the numerosities they denote. PMID:24372336

Adenovirus-Vectored Broadly Neutralizing Antibodies Directed Against gp120 Prevent Human Immunodeficiency Virus Type 1 Acquisition in Humanized Mice.

PubMed

Liu, Shan; Jackson, Andrew; Beloor, Jagadish; Kumar, Priti; Sutton, Richard E

2015-09-01

Despite nearly three decades of research, a safe and effective vaccine against human immunodeficiency virus type 1 (HIV-1) has yet to be achieved. More recently, the discovery of highly potent anti-gp160 broadly neutralizing antibodies (bNAbs) has garnered renewed interest in using antibody-based prophylactic and therapeutic approaches. Here, we encoded bNAbs in first-generation adenoviral (ADV) vectors, which have the distinctive features of a large coding capacity and ease of propagation. A single intramuscular injection of ADV-vectorized bNAbs in humanized mice generated high serum levels of bNAbs that provided protection against multiple repeated challenges with a high dose of HIV-1, prevented depletion of peripheral CD4(+) T cells, and reduced plasma viral loads to below detection limits. Our results suggest that ADV vectors may be a viable option for the prophylactic and perhaps therapeutic use of bNAbs in humans.

Proposed principles of maximum local entropy production.

PubMed

Ross, John; Corlan, Alexandru D; Müller, Stefan C

2012-07-12

Articles have appeared that rely on the application of some form of "maximum local entropy production principle" (MEPP). This is usually an optimization principle that is supposed to compensate for the lack of structural information and measurements about complex systems, even systems as complex and as little characterized as the whole biosphere or the atmosphere of the Earth or even of less known bodies in the solar system. We select a number of claims from a few well-known papers that advocate this principle and we show that they are in error with the help of simple examples of well-known chemical and physical systems. These erroneous interpretations can be attributed to ignoring well-established and verified theoretical results such as (1) entropy does not necessarily increase in nonisolated systems, such as "local" subsystems; (2) macroscopic systems, as described by classical physics, are in general intrinsically deterministic-there are no "choices" in their evolution to be selected by using supplementary principles; (3) macroscopic deterministic systems are predictable to the extent to which their state and structure is sufficiently well-known; usually they are not sufficiently known, and probabilistic methods need to be employed for their prediction; and (4) there is no causal relationship between the thermodynamic constraints and the kinetics of reaction systems. In conclusion, any predictions based on MEPP-like principles should not be considered scientifically founded.

Executive Financial Reporting: Seven Principles to Use in Developing Effective Reports.

ERIC Educational Resources Information Center

Jenkins, William A.; Fischer, Mary

1991-01-01

Higher education institution business officers need to follow principles of presentation, judgment, and measurement in developing effective executive financial reports. Principles include (1) keep the statement simple; (2) be consistent in reporting from year to year; (3) determine user needs and interests; (4) limit data; (5) provide trend lines;…

Precautionary Principles: General Definitions and Specific Applications to Genetically Modified Organisms

ERIC Educational Resources Information Center

Lofstedt, Ragnar E.; Fischhoff, Baruch; Fischhoff, Ilya R.

2002-01-01

Precautionary principles have been proposed as a fundamental element of sound risk management. Their advocates see them as guiding action in the face of uncertainty, encouraging the adoption of measures that reduce serious risks to health, safety, and the environment. Their opponents may reject the very idea of precautionary principles, find…

Driving Toward Guiding Principles

PubMed Central

Buckovich, Suzy A.; Rippen, Helga E.; Rozen, Michael J.

1999-01-01

As health care moves from paper to electronic data collection, providing easier access and dissemination of health information, the development of guiding privacy, confidentiality, and security principles is necessary to help balance the protection of patients' privacy interests against appropriate information access. A comparative review and analysis was done, based on a compilation of privacy, confidentiality, and security principles from many sources. Principles derived from ten identified sources were compared with each of the compiled principles to assess support level, uniformity, and inconsistencies. Of 28 compiled principles, 23 were supported by at least 50 percent of the sources. Technology could address at least 12 of the principles. Notable consistencies among the principles could provide a basis for consensus for further legislative and organizational work. It is imperative that all participants in our health care system work actively toward a viable resolution of this information privacy debate. PMID:10094065

Hidden Lineage Complexity of Glycan-Dependent HIV-1 Broadly Neutralizing Antibodies Uncovered by Digital Panning and Native-Like gp140 Trimer.

PubMed

He, Linling; Lin, Xiaohe; de Val, Natalia; Saye-Francisco, Karen L; Mann, Colin J; Augst, Ryan; Morris, Charles D; Azadnia, Parisa; Zhou, Bin; Sok, Devin; Ozorowski, Gabriel; Ward, Andrew B; Burton, Dennis R; Zhu, Jiang

2017-01-01

Germline precursors and intermediates of broadly neutralizing antibodies (bNAbs) are essential to the understanding of humoral response to HIV-1 infection and B-cell lineage vaccine design. Using a native-like gp140 trimer probe, we examined antibody libraries constructed from donor-17, the source of glycan-dependent PGT121-class bNAbs recognizing the N332 supersite on the HIV-1 envelope glycoprotein. To facilitate this analysis, a digital panning method was devised that combines biopanning of phage-displayed antibody libraries, 900 bp long-read next-generation sequencing, and heavy/light (H/L)-paired antibodyomics. In addition to single-chain variable fragments resembling the wild-type bNAbs, digital panning identified variants of PGT124 (a member of the PGT121 class) with a unique insertion in the heavy chain complementarity-determining region 1, as well as intermediates of PGT124 exhibiting notable affinity for the native-like trimer and broad HIV-1 neutralization. In a competition assay, these bNAb intermediates could effectively compete with mouse sera induced by a scaffolded BG505 gp140.681 trimer for the N332 supersite. Our study thus reveals previously unrecognized lineage complexity of the PGT121-class bNAbs and provides an array of library-derived bNAb intermediates for evaluation of immunogens containing the N332 supersite. Digital panning may prove to be a valuable tool in future studies of bNAb diversity and lineage development.

Hidden Lineage Complexity of Glycan-Dependent HIV-1 Broadly Neutralizing Antibodies Uncovered by Digital Panning and Native-Like gp140 Trimer

PubMed Central

He, Linling; Lin, Xiaohe; de Val, Natalia; Saye-Francisco, Karen L.; Mann, Colin J.; Augst, Ryan; Morris, Charles D.; Azadnia, Parisa; Zhou, Bin; Sok, Devin; Ozorowski, Gabriel; Ward, Andrew B.; Burton, Dennis R.; Zhu, Jiang

2017-01-01

Germline precursors and intermediates of broadly neutralizing antibodies (bNAbs) are essential to the understanding of humoral response to HIV-1 infection and B-cell lineage vaccine design. Using a native-like gp140 trimer probe, we examined antibody libraries constructed from donor-17, the source of glycan-dependent PGT121-class bNAbs recognizing the N332 supersite on the HIV-1 envelope glycoprotein. To facilitate this analysis, a digital panning method was devised that combines biopanning of phage-displayed antibody libraries, 900 bp long-read next-generation sequencing, and heavy/light (H/L)-paired antibodyomics. In addition to single-chain variable fragments resembling the wild-type bNAbs, digital panning identified variants of PGT124 (a member of the PGT121 class) with a unique insertion in the heavy chain complementarity-determining region 1, as well as intermediates of PGT124 exhibiting notable affinity for the native-like trimer and broad HIV-1 neutralization. In a competition assay, these bNAb intermediates could effectively compete with mouse sera induced by a scaffolded BG505 gp140.681 trimer for the N332 supersite. Our study thus reveals previously unrecognized lineage complexity of the PGT121-class bNAbs and provides an array of library-derived bNAb intermediates for evaluation of immunogens containing the N332 supersite. Digital panning may prove to be a valuable tool in future studies of bNAb diversity and lineage development. PMID:28883821

Canine distemper virus neutralization activity is low in human serum and it is sensitive to an amino acid substitution in the hemagglutinin protein

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Xinsheng, E-mail: xzhang@iavi.org; Molecular and Cellular Biology Program, State University of New York, Brooklyn, NY; Wallace, Olivia L.

Serum was analyzed from 146 healthy adult volunteers in eastern Africa to evaluate measles virus (MV) and canine distemper virus (CDV) neutralizing antibody (nAb) prevalence and potency. MV plaque reduction neutralization test (PRNT) results indicated that all sera were positive for MV nAbs. Furthermore, the 50% neutralizing dose (ND50) for the majority of sera corresponded to antibody titers induced by MV vaccination. CDV nAbs titers were low and generally were detected in sera with high MV nAb titers. A mutant CDV was generated that was less sensitive to neutralization by human serum. The mutant virus genome had 10 nucleotide substitutions,more » which coded for single amino acid substitutions in the fusion (F) and hemagglutinin (H) glycoproteins and two substitutions in the large polymerase (L) protein. The H substitution occurred in a conserved region involved in receptor interactions among morbilliviruses, implying that this region is a target for cross-reactive neutralizing antibodies. - Highlights: • Screened 146 serum samples for measles virus (MV) and canine distemper virus (CDV) neutralizing antibody (nAb). • MV nAb is prevalent in the sera. • CDV neutralizing activity is generally low or absent and when detected it is present in sera with high MV nAb titers. • A neutralization-resistant CDV mutant was isolated using human serum selection. • A mutation was identified in the receptor-binding region of CDV hemagglutinin protein that confers the neutralization resistance.« less

Principled Narrative

ERIC Educational Resources Information Center

MacBeath, John; Swaffield, Sue; Frost, David

2009-01-01

This article provides an overview of the "Carpe Vitam: Leadership for Learning" project, accounting for its provenance and purposes, before focusing on the principles for practice that constitute an important part of the project's legacy. These principles framed the dialogic process that was a dominant feature of the project and are presented,…

The natural antibody repertoire of sharks and humans recognizes the potential universe of antigens.

PubMed

Adelman, Miranda K; Schluter, Samuel F; Marchalonis, John J

2004-02-01

In ancestral sharks, a rapid emergence in the evolution of the immune system occurred, giving jawed-vertebrates the necessary components for the combinatorial immune response (CIR). To compare the natural antibody (NAb) repertoires of the most divergent vertebrates with the capacity to produce antibodies, we isolated NAbs to the same set of antigens by affinity chromatography from two species of Carcharhine sharks and from human polyclonal IgG and IgM antibody preparations. The activities of the affinity-purified anti-T-cell receptor (anti-TCR) NAbs were compared with those of monoclonal anti-TCR NAbs that were generated from a systemic lupus erythematosus patient. We report that sharks and humans, representing the evolutionary extremes of vertebrate species sharing the CIR, have NAbs to human TCRs, Igs, the human senescent cell antigen, and to numerous retroviral antigens, indicating that essential features of the combinatorial repertoire and the capacity to recognize the potential universe of antigens is shared among all jawed-vertebrates.

Recommendations for the validation of cell-based assays used for the detection of neutralizing antibody immune responses elicited against biological therapeutics.

PubMed

Gupta, Shalini; Devanarayan, Viswanath; Finco, Deborah; Gunn, George R; Kirshner, Susan; Richards, Susan; Rup, Bonita; Song, An; Subramanyam, Meena

2011-07-15

The administration of biological therapeutics may result in the development of anti-drug antibodies (ADAs) in treated subjects. In some cases, ADA responses may result in the loss of therapeutic efficacy due to the formation of neutralizing ADAs (NAbs). An important characteristic of anti-drug NAbs is their direct inhibitory effect on the pharmacological activity of the therapeutic. Neutralizing antibody responses are of particular concern for biologic products with an endogenous homolog whose activity can be potentially dampened or completely inhibited by the NAbs leading to an autoimmune-type deficiency syndrome. Therefore, it is important that ADAs are detected and characterized appropriately using sensitive and reliable methods. The design, development and optimization of cell-based assays used for detection of NAbs have been published previously by Gupta et al. 2007 [1]. This paper provides recommendations on best practices for the validation of cell-based NAb assay and suggested validation parameters based on the experience of the authors. Copyright © 2011 Elsevier B.V. All rights reserved.

Structural Constraints of Vaccine-Induced Tier-2 Autologous HIV Neutralizing Antibodies Targeting the Receptor-Binding Site.

PubMed

Bradley, Todd; Fera, Daniela; Bhiman, Jinal; Eslamizar, Leila; Lu, Xiaozhi; Anasti, Kara; Zhang, Ruijung; Sutherland, Laura L; Scearce, Richard M; Bowman, Cindy M; Stolarchuk, Christina; Lloyd, Krissey E; Parks, Robert; Eaton, Amanda; Foulger, Andrew; Nie, Xiaoyan; Karim, Salim S Abdool; Barnett, Susan; Kelsoe, Garnett; Kepler, Thomas B; Alam, S Munir; Montefiori, David C; Moody, M Anthony; Liao, Hua-Xin; Morris, Lynn; Santra, Sampa; Harrison, Stephen C; Haynes, Barton F

2016-01-05

Antibodies that neutralize autologous transmitted/founder (TF) HIV occur in most HIV-infected individuals and can evolve to neutralization breadth. Autologous neutralizing antibodies (nAbs) against neutralization-resistant (Tier-2) viruses are rarely induced by vaccination. Whereas broadly neutralizing antibody (bnAb)-HIV-Envelope structures have been defined, the structures of autologous nAbs have not. Here, we show that immunization with TF mutant Envs gp140 oligomers induced high-titer, V5-dependent plasma neutralization for a Tier-2 autologous TF evolved mutant virus. Structural analysis of autologous nAb DH427 revealed binding to V5, demonstrating the source of narrow nAb specificity and explaining the failure to acquire breadth. Thus, oligomeric TF Envs can elicit autologous nAbs to Tier-2 HIVs, but induction of bnAbs will require targeting of precursors of B cell lineages that can mature to heterologous neutralization. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Generalizing Landauer's principle

NASA Astrophysics Data System (ADS)

Maroney, O. J. E.

2009-03-01

In a recent paper [Stud. Hist. Philos. Mod. Phys. 36, 355 (2005)] it is argued that to properly understand the thermodynamics of Landauer’s principle it is necessary to extend the concept of logical operations to include indeterministic operations. Here we examine the thermodynamics of such operations in more detail, extending the work of Landauer to include indeterministic operations and to include logical states with variable entropies, temperatures, and mean energies. We derive the most general statement of Landauer’s principle and prove its universality, extending considerably the validity of previous proofs. This confirms conjectures made that all logical operations may, in principle, be performed in a thermodynamically reversible fashion, although logically irreversible operations would require special, practically rather difficult, conditions to do so. We demonstrate a physical process that can perform any computation without work requirements or heat exchange with the environment. Many widespread statements of Landauer’s principle are shown to be special cases of our generalized principle.

Potent Autologous and Heterologous Neutralizing Antibody Responses Occur in HIV-2 Infection across a Broad Range of Infection Outcomes

PubMed Central

Aasa-Chapman, Marlén; Cotten, Matthew; Hué, Stéphane; Robinson, James; Bibollet-Ruche, Frederic; Sarge-Njie, Ramu; Berry, Neil; Jaye, Assan; Aaby, Peter; Whittle, Hilton; Rowland-Jones, Sarah; Weiss, Robin

2012-01-01

Few studies have explored the role of neutralizing antibody (NAb) responses in controlling HIV-2 viremia and disease progression. Using a TZM-bl neutralization assay, we assessed heterologous and autologous NAb responses from a community cohort of HIV-2-infected individuals with a broad range of disease outcomes in rural Guinea-Bissau. All subjects (n = 40) displayed exceptionally high heterologous NAb titers (50% inhibitory plasma dilution or 50% inhibitory concentration [IC50], 1:7,000 to 1:1,000,000) against 5 novel primary HIV-2 envelopes and HIV-2 7312A, whereas ROD A and 3 primary envelopes were relatively resistant to neutralization. Most individuals also showed high autologous NAb against contemporaneous envelopes (78% of plasma-envelope combinations in 69 envelopes from 21 subjects), with IC50s above 1:10,000. No association between heterologous or autologous NAb titer and greater control of HIV-2 was found. A subset of envelopes was found to be more resistant to neutralization (by plasma and HIV-2 monoclonal antibodies). These envelopes were isolated from individuals with greater intrapatient sequence diversity and were associated with changes in potential N-linked glycosylation sites but not CD4 independence or CXCR4 use. Plasma collected from up to 15 years previously was able to potently neutralize recent autologous envelopes, suggesting a lack of escape from NAb and the persistence of neutralization-sensitive variants over time, despite significant NAb pressure. We conclude that despite the presence of broad and potent NAb responses in HIV-2-infected individuals, these are not the primary forces behind the dichotomous outcomes observed but reveal a limited capacity for adaptive selection and escape from host immunity in HIV-2 infection. PMID:22072758

The Development and Psychometric Evaluation of a Supplementary Index Score of the Neuropsychological Assessment Battery Screening Module that is Sensitive to Traumatic Brain Injury.

PubMed

Hacker, David; Jones, Christopher A; Clowes, Zoe; Belli, Antonio; Su, Zhangjie; Sitaraman, Murugan; Davies, David; Taylor, Ross; Flahive, Elizabeth; Travis, Clare; O'Neil, Nicci; Pettigrew, Yvonne

2017-03-01

This study examines the validity of the NAB Screening Module (screening module of the neuropsychological assessment battery, S-NAB) in an acute traumatic brain injury (TBI) inpatient population and provides psychometric evaluation of an original index sensitive to TBI impairment. The utility of the S-NAB as a TBI screen was examined using a between groups design. One-hundred and four patients with mild complicated to severe TBI were recruited from a consecutive cohort of patients admitted as inpatients to a UK Major Trauma Centre. Ninety-eight control participants were selected from the S-NAB normative sample. All TBI patients completed the S-NAB during their inpatient stay. Control participants scored significantly higher than TBI participants on the Total Screening index (t = 3.626, p < 0.01), The Attention index (t = 7.882, p < 0.01), and the Executive index (t = 5.577, p < 0.01). A briefer TBI Impairment index of six subtests was constructed which accurately discriminated TBI patients from normative controls (t = 9.9, p < 0.01; Cohen's d = 1.54). The TBI index had excellent classification accuracy (AUC = 0.83), superior to that of the standard S-NAB indices. The TBI Index, Attention Index, and Total Screening Index demonstrated increasing impairment with increased severity of injury. The S-NAB TBI index is a robust, reliable screening index for use with acute TBI patients, which is sensitive to the effects of acute TBI. It affords a briefer cognitive screen than the S-NAB and demonstrates a dose response relationship to TBI severity. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Cinnamon and Its Metabolite Sodium Benzoate Attenuate the Activation of p21rac and Protect Memory and Learning in an Animal Model of Alzheimer's Disease.

PubMed

Modi, Khushbu K; Roy, Avik; Brahmachari, Saurabh; Rangasamy, Suresh B; Pahan, Kalipada

2015-01-01

This study underlines the importance of cinnamon, a commonly used natural spice and flavoring material, and its metabolite sodium benzoate (NaB) in attenuating oxidative stress and protecting memory and learning in an animal model of Alzheimer's disease (AD). NaB, but not sodium formate, was found to inhibit LPS-induced production of reactive oxygen species (ROS) in mouse microglial cells. Similarly, NaB also inhibited fibrillar amyloid beta (Aβ)- and 1-methyl-4-phenylpyridinium(+)-induced microglial production of ROS. Although NaB reduced the level of cholesterol in vivo in mice, reversal of the inhibitory effect of NaB on ROS production by mevalonate, and geranylgeranyl pyrophosphate, but not cholesterol, suggests that depletion of intermediates, but not end products, of the mevalonate pathway is involved in the antioxidant effect of NaB. Furthermore, we demonstrate that an inhibitor of p21rac geranylgeranyl protein transferase suppressed the production of ROS and that NaB suppressed the activation of p21rac in microglia. As expected, marked activation of p21rac was observed in the hippocampus of subjects with AD and 5XFAD transgenic (Tg) mouse model of AD. However, oral feeding of cinnamon (Cinnamonum verum) powder and NaB suppressed the activation of p21rac and attenuated oxidative stress in the hippocampus of Tg mice as evident by decreased dihydroethidium (DHE) and nitrotyrosine staining, reduced homocysteine level and increased level of reduced glutathione. This was accompanied by suppression of neuronal apoptosis, inhibition of glial activation, and reduction of Aβ burden in the hippocampus and protection of memory and learning in transgenic mice. Therefore, cinnamon powder may be a promising natural supplement in halting or delaying the progression of AD.

TBCRC 019: A Phase II Trial of Nanoparticle Albumin-Bound Paclitaxel with or without the Anti-Death Receptor 5 Monoclonal Antibody Tigatuzumab in Patients with Triple-Negative Breast Cancer.

PubMed

Forero-Torres, Andres; Varley, Katherine E; Abramson, Vandana G; Li, Yufeng; Vaklavas, Christos; Lin, Nancy U; Liu, Minetta C; Rugo, Hope S; Nanda, Rita; Storniolo, Anna M; Traina, Tiffany A; Patil, Sujata; Van Poznak, Catherine H; Nangia, Julie R; Irvin, William J; Krontiras, Helen; De Los Santos, Jennifer F; Haluska, Paul; Grizzle, William; Myers, Richard M; Wolff, Antonio C

2015-06-15

Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5(+) human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4-5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation. ©2015 American Association for Cancer Research.

Module Cluster: TTP-001.00 (GSC) Reinforcement Principles for Classroom Use.

ERIC Educational Resources Information Center

Brent, George

The purpose of this module cluster is to enable students to define the basic operant terms, to state the basic operant principles, to read operant measurement charts, and to use operant principles in elementary classrooms with both social and academic behaviors. It is intended for use by teacher education students with the cooperation of an…

The effect of perceptual reasoning abilities on confrontation naming performance: An examination of three naming tests.

PubMed

Soble, Jason R; Marceaux, Janice C; Galindo, Juliette; Sordahl, Jeffrey A; Highsmith, Jonathan M; O'Rourke, Justin J F; González, David Andrés; Critchfield, Edan A; McCoy, Karin J M

2016-01-01

Confrontation naming tests are a common neuropsychological method of assessing language and a critical diagnostic tool in identifying certain neurodegenerative diseases; however, there is limited literature examining the visual-perceptual demands of these tasks. This study investigated the effect of perceptual reasoning abilities on three confrontation naming tests, the Boston Naming Test (BNT), Neuropsychological Assessment Battery (NAB) Naming Test, and Visual Naming Test (VNT) to elucidate the diverse cognitive functions underlying these tasks to assist with test selection procedures and increase diagnostic accuracy. A mixed clinical sample of 121 veterans were administered the BNT, NAB, VNT, and Wechsler Adult Intelligence Scale-4th Edition (WAIS-IV) Verbal Comprehension Index (VCI) and Perceptual Reasoning Index (PRI) as part of a comprehensive neuropsychological evaluation. Multiple regression indicated that PRI accounted for 23%, 13%, and 15% of the variance in BNT, VNT, and NAB scores, respectively, but dropped out as a significant predictor once VCI was added. Follow-up bootstrap mediation analyses revealed that PRI had a significant indirect effect on naming performance after controlling education, primary language, and severity of cognitive impairment, as well as the mediating effect of general verbal abilities for the BNT (B = 0.13; 95% confidence interval, CI [.07, .20]), VNT (B = 0.01; 95% CI [.002, .03]), and NAB (B = 0.03; 95% CI [.01, .06]). Findings revealed a complex relationship between perceptual reasoning abilities and confrontation naming that is mediated by general verbal abilities. However, when verbal abilities were statistically controlled, perceptual reasoning abilities were found to have a significant indirect effect on performance across all three confrontation naming measures with the largest effect noted with the BNT relative to the VNT and NAB Naming Test.

Interference of the Histone Deacetylase Inhibits Pollen Germination and Pollen Tube Growth in Picea wilsonii Mast

PubMed Central

Zhou, Junhui; Li, Xiaojuan

2015-01-01

Histone deacetylase (HDAC) is a crucial component in the regulation of gene expression in various cellular processes in animal and plant cells. HDAC has been reported to play a role in embryogenesis. However, the effect of HDAC on androgamete development remains unclear, especially in gymnosperms. In this study, we used the HDAC inhibitors trichostatin A (TSA) and sodium butyrate (NaB) to examine the role of HDAC in Picea wilsonii pollen germination and pollen tube elongation. Measurements of the tip-focused Ca2+ gradient revealed that TSA and NaB influenced this gradient. Immunofluorescence showed that actin filaments were disrupted into disorganized fragments. As a result, the vesicle trafficking was disturbed, as determined by FM4-64 labeling. Moreover, the distribution of pectins and callose in cell walls was significantly altered in response to TSA and NaB. Our results suggest that HDAC affects pollen germination and polarized pollen tube growth in Picea wilsonii by affecting the intracellular Ca2+ concentration gradient, actin organization patterns, vesicle trafficking, as well as the deposition and configuration of cell wall components. PMID:26710276

Protective immunity and lack of histopathological damage two years after DNA vaccination against infectious hematopoietic necrosis virus in trout

USGS Publications Warehouse

Kurath, Gael; Garver, Kyle A.; Corbeil, Serge; Elliott, Diane G.; Anderson, Eric D.; LaPatra, Scott E.

2006-01-01

The DNA vaccine pIHNw-G encodes the glycoprotein of the fish rhabdovirus infectious hematopoietic necrosis virus (IHNV). Vaccine performance in rainbow trout was measured 3, 6, 13, 24, and 25 months after vaccination. At three months all fish vaccinated with 0.1 μg pIHNw-G had detectable neutralizing antibody (NAb) and they were completely protected from lethal IHNV challenge with a relative percent survival (RPS) of 100% compared to control fish. Viral challenges at 6, 13, 24, and 25 months post-vaccination showed protection with RPS values of 47–69%, while NAb seroprevalence declined to undetectable levels. Passive transfer experiments with sera from fish after two years post-vaccination were inconsistent but significant protection was observed in some cases. The long-term duration of protection observed here defined a third temporal phase in the immune response to IHNV DNA vaccination, characterized by reduced but significant levels of protection, and decline or absence of detectable NAb titers. Examination of multiple tissues showed an absence of detectable long-term histopathological damage due to DNA vaccination.

The genetic difference principle.

PubMed

Farrelly, Colin

2004-01-01

In the newly emerging debates about genetics and justice three distinct principles have begun to emerge concerning what the distributive aim of genetic interventions should be. These principles are: genetic equality, a genetic decent minimum, and the genetic difference principle. In this paper, I examine the rationale of each of these principles and argue that genetic equality and a genetic decent minimum are ill-equipped to tackle what I call the currency problem and the problem of weight. The genetic difference principle is the most promising of the three principles and I develop this principle so that it takes seriously the concerns of just health care and distributive justice in general. Given the strains on public funds for other important social programmes, the costs of pursuing genetic interventions and the nature of genetic interventions, I conclude that a more lax interpretation of the genetic difference principle is appropriate. This interpretation stipulates that genetic inequalities should be arranged so that they are to the greatest reasonable benefit of the least advantaged. Such a proposal is consistent with prioritarianism and provides some practical guidance for non-ideal societies--that is, societies that do not have the endless amount of resources needed to satisfy every requirement of justice.

Smoking and risk of treatment-induced neutralizing antibodies to interferon β-1a.

PubMed

Hedström, Anna Karin; Ryner, Malin; Fink, Katarina; Fogdell-Hahn, Anna; Alfredsson, Lars; Olsson, Tomas; Hillert, Jan

2014-04-01

Neutralizing antibodies (NAbs) to interferon β (IFNβ) products that develop during treatment are associated with a loss of clinical efficacy. The aim of this study was to investigate the influence of smoking habits on the risk of developing NAbs to IFNβ, in the treatment of multiple sclerosis (MS). This report is based on 695 MS patients treated with IFNβ-1a, included in two Swedish case-control studies that collected information on smoking habits. Using logistic regression, the development of NAbs to IFNβ-1a among current smokers was compared with that of non-smokers, by calculating the odds ratio (OR) with a 95% confidence interval (CI). Current smokers showed an increased risk of developing NAbs to IFNβ-1a, compared with non-smokers (OR 1.9; 95% CI 1.3-2.8; p = 0.002). There were no gender differences. We observed no association between past smoking and the risk of developing NAbs to IFNβ-1a. The finding that current smokers have an increased risk of developing NAbs to IFNβ-1a has implications, both for the practical care and the treatment of MS; it also provides an interesting perspective of the lungs as an immune-reactive organ, reacting upon irritation.

Ascorbic acid and sodium benzoate synergistically aggravates testicular dysfunction in adult Wistar rats.

PubMed

Kehinde, Olaniyi S; Christianah, Oyewopo I; Oyetunji, Oyewopo A

2018-01-01

The effect of the concomitant use of sodium benzoate (NaB) and ascorbic acid on human health remains controversial. Therefore, the current study is designed to investigate the effect of NaB and ascorbic acid on the testicular function of adult Wistar rats. Adult Wistar rats were randomly allotted into Control (vehicle; received 1 ml of distilled water), NaB-treated (SB-treated; received 100 mg/kg body weight; b.w ), ascorbic acid-treated (AA-treated; received 150 mg/kg b.w ) and NaB+ ascorbic acid-treated (SB+AA-treated) groups. The treatment lasted for 28 days and the administration was given orally. The body weight change was monitored. Semen analysis, biochemical assay and histological examination were performed. Treatment with NaB significantly altered the cytoarchitecture of testicular tissue, sperm quality, testicular endocrine function and oxidative stress status without any alteration in body weight gain compared to control. In addition, treatment with NaB+ ascorbic acid exacerbated testicular tissue disruption, impaired sperm quality and testicular endocrine impairment with significant reduction in oxidative stress and unaltered body weight gain when compared with NaB-treated group. This study suggests that ascorbic acid and NaB synergistically aggravates testicular dysfunction. This is independent of oxidative stress status.

B-1 Cell Immunoglobulin Directed Against Oxidation-Specific Epitopes

PubMed Central

Tsiantoulas, Dimitrios; Gruber, Sabrina; Binder, Christoph J.

2013-01-01

Natural antibodies (NAbs) are pre-existing antibodies with germline origin that arise in the absence of previous exposure to foreign antigens. NAbs are produced by B-1 lymphocytes and are primarily of the IgM isotype. There is accumulating evidence that – in addition to their role in antimicrobial host defense – NAbs exhibit important housekeeping functions by facilitating the non-immunogenic clearance of apoptotic cells as well as the removal of (neo-)self antigens. These properties are largely mediated by the ability of NAbs to recognize highly conserved and endogenously generated structures, which are exemplified by so-called oxidation-specific epitopes (OSEs) that are products of lipid peroxidation. The generation of OSEs as well as their interaction with the immune system have been studied extensively in the context of atherosclerosis, a chronic inflammatory disease of the vascular wall that is characterized by the accumulation of cellular debris and oxidized low-density lipoproteins (OxLDL). Both apoptotic cells as well as OxLDL carry OSEs that are targeted by NAbs. Therefore, OSEs represent stress-induced neo self-structures that mediate recognition of metabolic waste (e.g., cellular debris) by NAbs, allowing its safe disposal, which has fundamental implications in health and disease. PMID:23316200

The principle of finiteness - a guideline for physical laws

NASA Astrophysics Data System (ADS)

Sternlieb, Abraham

2013-04-01

I propose a new principle in physics-the principle of finiteness (FP). It stems from the definition of physics as a science that deals with measurable dimensional physical quantities. Since measurement results including their errors, are always finite, FP postulates that the mathematical formulation of legitimate laws in physics should prevent exactly zero or infinite solutions. I propose finiteness as a postulate, as opposed to a statement whose validity has to be corroborated by, or derived theoretically or experimentally from other facts, theories or principles. Some consequences of FP are discussed, first in general, and then more specifically in the fields of special relativity, quantum mechanics, and quantum gravity. The corrected Lorentz transformations include an additional translation term depending on the minimum length epsilon. The relativistic gamma is replaced by a corrected gamma, that is finite for v=c. To comply with FP, physical laws should include the relevant extremum finite values in their mathematical formulation. An important prediction of FP is that there is a maximum attainable relativistic mass/energy which is the same for all subatomic particles, meaning that there is a maximum theoretical value for cosmic rays energy. The Generalized Uncertainty Principle required by Quantum Gravity is actually a necessary consequence of FP at Planck's scale. Therefore, FP may possibly contribute to the axiomatic foundation of Quantum Gravity.

Meta-Analyses of Seven of NIDA’s Principles of Drug Addiction Treatment

PubMed Central

Pearson, Frank S.; Prendergast, Michael L.; Podus, Deborah; Vazan, Peter; Greenwell, Lisa; Hamilton, Zachary

2011-01-01

Seven of the 13 Principles of Drug Addiction Treatment disseminated by the National Institute on Drug Abuse (NIDA) were meta-analyzed as part of the Evidence-based Principles of Treatment (EPT) project. By averaging outcomes over the diverse programs included in EPT, we found that five of the NIDA principles examined are supported: matching treatment to the client’s needs; attending to the multiple needs of clients; behavioral counseling interventions; treatment plan reassessment; and counseling to reduce risk of HIV. Two of the NIDA principles are not supported: remaining in treatment for an adequate period of time and frequency of testing for drug use. These weak effects could be the result of the principles being stated too generally to apply to the diverse interventions and programs that exist or of unmeasured moderator variables being confounded with the moderators that measured the principles. Meta-analysis should be a standard tool for developing principles of effective treatment for substance use disorders. PMID:22119178

Core principles of evolutionary medicine

PubMed Central

Grunspan, Daniel Z; Nesse, Randolph M; Barnes, M Elizabeth; Brownell, Sara E

2018-01-01

Abstract Background and objectives Evolutionary medicine is a rapidly growing field that uses the principles of evolutionary biology to better understand, prevent and treat disease, and that uses studies of disease to advance basic knowledge in evolutionary biology. Over-arching principles of evolutionary medicine have been described in publications, but our study is the first to systematically elicit core principles from a diverse panel of experts in evolutionary medicine. These principles should be useful to advance recent recommendations made by The Association of American Medical Colleges and the Howard Hughes Medical Institute to make evolutionary thinking a core competency for pre-medical education. Methodology The Delphi method was used to elicit and validate a list of core principles for evolutionary medicine. The study included four surveys administered in sequence to 56 expert panelists. The initial open-ended survey created a list of possible core principles; the three subsequent surveys winnowed the list and assessed the accuracy and importance of each principle. Results Fourteen core principles elicited at least 80% of the panelists to agree or strongly agree that they were important core principles for evolutionary medicine. These principles over-lapped with concepts discussed in other articles discussing key concepts in evolutionary medicine. Conclusions and implications This set of core principles will be helpful for researchers and instructors in evolutionary medicine. We recommend that evolutionary medicine instructors use the list of core principles to construct learning goals. Evolutionary medicine is a young field, so this list of core principles will likely change as the field develops further. PMID:29493660

Nanoparticle albumin-bound paclitaxel as neoadjuvant chemotherapy of breast cancer: a systematic review and meta-analysis.

PubMed

Zong, Yu; Wu, Jiayi; Shen, Kunwei

2017-03-07

The value of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) in neoadjuvant systemic therapy for breast cancer remains uncertain. Both electronic databases and proceedings of oncologic meetings were included in systematic literature search. Pooled rates of pathological complete response (pCR), odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using fixed-effect or random-effect model to determine the effect of neoadjuvant nab-paclitaxel. Twenty-one studies with 2357 patients were included, 3 of which were randomized clinical trials. The aggregate pCR(ypT0/is ypN0) rate was 32% (95% CI 25-38%) in unselected breast cancer patients and variated in different subtypes. Within randomized clinical trials, the probability of achieving pCR was significantly higher in the nab-paclitaxel group than in the conventional taxanes group (OR = 1.383, 95%CI 1.141-1.676, p = 0.001). For non-hematological toxic effect, any grade and grade 3-4 peripheral sensory neuropathy occurred more frequently with nab-paclitaxel compared to paclitaxel (any grade, OR = 2.090, 95%CI 1.016-4.302, p = 0.045; grade3-4, OR = 3.766, 95%CI 2.324-6.100, p < 0.001). Hypersensitivity was more common with paclitaxel than nab-paclitaxel at any grade and grade 3-4. nab-paclitaxel is an effective cytotoxic drug in neoadjuvant treatment of breast cancer, especially for aggressive tumors in terms of pCR. Exchange of nab-paclitaxel for conventional taxanes could significantly improve pCR rate with reasonable toxicities.

Characterization of broadly neutralizing antibody responses to HIV-1 in a cohort of long term non-progressors.

PubMed

González, Nuria; McKee, Krisha; Lynch, Rebecca M; Georgiev, Ivelin S; Jimenez, Laura; Grau, Eulalia; Yuste, Eloísa; Kwong, Peter D; Mascola, John R; Alcamí, José

2018-01-01

Only a small fraction of HIV-1-infected patients develop broadly neutralizing antibodies (bNAbs), a process generally associated to chronic antigen stimulation. It has been described that rare aviremic HIV-1-infected patients can generate bNAbs but this issue remains controversial. To address this matter we have assessed bNAb responses in a large cohort of long-term non-progressors (LTNPs) with low or undetectable viremia. Samples from the LTNP cohort of the Spanish AIDS Research Network (87 elite and 42 viremic controllers) and a control population of 176 viremic typical-progressors (TPs) were screened for bNAbs using Env-recombinant viruses. bNAb specificities were studied by ELISA using mutated gp120, neutralization assays with mutated viruses, and peptide competition. Epitope specificities were also elucidated from the serum pattern of neutralization against a panel of diverse HIV-1 isolates. Broadly neutralizing sera were found among 9.3% LTNPs, both elite (7%) and viremic controllers (14%). Within the broadly neutralizing sera, CD4 binding site antibodies were detected by ELISA in 4/12 LTNPs (33%), and 16/33 of TPs (48%). Anti-MPER antibodies were detected in 6/12 LTNPs (50%) and 14/33 TPs (42%) whereas glycan-dependent HIV-1 bNAbs were more frequent in LTNPs (11/12, 92%) as compared to TPs (12/33, 36%). A good concordance between standard serum mapping and neutralization-based mapping was observed. LTNPs, both viremic and elite controllers, showed broad humoral immune responses against HIV-1, including activity against many major epitopes involved in bNAbs-mediated protection.

Novel Polymyxin Derivatives Carrying Only Three Positive Charges Are Effective Antibacterial Agents ▿

PubMed Central

Vaara, Martti; Fox, John; Loidl, Günther; Siikanen, Osmo; Apajalahti, Juha; Hansen, Frank; Frimodt-Møller, Niels; Nagai, Junya; Takano, Mikihisa; Vaara, Timo

2008-01-01

The lack of novel antibiotics against gram-negative bacteria has reinstated polymyxins as the drugs of last resort to treat serious infections caused by extremely multiresistant gram-negative organisms. However, polymyxins are nephrotoxic, and this feature may complicate therapy or even require its discontinuation. Like that of aminoglycosides, the nephrotoxicity of polymyxins might be related to the highly cationic nature of the molecule. Colistin and polymyxin B carry five positive charges. Here we show that novel polymyxin derivatives carrying only three positive charges are effective antibacterial agents. NAB739 has a cyclic peptide portion identical to that of polymyxin B, but in the linear portion of the peptide, it carries the threonyl-d-serinyl residue (no cationic charges) instead of the diaminobutyryl-threonyl-diaminobutyryl residue (two cationic charges). The MICs of NAB739 for 17 strains of Escherichia coli were identical, or very close, to those of polymyxin B. Furthermore, NAB739 was effective against other polymyxin-susceptible strains of Enterobacteriaceae and against Acinetobacter baumannii. At subinhibitory concentrations, it dramatically sensitized A. baumannii to low concentrations of antibiotics such as rifampin, clarithromycin, vancomycin, fusidic acid, and meropenem. NAB739 methanesulfonate was a prodrug analogous to colistin methanesulfonate. NAB740 was the most active derivative against Pseudomonas aeruginosa. NAB7061 (linear portion of the peptide, threonyl-aminobutyryl) lacked direct antibacterial activity but sensitized the targets to hydrophobic antibiotics by factors up to 2,000. The affinities of the NAB compounds for isolated rat kidney brush border membrane were significantly lower than that of polymyxin B. PMID:18591267

The Basic Principles and Methods of the System Approach to Compression of Telemetry Data

NASA Astrophysics Data System (ADS)

Levenets, A. V.

2018-01-01

The task of data compressing of measurement data is still urgent for information-measurement systems. In paper the basic principles necessary for designing of highly effective systems of compression of telemetric information are offered. A basis of the offered principles is representation of a telemetric frame as whole information space where we can find of existing correlation. The methods of data transformation and compressing algorithms realizing the offered principles are described. The compression ratio for offered compression algorithm is about 1.8 times higher, than for a classic algorithm. Thus, results of a research of methods and algorithms showing their good perspectives.

Chemical Principls Exemplified

ERIC Educational Resources Information Center

Plumb, Robert C.

1973-01-01

Two topics are discussed: (1) Stomach Upset Caused by Aspirin, illustrating principles of acid-base equilibrium and solubility; (2) Physical Chemistry of the Drinking Duck, illustrating principles of phase equilibria and thermodynamics. (DF)

The Holographic Principle and the Emergence of Spacetime

NASA Astrophysics Data System (ADS)

Rosenhaus, Vladimir

Results within string theory and quantum gravity suggest that spacetime is not fundamental but rather emergent, with the fundamental degrees of freedom living on a boundary surface of one lower dimension than the bulk. This thesis is devoted to studying the holographic principle and its realization for spacetimes with both negative and positive cosmological constant. The holographic principle is most explicitly realized in the context of the AdS/CFT correspondence. We examine the extent to which AdS/CFT realizes the holographic principle and study the UV/IR relation. We study aspects of how bulk locality emerges within AdS/CFT. To this effect, we study how to reconstruct the bulk from boundary data. We study how such a reconstruction procedure is sensitive to large changes in the bulk geometry. We study if it is possible to reconstruct a subset of the bulk from a subset of the boundary data. We explore both local and nonlocal CFT quantities as probes of the bulk. One nonlocal quantity is entanglement entropy, and to this effect we construct a framework for computing entanglement entropy within the field theory. The most ambitious application of the holographic principle would be finding the holographic dual to the multiverse. We investigate properties of this putative duality. We extend the UV/IR relation of AdS/CFT to the multiverse, with the UV cutoff of the theory on future infinity being dual to a late time cutoff (measure) in the bulk. We compare various measure proposals and examine their predictions.

Hepatitis C virus resistance to broadly neutralizing antibodies measured using replication-competent virus and pseudoparticles

PubMed Central

Wasilewski, Lisa N.; Ray, Stuart C.

2016-01-01

A better understanding of natural variation in neutralization resistance and fitness of diverse hepatitis C virus (HCV) envelope (E1E2) variants will be critical to guide rational development of an HCV vaccine. This work has been hindered by inadequate genetic diversity in viral panels and by a lack of standardization of HCV entry assays. Neutralization assays generally use lentiviral pseudoparticles expressing HCV envelope proteins (HCVpp) or chimeric full-length viruses that are replication competent in cell culture (HCVcc). There have been few systematic comparisons of specific infectivities of E1E2-matched HCVcc and HCVpp, and to our knowledge, neutralization of E1E2-matched HCVpp and HCVcc has never been compared using a diverse panel of human broadly neutralizing monoclonal antibodies (bNAbs) targeting distinct epitopes. Here, we describe an efficient method for introduction of naturally occurring E1E2 genes into a full-length HCV genome, producing replication-competent chimeric HCVcc. We generated diverse panels of E1E2-matched HCVcc and HCVpp and measured the entry-mediating fitness of E1E2 variants using the two systems. We also compared neutralization of E1E2-matched HCVcc and HCVpp by a diverse panel of human bNAbs targeting epitopes across E1E2. We found no correlation between specific infectivities of E1E2-matched HCVcc versus HCVpp, but found a very strong positive correlation between relative neutralization resistance of these same E1E2-matched HCVcc and HCVpp variants. These results suggest that quantitative comparisons of neutralization resistance of E1E2 variants can be made with confidence using either HCVcc or HCVpp, allowing the use of either or both systems to maximize diversity of neutralization panels. PMID:27667373

Hepatitis C virus resistance to broadly neutralizing antibodies measured using replication-competent virus and pseudoparticles.

PubMed

Wasilewski, Lisa N; Ray, Stuart C; Bailey, Justin R

2016-11-01

A better understanding of natural variation in neutralization resistance and fitness of diverse hepatitis C virus (HCV) envelope (E1E2) variants will be critical to guide rational development of an HCV vaccine. This work has been hindered by inadequate genetic diversity in viral panels and by a lack of standardization of HCV entry assays. Neutralization assays generally use lentiviral pseudoparticles expressing HCV envelope proteins (HCVpp) or chimeric full-length viruses that are replication competent in cell culture (HCVcc). There have been few systematic comparisons of specific infectivities of E1E2-matched HCVcc and HCVpp, and to our knowledge, neutralization of E1E2-matched HCVpp and HCVcc has never been compared using a diverse panel of human broadly neutralizing monoclonal antibodies (bNAbs) targeting distinct epitopes. Here, we describe an efficient method for introduction of naturally occurring E1E2 genes into a full-length HCV genome, producing replication-competent chimeric HCVcc. We generated diverse panels of E1E2-matched HCVcc and HCVpp and measured the entry-mediating fitness of E1E2 variants using the two systems. We also compared neutralization of E1E2-matched HCVcc and HCVpp by a diverse panel of human bNAbs targeting epitopes across E1E2. We found no correlation between specific infectivities of E1E2-matched HCVcc versus HCVpp, but found a very strong positive correlation between relative neutralization resistance of these same E1E2-matched HCVcc and HCVpp variants. These results suggest that quantitative comparisons of neutralization resistance of E1E2 variants can be made with confidence using either HCVcc or HCVpp, allowing the use of either or both systems to maximize diversity of neutralization panels.

Measurement standards for interdisciplinary medical rehabilitation.

PubMed

Johnston, M V; Keith, R A; Hinderer, S R

1992-12-01

Rehabilitation must address problems inherent in the measurement of human function and health-related quality of life, as well as problems in diagnosis and measurement of impairment. This educational document presents an initial set of standards to be used as guidelines for development and use of measurement and evaluation procedures and instruments for interdisciplinary, health-related rehabilitation. Part I covers general measurement principles and technical standards, beginning with validity, the central consideration for use of measures. Subsequent sections focus on reliability and errors of measurement, norms and scaling, development of measures, and technical manuals and guides. Part II covers principles and standards for use of measures. General principles of application of measures in practice are discussed first, followed by standards to protect persons being measured and then by standards for administrative applications. Many explanations, examples, and references are provided to help professionals understand measurement principles. Improved measurement will ensure the basis of rehabilitation as a science and nourish its success as a clinical service.

Infection with novel respiratory syncytial virus genotype Ontario (ON1) in adult hematopoietic cell transplant recipients, Texas, 2011-2013.

PubMed

Avadhanula, Vasanthi; Chemaly, Roy F; Shah, Dimpy P; Ghantoji, Shashank S; Azzi, Jacques M; Aideyan, Letisha O; Mei, Minghua; Piedra, Pedro A

2015-02-15

Respiratory syncytial virus (RSV) can cause severe respiratory disease in adult hematopoietic cell transplant (HCT) recipients. RSV subgroups A and B have evolved into multiple genotypes. We report on a recently described RSV genotype (ON1) in a cohort of adult HCT recipients in Texas. Twenty adult HCT recipients were enrolled as a part of an efficacy trial of ribavirin therapy. RSV identification and genotyping was performed using molecular techniques. RSV-specific neutralizing antibody (NAb) responses were measured. ON1 genotype was detected in 3 of 6 patients in the 2011-2012 season and in 8 of 14 patients in 2012-2013 season. Other genotypes detected were NA1 and BA. NAb levels were low at enrollment. Eight of 9 patients who cleared the RSV infection within 2 weeks mounted a ≥4-fold NAb response, compared with 2 of 8 who shed the virus for >2 weeks. The clinical course of those infected with ON1 was comparable to the course for individuals infected with other genotypes. This is the first report of RSV ON1 genotype in the United States, and ON1 genotype was dominant genotype in adult HCT recipients. Interestingly, faster viral clearance was associated with a ≥4-fold NAb response, likely indicating a reconstituted immune system. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Dengue-Immune Humans Have Higher Levels of Complement-Independent Enhancing Antibody than Complement-Dependent Neutralizing Antibody.

PubMed

Yamanaka, Atsushi; Konishi, Eiji

2017-09-25

Dengue is the most important arboviral disease worldwide. We previously reported that most inhabitants of dengue-endemic countries who are naturally immune to the disease have infection-enhancing antibodies whose in vitro activity does not decrease in the presence of complement (complement-independent enhancing antibodies, or CiEAb). Here, we compared levels of CiEAb and complement-dependent neutralizing antibodies (CdNAb) in dengue-immune humans. A typical antibody dose-response pattern obtained in our assay system to measure the balance between neutralizing and enhancing antibodies showed both neutralizing and enhancing activities depending on serum dilution factor. The addition of complement to the assay system increased the activity of neutralizing antibodies at lower dilutions, indicating the presence of CdNAb. In contrast, similar dose-response curves were obtained with and without complement at higher dilutions, indicating higher levels of CiEAb than CdNAb. For experimental support for the higher CiEAb levels, a cocktail of mouse monoclonal antibodies against dengue virus type 1 was prepared. The antibody dose-response curves obtained in this assay, with or without complement, were similar to those obtained with human serum samples when a high proportion of D1-V-3H12 (an antibody exhibiting only enhancing activity and thus a model for CiEAb) was used in the cocktail. This study revealed higher-level induction of CiEAb than CdNAb in humans naturally infected with dengue viruses.

Lorentz invariance violation and generalized uncertainty principle

NASA Astrophysics Data System (ADS)

Tawfik, Abdel Nasser; Magdy, H.; Ali, A. Farag

2016-01-01

There are several theoretical indications that the quantum gravity approaches may have predictions for a minimal measurable length, and a maximal observable momentum and throughout a generalization for Heisenberg uncertainty principle. The generalized uncertainty principle (GUP) is based on a momentum-dependent modification in the standard dispersion relation which is conjectured to violate the principle of Lorentz invariance. From the resulting Hamiltonian, the velocity and time of flight of relativistic distant particles at Planck energy can be derived. A first comparison is made with recent observations for Hubble parameter in redshift-dependence in early-type galaxies. We find that LIV has two types of contributions to the time of flight delay Δ t comparable with that observations. Although the wrong OPERA measurement on faster-than-light muon neutrino anomaly, Δ t, and the relative change in the speed of muon neutrino Δ v in dependence on redshift z turn to be wrong, we utilize its main features to estimate Δ v. Accordingly, the results could not be interpreted as LIV. A third comparison is made with the ultra high-energy cosmic rays (UHECR). It is found that an essential ingredient of the approach combining string theory, loop quantum gravity, black hole physics and doubly spacial relativity and the one assuming a perturbative departure from exact Lorentz invariance. Fixing the sensitivity factor and its energy dependence are essential inputs for a reliable confronting of our calculations to UHECR. The sensitivity factor is related to the special time of flight delay and the time structure of the signal. Furthermore, the upper and lower bounds to the parameter, a that characterizes the generalized uncertainly principle, have to be fixed in related physical systems such as the gamma rays bursts.

The FAIR Guiding Principles for scientific data management and stewardship

PubMed Central

Wilkinson, Mark D.; Dumontier, Michel; Aalbersberg, IJsbrand Jan; Appleton, Gabrielle; Axton, Myles; Baak, Arie; Blomberg, Niklas; Boiten, Jan-Willem; da Silva Santos, Luiz Bonino; Bourne, Philip E.; Bouwman, Jildau; Brookes, Anthony J.; Clark, Tim; Crosas, Mercè; Dillo, Ingrid; Dumon, Olivier; Edmunds, Scott; Evelo, Chris T.; Finkers, Richard; Gonzalez-Beltran, Alejandra; Gray, Alasdair J.G.; Groth, Paul; Goble, Carole; Grethe, Jeffrey S.; Heringa, Jaap; ’t Hoen, Peter A.C; Hooft, Rob; Kuhn, Tobias; Kok, Ruben; Kok, Joost; Lusher, Scott J.; Martone, Maryann E.; Mons, Albert; Packer, Abel L.; Persson, Bengt; Rocca-Serra, Philippe; Roos, Marco; van Schaik, Rene; Sansone, Susanna-Assunta; Schultes, Erik; Sengstag, Thierry; Slater, Ted; Strawn, George; Swertz, Morris A.; Thompson, Mark; van der Lei, Johan; van Mulligen, Erik; Velterop, Jan; Waagmeester, Andra; Wittenburg, Peter; Wolstencroft, Katherine; Zhao, Jun; Mons, Barend

2016-01-01

There is an urgent need to improve the infrastructure supporting the reuse of scholarly data. A diverse set of stakeholders—representing academia, industry, funding agencies, and scholarly publishers—have come together to design and jointly endorse a concise and measureable set of principles that we refer to as the FAIR Data Principles. The intent is that these may act as a guideline for those wishing to enhance the reusability of their data holdings. Distinct from peer initiatives that focus on the human scholar, the FAIR Principles put specific emphasis on enhancing the ability of machines to automatically find and use the data, in addition to supporting its reuse by individuals. This Comment is the first formal publication of the FAIR Principles, and includes the rationale behind them, and some exemplar implementations in the community. PMID:26978244

Archimedes' principle in fluidized granular systems.

PubMed

Huerta, D A; Sosa, Victor; Vargas, M C; Ruiz-Suárez, J C

2005-09-01

We fluidize a granular bed in a rectangular container by injecting energy through the lateral walls with high-frequency sinusoidal horizontal vibrations. In this way, the bed is brought to a steady state with no convection. We measured buoyancy forces on light spheres immersed in the bed and found that they obey Archimedes' principle. The buoyancy forces decrease when we reduce the injected energy. By measuring ascension velocities as a function of gamma, we can evaluate the frictional drag of the bed; its exponential dependence agrees very well with previous findings. Rising times of the intruders ascending through the bed were also measured, they increase monotonically as we increase the density.

Basic principles for measurement of intramuscular pressure

NASA Technical Reports Server (NTRS)

Hargens, A. R.; Ballard, R. E.

1995-01-01

We review historical and methodological approaches to measurements of intramuscular pressure (IMP) in humans. These techniques provide valuable measures of muscle tone and activity as well as diagnostic criteria for evaluation of exertional compartment syndrome. Although the wick and catheter techniques provide accurate measurements of IMP at rest, their value for exercise studies and diagnosis of exertional compartment syndrome is limited because of low frequency response and hydrostatic (static and inertial) pressure artifacts. Presently, most information on diagnosis of exertional compartment syndromes during dynamic exercise is available using the Myopress catheter. However, future research and clinical diagnosis using IMP can be optimized by the use of a miniature transducer-tipped catheter such as the Millar Mikro-tip.

Determination of Anti-Adeno-Associated Virus Vector Neutralizing Antibody Titer with an In Vitro Reporter System

PubMed Central

Meliani, Amine; Leborgne, Christian; Triffault, Sabrina; Jeanson-Leh, Laurence; Veron, Philippe

2015-01-01

Abstract Adeno-associated virus (AAV) vectors are a platform of choice for in vivo gene transfer applications. However, neutralizing antibodies (NAb) to AAV can be found in humans and some animal species as a result of exposure to the wild-type virus, and high-titer NAb develop following AAV vector administration. In some conditions, anti-AAV NAb can block transduction with AAV vectors even when present at low titers, thus requiring prescreening before vector administration. Here we describe an improved in vitro, cell-based assay for the determination of NAb titer in serum or plasma samples. The assay is easy to setup and sensitive and, depending on the purpose, can be validated to support clinical development of gene therapy products based on AAV vectors. PMID:25819687

Principles to promote physician satisfaction and work-life balance.

PubMed

Shanafelt, Tait D; West, Colin P; Poland, Gregory A; LaRusso, Nicolas F; Menaker, Ronald; Bahn, Rebecca S

2008-12-01

Substantial evidence suggests that difficulty balancing their personal and professional life is a major contributor to physician distress. Limited evidence suggests that the mission and policies of health care organizations may relate to physician satisfaction. In this article, we describe principles to promote professional satisfaction and work-life integration developed by the Mayo Clinic department of medicine. These principles can be used to measure and align policies. It is hoped they will serve as a model that can be used by other health care organizations.

Successful affiliations: principles and practices.

PubMed

Rice, Ann Madden

2011-01-01

An affiliation can help a healthcare provider prepare for the challenges of healthcare reform, the rapidly changing landscapes of the commercial insurance industry, and the public's expectations about service and quality. UC Davis Medical Center, a 645-bed tertiary hospital in Sacramento, California, with many hospital-based clinics and a community-based group of primary care clinics, has developed a number of principles for affiliation. These principles are based on its experience in legal and financial affiliations with an academic practice group, with individual and small groups of primary care physicians, and with community hospitals around oncology services linked with U.C. Davis' National Cancer Institute-designated cancer center. This article offers a process for evaluating the appropriateness of an affiliation. The chances for a successful affiliation improve if each party has indicated the value it hopes to derive and how to measure that value, has communicated with all affected constituents, and has an agreed-upon method for resolving disputes.

[Bioethics of principles].

PubMed

Pérez-Soba Díez del Corral, Juan José

2008-01-01

Bioethics emerges about the tecnological problems of acting in human life. Emerges also the problem of the moral limits determination, because they seem exterior of this practice. The Bioethics of Principles, take his rationality of the teleological thinking, and the autonomism. These divergence manifest the epistemological fragility and the great difficulty of hmoralñ thinking. This is evident in the determination of autonomy's principle, it has not the ethical content of Kant's propose. We need a new ethic rationality with a new refelxion of new Principles whose emerges of the basic ethic experiences.

32 CFR 776.19 - Principles.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 5 2010-07-01 2010-07-01 false Principles. 776.19 Section 776.19 National... Professional Conduct § 776.19 Principles. The Rules of this subpart are based on the following principles... exists, this subpart should be interpreted consistent with these general principles. (a) Covered...

Antibacterial activity of acidified sodium benzoate against Escherichia coli O157:H7, Salmonella enterica, and Listeria monocytogenes in tryptic soy broth and on cherry tomatoes.

PubMed

Chen, Huaiqiong; Zhong, Qixin

2018-06-02

Concerns about undesirable by-products from chlorine sanitation of fresh produce and the limited efficacy with the presence of organic matter, have led to studies on alternative washing solutions. The aim of this study was to evaluate the antibacterial activities of acidified sodium benzoate (NaB) solutions against Escherichia coli O157:H7, Salmonella enterica and Listeria monocytogenes in growth medium and on cherry tomatoes. Experimentally, the minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs, >3 Log reduction) of NaB against E. coli O157:H7 ATCC 43895, S. Enteritidis, and L. monocytogenes Scott A were determined at pH 7.0-4.0 using micro-broth dilution method and agar plating method, respectively. The reduction of the three bacteria in tryptic soy broth (TSB) by 500 and 1000 ppm NaB at pH 2.0, 2.5 and 3.0 for 30 min at 21 °C was compared. Residual bacterial cocktails inoculated on cherry tomatoes were determined after soaking in 3000 ppm NaB solution adjusted to pH 2.0 for 3 min at 21 °C. Results showed that the MBC of NaB reduced from >10,000 ppm at pH 7.0 to 1000 ppm at pH 4.0 and was identical for the three bacteria. The log reduction of bacteria in TSB indicated that 1000 ppm NaB at pH 2.0 was the most effective in killing the three pathogens. The respective reduction of E. coli O157:H7 and S. enterica cocktails inoculated on cherry tomatoes immersed in 3000 ppm NaB (pH 2.0) at 21 °C for 3 min was 4.99 ± 0.57 and 4.08 ± 0.65 log CFU/g, which was significantly higher (p < 0.05) than the treatments of 200 ppm free chlorine at pH 6.5. Conversely, the reduction of L. monocytogenes on tomatoes by 3000 ppm NaB (4.88 ± 0.73 log CFU/g) was similar (p > 0.05) to 200 ppm chlorine. Furthermore, the reduction of bacterial cocktails on tomatoes by 3000 ppm NaB at pH 2.0 was not affected after adding 1% tomato puree, and bacteria were not detected in

Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo

DOE Office of Scientific and Technical Information (OSTI.GOV)

Medina-Ramírez, Max; Garces, Fernando; Escolano, Amelia

Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOSIP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOSIP.v4.1-GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resultingmore » in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-Å resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors.« less

Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo

DOE PAGES

Medina-Ramírez, Max; Garces, Fernando; Escolano, Amelia; ...

2017-08-28

Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOSIP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOSIP.v4.1-GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resultingmore » in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-Å resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors.« less

Elicitation of Robust Tier 2 Neutralizing Antibody Responses in Nonhuman Primates by HIV Envelope Trimer Immunization Using Optimized Approaches.

PubMed

Pauthner, Matthias; Havenar-Daughton, Colin; Sok, Devin; Nkolola, Joseph P; Bastidas, Raiza; Boopathy, Archana V; Carnathan, Diane G; Chandrashekar, Abishek; Cirelli, Kimberly M; Cottrell, Christopher A; Eroshkin, Alexey M; Guenaga, Javier; Kaushik, Kirti; Kulp, Daniel W; Liu, Jinyan; McCoy, Laura E; Oom, Aaron L; Ozorowski, Gabriel; Post, Kai W; Sharma, Shailendra K; Steichen, Jon M; de Taeye, Steven W; Tokatlian, Talar; Torrents de la Peña, Alba; Butera, Salvatore T; LaBranche, Celia C; Montefiori, David C; Silvestri, Guido; Wilson, Ian A; Irvine, Darrell J; Sanders, Rogier W; Schief, William R; Ward, Andrew B; Wyatt, Richard T; Barouch, Dan H; Crotty, Shane; Burton, Dennis R

2017-06-20

The development of stabilized recombinant HIV envelope trimers that mimic the virion surface molecule has increased enthusiasm for a neutralizing antibody (nAb)-based HIV vaccine. However, there is limited experience with recombinant trimers as immunogens in nonhuman primates, which are typically used as a model for humans. Here, we tested multiple immunogens and immunization strategies head-to-head to determine their impact on the quantity, quality, and kinetics of autologous tier 2 nAb development. A bilateral, adjuvanted, subcutaneous immunization protocol induced reproducible tier 2 nAb responses after only two immunizations 8 weeks apart, and these were further enhanced by a third immunization with BG505 SOSIP trimer. We identified immunogens that minimized non-neutralizing V3 responses and demonstrated that continuous immunogen delivery could enhance nAb responses. nAb responses were strongly associated with germinal center reactions, as assessed by lymph node fine needle aspiration. This study provides a framework for preclinical and clinical vaccine studies targeting nAb elicitation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

The Principle of General Tovariance

NASA Astrophysics Data System (ADS)

Heunen, C.; Landsman, N. P.; Spitters, B.

2008-06-01

We tentatively propose two guiding principles for the construction of theories of physics, which should be satisfied by a possible future theory of quantum gravity. These principles are inspired by those that led Einstein to his theory of general relativity, viz. his principle of general covariance and his equivalence principle, as well as by the two mysterious dogmas of Bohr's interpretation of quantum mechanics, i.e. his doctrine of classical concepts and his principle of complementarity. An appropriate mathematical language for combining these ideas is topos theory, a framework earlier proposed for physics by Isham and collaborators. Our principle of general tovariance states that any mathematical structure appearing in the laws of physics must be definable in an arbitrary topos (with natural numbers object) and must be preserved under so-called geometric morphisms. This principle identifies geometric logic as the mathematical language of physics and restricts the constructions and theorems to those valid in intuitionism: neither Aristotle's principle of the excluded third nor Zermelo's Axiom of Choice may be invoked. Subsequently, our equivalence principle states that any algebra of observables (initially defined in the topos Sets) is empirically equivalent to a commutative one in some other topos.

A critique of principlism.

PubMed

Clouser, K D; Gert, B

1990-04-01

The authors use the term "principlism" to refer to the practice of using "principles" to replace both moral theory and particular moral rules and ideals in dealing with the moral problems that arise in medical practice. The authors argue that these "principles" do not function as claimed, and that their use is misleading both practically and theoretically. The "principles" are in fact not guides to action, but rather they are merely names for a collection of sometimes superficially related matters for consideration when dealing with a moral problem. The "principles" lack any systematic relationship to each other, and they often conflict with each other. These conflicts are unresolvable, since there is no unified moral theory from which they are all derived. For comparison the authors sketch the advantages of using a unified moral theory.

Principles for valid histopathologic scoring in research

PubMed Central

Gibson-Corley, Katherine N.; Olivier, Alicia K.; Meyerholz, David K.

2013-01-01

Histopathologic scoring is a tool by which semi-quantitative data can be obtained from tissues. Initially, a thorough understanding of the experimental design, study objectives and methods are required to allow the pathologist to appropriately examine tissues and develop lesion scoring approaches. Many principles go into the development of a scoring system such as tissue examination, lesion identification, scoring definitions and consistency in interpretation. Masking (a.k.a. “blinding”) of the pathologist to experimental groups is often necessary to constrain bias and multiple mechanisms are available. Development of a tissue scoring system requires appreciation of the attributes and limitations of the data (e.g. nominal, ordinal, interval and ratio data) to be evaluated. Incidence, ordinal and rank methods of tissue scoring are demonstrated along with key principles for statistical analyses and reporting. Validation of a scoring system occurs through two principal measures: 1) validation of repeatability and 2) validation of tissue pathobiology. Understanding key principles of tissue scoring can help in the development and/or optimization of scoring systems so as to consistently yield meaningful and valid scoring data. PMID:23558974

Improved anticancer effects of albumin-bound paclitaxel nanoparticle via augmentation of EPR effect and albumin-protein interactions using S-nitrosated human serum albumin dimer.

PubMed

Kinoshita, Ryo; Ishima, Yu; Chuang, Victor T G; Nakamura, Hideaki; Fang, Jun; Watanabe, Hiroshi; Shimizu, Taro; Okuhira, Keiichiro; Ishida, Tatsuhiro; Maeda, Hiroshi; Otagiri, Masaki; Maruyama, Toru

2017-09-01

In the latest trend of anticancer chemotherapy research, there were many macromolecular anticancer drugs developed based on enhanced permeability and retention (EPR) effect, such as albumin bound paclitaxel nanoparticle (nab- PTX, also called Abraxane ® ). However, cancers with low vascular permeability posed a challenge for these EPR based therapeutic systems. Augmenting the intrinsic EPR effect with an intrinsic vascular modulator such as nitric oxide (NO) could be a promising strategy. S-nitrosated human serum albumin dimer (SNO-HSA Dimer) shown promising activity previously was evaluated for the synergistic effect when used as a pretreatment agent in nab-PTX therapy against various tumor models. In the high vascular permeability C26 murine colon cancer subcutaneous inoculation model, SNO-HSA Dimer enhanced tumor selectivity of nab-PTX, and attenuated myelosuppression. SNO-HSA Dimer also augmented the tumor growth inhibition of nab-PTX in low vascular permeability B16 murine melanoma subcutaneous inoculation model. Furthermore, nab-PTX therapy combined with SNO-HSA Dimer showed higher antitumor activity and improved survival rate of SUIT2 human pancreatic cancer orthotopic model. In conclusion, SNO-HSA Dimer could enhance the therapeutic effect of nab-PTX even in low vascular permeability or intractable pancreatic cancers. The possible underlying mechanisms of action of SNO-HSA Dimer were discussed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Factor investing based on Musharakah principle

NASA Astrophysics Data System (ADS)

Simon, Shahril; Omar, Mohd; Lazam, Norazliani Md; Amin, Mohd Nazrul Mohd

2015-10-01

Shariah stock investing has become a widely discussed topic in financial industry as part of today's investment strategy. The strategy primarily applies market capitalization allocations. However, some researchers have argued that market capitalization weighting is inherently flawed and have advocated replacing market capitalization allocations with factor allocations. In this paper, we discuss the rationale for factor investing based on Musharakah principle. The essential elements or factors of Musharakah principle such as business sector, management capability, profitability growth and capital efficiency are embedded in the Shariah-compliant stock. We then transform these factors into indexation for better analysis and performance measurement. Investment universe for this research covers Malaysian stocks for the period of January 2009 to December 2013. We found out that these factor indexes have historically earned excess returns over market capitalization weighted indexes and experienced higher Sharpe Ratios.

Detection principle of gravitational wave detectors

NASA Astrophysics Data System (ADS)

Congedo, Giuseppe

With the first two detections in late 2015, astrophysics has officially entered into the new era of gravitational wave (GW) observations. Since then, much has been going on in the field with a lot of work focusing on the observations and implications for astrophysics and tests of general relativity in the strong regime. However, much less is understood about how gravitational detectors really work at their fundamental level. For decades, the response to incoming signals has been customarily calculated using the very same physical principle, which has proved so successful in the first detections. In this paper, we review the physical principle that is behind such a detection at the very fundamental level, and we try to highlight the peculiar subtleties that make it so hard in practice. We will then mention how detectors are built starting from this fundamental measurement element.

A new adaptive light beam focusing principle for scanning light stimulation systems.

PubMed

Bitzer, L A; Meseth, M; Benson, N; Schmechel, R

2013-02-01

In this article a novel principle to achieve optimal focusing conditions or rather the smallest possible beam diameter for scanning light stimulation systems is presented. It is based on the following methodology: First, a reference point on a camera sensor is introduced where optimal focusing conditions are adjusted and the distance between the light focusing optic and the reference point is determined using a laser displacement sensor. In a second step, this displacement sensor is used to map the topography of the sample under investigation. Finally, the actual measurement is conducted, using optimal focusing conditions in each measurement point at the sample surface, that are determined by the height difference between camera sensor and the sample topography. This principle is independent of the measurement values, the optical or electrical properties of the sample, the used light source, or the selected wavelength. Furthermore, the samples can be tilted, rough, bent, or of different surface materials. In the following the principle is implemented using an optical beam induced current system, but basically it can be applied to any other scanning light stimulation system. Measurements to demonstrate its operation are shown, using a polycrystalline silicon solar cell.

Nonneutralizing Functional Antibodies: a New “Old” Paradigm for HIV Vaccines

PubMed Central

Ake, Julie; Robb, Merlin L.; Kim, Jerome H.; Plotkin, Stanley A.

2014-01-01

Animal and human data from various viral infections and vaccine studies suggest that nonneutralizing antibodies (nNAb) without neutralizing activity in vitro may play an important role in protection against viral infection in vivo. This was illustrated by the recent human immunodeficiency virus (HIV) RV144 vaccine efficacy trial, which demonstrated that HIV-specific IgG-mediated nNAb directed against the V2 loop of HIV type 1 envelope (Env) were inversely correlated with risk for HIV acquisition, while Env-specific plasma IgA-mediated antibodies were directly correlated with risk. However, tier 1 NAb in the subset of responders with a low level of plasma Env-specific IgA correlated with decreased risk. Nonhuman primate simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) challenge studies suggest that Env-mediated antibodies are essential and sufficient for protection. A comparison of immune responses generated in human efficacy trials reveals subtle differences in the fine specificities of the antibody responses, in particular in HIV-specific IgG subclasses. The underlying mechanisms that may have contributed to protection against HIV acquisition in humans, although not fully understood, are possibly mediated by antibody-dependent cell-mediated cytotoxicity (ADCC) and/or other nonneutralizing humoral effector functions, such as antibody-mediated phagocytosis. The presence of such functional nNAb in mucosal tissues and cervico-vaginal and rectal secretions challenges the paradigm that NAb are the predominant immune response conferring protection, although this does not negate the desirability of evoking neutralizing antibodies through vaccination. Instead, NAb and nNAb should be looked upon as complementary or synergistic humoral effector functions. Several HIV vaccine clinical trials to study these antibody responses in various prime-boost modalities in the systemic and mucosal compartments are ongoing. The induction of high

Ubiquity and Diversity of Heterotrophic Bacterial nasA Genes in Diverse Marine Environments

PubMed Central

Jiang, Xuexia; Dang, Hongyue; Jiao, Nianzhi

2015-01-01

Nitrate uptake by heterotrophic bacteria plays an important role in marine N cycling. However, few studies have investigated the diversity of environmental nitrate assimilating bacteria (NAB). In this study, the diversity and biogeographical distribution of NAB in several global oceans and particularly in the western Pacific marginal seas were investigated using both cultivation and culture-independent molecular approaches. Phylogenetic analyses based on 16S rRNA and nasA (encoding the large subunit of the assimilatory nitrate reductase) gene sequences indicated that the cultivable NAB in South China Sea belonged to the α-Proteobacteria, γ-Proteobacteria and CFB (Cytophaga-Flavobacteria-Bacteroides) bacterial groups. In all the environmental samples of the present study, α-Proteobacteria, γ-Proteobacteria and Bacteroidetes were found to be the dominant nasA-harboring bacteria. Almost all of the α-Proteobacteria OTUs were classified into three Roseobacter-like groups (I to III). Clone library analysis revealed previously underestimated nasA diversity; e.g. the nasA gene sequences affiliated with β-Proteobacteria, ε-Proteobacteria and Lentisphaerae were observed in the field investigation for the first time, to the best of our knowledge. The geographical and vertical distributions of seawater nasA-harboring bacteria indicated that NAB were highly diverse and ubiquitously distributed in the studied marginal seas and world oceans. Niche adaptation and separation and/or limited dispersal might mediate the NAB composition and community structure in different water bodies. In the shallow-water Kueishantao hydrothermal vent environment, chemolithoautotrophic sulfur-oxidizing bacteria were the primary NAB, indicating a unique nitrate-assimilating community in this extreme environment. In the coastal water of the East China Sea, the relative abundance of Alteromonas and Roseobacter-like nasA gene sequences responded closely to algal blooms, indicating that NAB may be

Protein structure similarity from Principle Component Correlation analysis.

PubMed

Zhou, Xiaobo; Chou, James; Wong, Stephen T C

2006-01-25

Owing to rapid expansion of protein structure databases in recent years, methods of structure comparison are becoming increasingly effective and important in revealing novel information on functional properties of proteins and their roles in the grand scheme of evolutionary biology. Currently, the structural similarity between two proteins is measured by the root-mean-square-deviation (RMSD) in their best-superimposed atomic coordinates. RMSD is the golden rule of measuring structural similarity when the structures are nearly identical; it, however, fails to detect the higher order topological similarities in proteins evolved into different shapes. We propose new algorithms for extracting geometrical invariants of proteins that can be effectively used to identify homologous protein structures or topologies in order to quantify both close and remote structural similarities. We measure structural similarity between proteins by correlating the principle components of their secondary structure interaction matrix. In our approach, the Principle Component Correlation (PCC) analysis, a symmetric interaction matrix for a protein structure is constructed with relationship parameters between secondary elements that can take the form of distance, orientation, or other relevant structural invariants. When using a distance-based construction in the presence or absence of encoded N to C terminal sense, there are strong correlations between the principle components of interaction matrices of structurally or topologically similar proteins. The PCC method is extensively tested for protein structures that belong to the same topological class but are significantly different by RMSD measure. The PCC analysis can also differentiate proteins having similar shapes but different topological arrangements. Additionally, we demonstrate that when using two independently defined interaction matrices, comparison of their maximum eigenvalues can be highly effective in clustering structurally or

A General Conditional Large Deviation Principle

DOE PAGES

La Cour, Brian R.; Schieve, William C.

2015-07-18

Given a sequence of Borel probability measures on a Hausdorff space which satisfy a large deviation principle (LDP), we consider the corresponding sequence of measures formed by conditioning on a set B. If the large deviation rate function I is good and effectively continuous, and the conditioning set has the property that (1)more » $$\\overline{B°}$$=$$\\overline{B}$$ and (2) I(x)<∞ for all xε$$\\overline{B}$$, then the sequence of conditional measures satisfies a LDP with the good, effectively continuous rate function I B, where I B(x)=I(x)-inf I(B) if xε$$\\overline{B}$$ and I B(x)=∞ otherwise.« less

The inconstant "principle of constancy".

PubMed

Kanzer, M

1983-01-01

A review of the principle of constancy, as it appeared in Freud's writings, shows that it was inspired by his clinical observations, first with Breuer in the field of cathartic therapy and then through experiences in the early usage of psychoanalysis. The recognition that memories repressed in the unconscious created increasing tension, and that this was relieved with dischargelike phenomena when the unconscious was made conscious, was the basis for his claim to originality in this area. The two principles of "neuronic inertia" Freud expounded in the Project (1895), are found to offer the key to the ambiguous definition of the principle of constancy he was to offer in later years. The "original" principle, which sought the complete discharge of energy (or elimination of stimuli), became the forerunner of the death drive; the "extended" principle achieved balances that were relatively constant, but succumbed in the end to complete discharge. This was the predecessor of the life drives. The relation between the constancy and pleasure-unpleasure principles was maintained for twenty-five years largely on an empirical basis which invoked the concept of psychophysical parallelism between "quantity" and "quality." As the links between the two principles were weakened by clinical experiences attendant upon the growth of ego psychology, a revision of the principle of constancy was suggested, and it was renamed the Nirvana principle. Actually it was shifted from alignment with the "extended" principle of inertia to the original, so that "constancy" was incongruously identified with self-extinction. The former basis for the constancy principle, the extended principle of inertia, became identified with Eros. Only a few commentators seem aware of this radical transformation, which has been overlooked in the Standard Edition of Freud's writings. Physiological biases in the history and conception of the principle of constancy are noted in the Standard Edition. The historical

Routine internal- and external-quality control data in clinical laboratories for estimating measurement and diagnostic uncertainty using GUM principles.

PubMed

Magnusson, Bertil; Ossowicki, Haakan; Rienitz, Olaf; Theodorsson, Elvar

2012-05-01

Healthcare laboratories are increasingly joining into larger laboratory organizations encompassing several physical laboratories. This caters for important new opportunities for re-defining the concept of a 'laboratory' to encompass all laboratories and measurement methods measuring the same measurand for a population of patients. In order to make measurement results, comparable bias should be minimized or eliminated and measurement uncertainty properly evaluated for all methods used for a particular patient population. The measurement as well as diagnostic uncertainty can be evaluated from internal and external quality control results using GUM principles. In this paper the uncertainty evaluations are described in detail using only two main components, within-laboratory reproducibility and uncertainty of the bias component according to a Nordtest guideline. The evaluation is exemplified for the determination of creatinine in serum for a conglomerate of laboratories both expressed in absolute units (μmol/L) and relative (%). An expanded measurement uncertainty of 12 μmol/L associated with concentrations of creatinine below 120 μmol/L and of 10% associated with concentrations above 120 μmol/L was estimated. The diagnostic uncertainty encompasses both measurement uncertainty and biological variation, and can be estimated for a single value and for a difference. This diagnostic uncertainty for the difference for two samples from the same patient was determined to be 14 μmol/L associated with concentrations of creatinine below 100 μmol/L and 14 % associated with concentrations above 100 μmol/L.

Hawking radiation, Unruh radiation, and the equivalence principle.

PubMed

Singleton, Douglas; Wilburn, Steve

2011-08-19

We compare the response function of an Unruh-DeWitt detector for different space-times and different vacua and show that there is a detailed violation of the equivalence principle. In particular comparing the response of an accelerating detector to a detector at rest in a Schwarzschild space-time we find that both detectors register thermal radiation, but for a given, equivalent acceleration the fixed detector in the Schwarzschild space-time measures a higher temperature. This allows one to locally distinguish the two cases. As one approaches the horizon the two temperatures have the same limit so that the equivalence principle is restored at the horizon. © 2011 American Physical Society

An uncertainty principle for unimodular quantum groups

DOE Office of Scientific and Technical Information (OSTI.GOV)

Crann, Jason; Université Lille 1 - Sciences et Technologies, UFR de Mathématiques, Laboratoire de Mathématiques Paul Painlevé - UMR CNRS 8524, 59655 Villeneuve d'Ascq Cédex; Kalantar, Mehrdad, E-mail: jason-crann@carleton.ca, E-mail: mkalanta@math.carleton.ca

2014-08-15

We present a generalization of Hirschman's entropic uncertainty principle for locally compact Abelian groups to unimodular locally compact quantum groups. As a corollary, we strengthen a well-known uncertainty principle for compact groups, and generalize the relation to compact quantum groups of Kac type. We also establish the complementarity of finite-dimensional quantum group algebras. In the non-unimodular setting, we obtain an uncertainty relation for arbitrary locally compact groups using the relative entropy with respect to the Haar weight as the measure of uncertainty. We also show that when restricted to q-traces of discrete quantum groups, the relative entropy with respect tomore » the Haar weight reduces to the canonical entropy of the random walk generated by the state.« less

Reducing V3 Antigenicity and Immunogenicity on Soluble, Native-Like HIV-1 Env SOSIP Trimers.

PubMed

Ringe, Rajesh P; Ozorowski, Gabriel; Rantalainen, Kimmo; Struwe, Weston B; Matthews, Katie; Torres, Jonathan L; Yasmeen, Anila; Cottrell, Christopher A; Ketas, Thomas J; LaBranche, Celia C; Montefiori, David C; Cupo, Albert; Crispin, Max; Wilson, Ian A; Ward, Andrew B; Sanders, Rogier W; Klasse, P J; Moore, John P

2017-08-01

Native-like trimers of the SOSIP design are being developed as immunogens in human immunodeficiency virus type 1 (HIV-1) vaccine development programs. These trimers display the epitopes for multiple broadly neutralizing antibodies (bNAbs) but can also expose binding sites for some types of nonneutralizing antibodies (non-NAbs). Among the latter are epitopes in the gp120 V3 region that are highly immunogenic when SOSIP trimers are evaluated in animal models. It is presently uncertain whether antibodies against V3 can interfere with the induction of NAbs, but there are good arguments in favor of suppressing such "off-target" immune responses. Accordingly, we have assessed how to minimize the exposure of V3 non-NAb epitopes and thereby reduce their immunogenicity by introducing N -glycans within the V3 region of BG505 SOSIP trimers. We found that inserting glycans at positions 306 and 314 (termed M1 and M7) markedly reduced V3 antigenicity while improving the presentation of trimer apex bNAb epitopes. Both added glycans were shown to be predominantly of the Man 6 GlcNAc 2 form. The additional introduction of the E64K ground-state stabilizing substitution markedly reduced or ablated soluble CD4 (sCD4) induction of non-NAb epitopes in V3 and/or associated with the coreceptor binding site. When a V3 glycan- and E64K-modified trimer variant, BG505 SOSIP.664-E64K.M1M7, was tested in rabbits, V3 immunogenicity was eliminated while the autologous NAb response was unchanged. IMPORTANCE Trimeric proteins are being developed for future HIV-1 vaccine trials in humans, with the goal of eliciting broadly active neutralizing antibodies (NAbs) that are active against a wide variety of circulating strains. In animal models, the present generation of native-like trimer immunogens, exemplified by the BG505 SOSIP.664 construct, induces narrow-specificity antibodies against the neutralization-resistant (tier-2), sequence-matched virus and more broadly active antibodies against sequence

Reducing V3 Antigenicity and Immunogenicity on Soluble, Native-Like HIV-1 Env SOSIP Trimers

PubMed Central

Ringe, Rajesh P.; Ozorowski, Gabriel; Rantalainen, Kimmo; Struwe, Weston B.; Matthews, Katie; Torres, Jonathan L.; Yasmeen, Anila; Cottrell, Christopher A.; Ketas, Thomas J.; LaBranche, Celia C.; Montefiori, David C.; Cupo, Albert; Crispin, Max; Wilson, Ian A.; Ward, Andrew B.; Sanders, Rogier W.; Klasse, P. J.

2017-01-01

ABSTRACT Native-like trimers of the SOSIP design are being developed as immunogens in human immunodeficiency virus type 1 (HIV-1) vaccine development programs. These trimers display the epitopes for multiple broadly neutralizing antibodies (bNAbs) but can also expose binding sites for some types of nonneutralizing antibodies (non-NAbs). Among the latter are epitopes in the gp120 V3 region that are highly immunogenic when SOSIP trimers are evaluated in animal models. It is presently uncertain whether antibodies against V3 can interfere with the induction of NAbs, but there are good arguments in favor of suppressing such “off-target” immune responses. Accordingly, we have assessed how to minimize the exposure of V3 non-NAb epitopes and thereby reduce their immunogenicity by introducing N-glycans within the V3 region of BG505 SOSIP trimers. We found that inserting glycans at positions 306 and 314 (termed M1 and M7) markedly reduced V3 antigenicity while improving the presentation of trimer apex bNAb epitopes. Both added glycans were shown to be predominantly of the Man6GlcNAc2 form. The additional introduction of the E64K ground-state stabilizing substitution markedly reduced or ablated soluble CD4 (sCD4) induction of non-NAb epitopes in V3 and/or associated with the coreceptor binding site. When a V3 glycan- and E64K-modified trimer variant, BG505 SOSIP.664-E64K.M1M7, was tested in rabbits, V3 immunogenicity was eliminated while the autologous NAb response was unchanged. IMPORTANCE Trimeric proteins are being developed for future HIV-1 vaccine trials in humans, with the goal of eliciting broadly active neutralizing antibodies (NAbs) that are active against a wide variety of circulating strains. In animal models, the present generation of native-like trimer immunogens, exemplified by the BG505 SOSIP.664 construct, induces narrow-specificity antibodies against the neutralization-resistant (tier-2), sequence-matched virus and more broadly active antibodies against

Can quantum probes satisfy the weak equivalence principle?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Seveso, Luigi, E-mail: luigi.seveso@unimi.it; Paris, Matteo G.A.; INFN, Sezione di Milano, I-20133 Milano

We address the question whether quantum probes in a gravitational field can be considered as test particles obeying the weak equivalence principle (WEP). A formulation of the WEP is proposed which applies also in the quantum regime, while maintaining the physical content of its classical counterpart. Such formulation requires the introduction of a gravitational field not to modify the Fisher information about the mass of a freely-falling probe, extractable through measurements of its position. We discover that, while in a uniform field quantum probes satisfy our formulation of the WEP exactly, gravity gradients can encode nontrivial information about the particle’smore » mass in its wavefunction, leading to violations of the WEP. - Highlights: • Can quantum probes under gravity be approximated as test-bodies? • A formulation of the weak equivalence principle for quantum probes is proposed. • Quantum probes are found to violate it as a matter of principle.« less

[The precautionary principle: advantages and risks].

PubMed

Tubiana, M

2001-04-01

The extension of the precautionary principle to the field of healthcare is the social response to two demands of the population: improved health safety and the inclusion of an informed public in the decision-making process. The necessary balance between cost (treatment-induced risk) and benefit (therapeutic effect) underlies all healthcare decisions. An underestimation or an overestimation of cost, i.e. risk, is equally harmful in public healthcare. A vaccination should be prescribed when its beneficial effect outweighs its inevitable risk. Mandatory vaccination, such as in the case of the Hepatitis B virus, is a health policy requiring some courage because those who benefit will never be aware of its positive effect while those who are victims of the risk could resort to litigation. Defense against such accusations requires an accurate assessment of risk and benefit, which underlines the importance of expertise. Even within the framework of the precautionary principle, it is impossible to act without knowledge, or at least a plausible estimation, of expected effects. Recent affairs (blood contamination, transmissible spongiform encephalitis by growth hormone, and new variant of Creutzfeldt-Jacob disease) illustrate that in such cases the precautionary principle would have had limited impact and it is only when enough knowledge was available that effective action could be taken. Likewise, in current debates concerning the possible risks of electromagnetic fields, cellular phones and radon, research efforts must be given priority. The general public understands intuitively the concept of cost and benefit. For example, the possible health risks of oral contraceptives and hormone replacement therapy were not ignored, but the public has judged that their advantages justify the risk. Estimating risk and benefit and finding a balance between risk and preventive measures could help avoid the main drawbacks of the precautionary principle, i.e. inaction and refusal of

Cross-hierarchy systems principles.

PubMed

Goentoro, Lea

2017-02-01

One driving motivation of systems biology is the search for general principles that govern the design of biological systems. But questions often arise as to what kind of general principles biology could have. Concepts from engineering such as robustness and modularity are indeed becoming a regular way of describing biological systems. Another source of potential general principles is the emerging similarities found in processes across biological hierarchies. In this piece, I describe several emerging cross-hierarchy similarities. Identification of more cross-hierarchy principles, and understanding the implications these convergence have on the construction of biological systems, I believe, present exciting challenges for systems biology in the decades to come.

Non-destructive testing principles and accurate evaluation of the hydraulic measure impact range using the DC method

NASA Astrophysics Data System (ADS)

Qiu, Liming; Shen, Rongxi; Song, Dazhao; Wang, Enyuan; Liu, Zhentang; Niu, Yue; Jia, Haishan; Xia, Shankui; Zheng, Xiangxin

2017-12-01

An accurate and non-destructive evaluation method for the hydraulic measure impact range in coal seams is urgently needed. Aiming at the application demands, a theoretical study and field test are presented using the direct current (DC) method to evaluate the impact range of coal seam hydraulic measures. We firstly analyzed the law of the apparent resistivity response of an abnormal conductive zone in a coal seam, and then investigated the principle of non-destructive testing of the coal seam hydraulic measure impact range using the DC method, and used an accurate evaluation method based on the apparent resistivity cloud chart. Finally, taking hydraulic fracturing and hydraulic flushing as examples, field experiments were carried out in coal mines to evaluate the impact ranges. The results showed that: (1) in the process of hydraulic fracturing, coal conductivity was enhanced by high-pressure water in the coal seam, and after hydraulic fracturing, the boundary of the apparent resistivity decrease area was the boundary impact range. (2) In the process of hydraulic flushing, coal conductivity was reduced by holes and cracks in the coal seam, and after hydraulic flushing, the boundary of the apparent resistivity increase area was the boundary impact range. (3) After the implementation of the hydraulic measures, there may be some blind zones in the coal seam; in hydraulic fracturing blind zones, the apparent resistivity increased or stayed constant, while in hydraulic flushing blind zones, the apparent resistivity decreased or stayed constant. The DC method realized a comprehensive and non-destructive evaluation of the impact range of the hydraulic measures, and greatly reduced the time and cost of evaluation.

Neutralizing Antibodies against IFN-[Beta] in Multiple Sclerosis: Antagonization of IFN-[Beta] Mediated Suppression of MMPs

ERIC Educational Resources Information Center

Gilli, Francesca; Bertolotto, Antonio; Sala, Arianna; Hoffmann, Francine; Capobianco, Marco; Malucchi, Simona; Glass, Tracy; Kappos, Ludwig; Lindberg, Raija L. P.; Leppert, David

2004-01-01

Neutralizing antibodies (NAb) against interferon-[Beta] (IFN-Beta) develop in about a third of treated multiple sclerosis patients and are believed to reduce therapeutic efficacy of IFN-[Beta] on clinical and MRI measures. The expression of the interferon acute-response protein, myxovirus resistance protein A (MxA) is a sensitive measure of the…

The Rosiwal Principle and the regolithic distributions of solar-wind elements

NASA Technical Reports Server (NTRS)

Criswell, D. R.

1975-01-01

In situ accumulation of solar elements is studied for the purpose of determining the extent of applicability of the Rosiwal Principle. The Rosiwal Principle states that the grain exposure area is proportional to the fraction of the unit volume occupied by the grains, and the test involves measurement of the relative concentrations of inert gases and reactive elements across sets of lunar fines samples for which mean grain size, sorting, and minimum radius of surface correlation are known. In some cases, the quantity of an element implanted into the lunar fines from the solar wind is found to be surface correlated, and the implications of this relationship are considered. According to the Rosiwal Principle, coarse soils should retain less inert gas than fine soil. The Principle can also be applied to species volatized or sputtered from the lunar surface and redeposited locally.

Laser principles.

PubMed

Bogdan Allemann, Inja; Kaufman, Joely

2011-01-01

Since the construction of the first laser in the 1960s, the role that lasers play in various medical specialities, including dermatology, has steadily increased. However, within the last 2 decades, the technological advances and the use of lasers in the field of dermatology have virtually exploded. Many treatments have only become possible with the use of lasers. Especially in aesthetic medicine, lasers are an essential tool in the treatment armamentarium. Due to better research and understanding of the physics of light and skin, there is now a wide and increasing array of different lasers and devices to choose from. The proper laser selection for each indication and treatment requires a profound understanding of laser physics and the basic laser principles. Understanding these principles will allow the laser operator to obtain better results and help avoid complications. This chapter will give an in-depth overview of the physical principles relevant in cutaneous laser surgery. Copyright © 2011 S. Karger AG, Basel.

Through the Looking Glass: Symmetry in Behavioral Principles?

ERIC Educational Resources Information Center

Marr, M. Jackson

2006-01-01

In this article, the author discusses and presents seven possibilities that describe how symmetry principles are reflected in behavior analysis. First, if there are apparently no functional distinctions to be made between positive and negative reinforcement, then reinforcer effectiveness (by various measures) is invariant under a simple inversion…

Basic design principles of colorimetric vision systems

NASA Astrophysics Data System (ADS)

Mumzhiu, Alex M.

1998-10-01

Color measurement is an important part of overall production quality control in textile, coating, plastics, food, paper and other industries. The color measurement instruments such as colorimeters and spectrophotometers, used for production quality control have many limitations. In many applications they cannot be used for a variety of reasons and have to be replaced with human operators. Machine vision has great potential for color measurement. The components for color machine vision systems, such as broadcast quality 3-CCD cameras, fast and inexpensive PCI frame grabbers, and sophisticated image processing software packages are available. However the machine vision industry has only started to approach the color domain. The few color machine vision systems on the market, produced by the largest machine vision manufacturers have very limited capabilities. A lack of understanding that a vision based color measurement system could fail if it ignores the basic principles of colorimetry is the main reason for the slow progress of color vision systems. the purpose of this paper is to clarify how color measurement principles have to be applied to vision systems and how the electro-optical design features of colorimeters have to be modified in order to implement them for vision systems. The subject of this presentation far exceeds the limitations of a journal paper so only the most important aspects will be discussed. An overview of the major areas of applications for colorimetric vision system will be discussed. Finally, the reasons why some customers are happy with their vision systems and some are not will be analyzed.

Theoretical principles for biology: Variation.

PubMed

Montévil, Maël; Mossio, Matteo; Pocheville, Arnaud; Longo, Giuseppe

2016-10-01

Darwin introduced the concept that random variation generates new living forms. In this paper, we elaborate on Darwin's notion of random variation to propose that biological variation should be given the status of a fundamental theoretical principle in biology. We state that biological objects such as organisms are specific objects. Specific objects are special in that they are qualitatively different from each other. They can undergo unpredictable qualitative changes, some of which are not defined before they happen. We express the principle of variation in terms of symmetry changes, where symmetries underlie the theoretical determination of the object. We contrast the biological situation with the physical situation, where objects are generic (that is, different objects can be assumed to be identical) and evolve in well-defined state spaces. We derive several implications of the principle of variation, in particular, biological objects show randomness, historicity and contextuality. We elaborate on the articulation between this principle and the two other principles proposed in this special issue: the principle of default state and the principle of organization. Copyright © 2016 Elsevier Ltd. All rights reserved.

The precautionary principle is incoherent.

PubMed

Peterson, Martin

2006-06-01

This article argues that no version of the precautionary principle can be reasonably applied to decisions that may lead to fatal outcomes. In support of this strong claim, a number of desiderata are proposed, which reasonable rules for rational decision making ought to satisfy. Thereafter, two impossibility theorems are proved, showing that no version of the precautionary principle can satisfy the proposed desiderata. These theorems are directly applicable to recent discussions of the precautionary principle in medicine, biotechnology, environmental management, and related fields. The impossibility theorems do not imply, however, that the precautionary principle is of no relevance at all in policy discussions. Even if it is not a reasonable rule for rational decision making, it is possible to interpret the precautionary principle in other ways, e.g., as an argumentative tool or as an epistemic principle favoring a reversed burden of proof.

Determination of Anti-Adeno-Associated Viral Vector Neutralizing Antibodies in Patients With Heart Failure in the Cardiovascular Foundation of Colombia (ANVIAS): Study Protocol

PubMed Central

Prada, Carlos E; Lopez, Marcos; Castillo, Victor; Echeverria, Luis Eduardo; Serrano, Norma

2016-01-01

Background Recent progress in the pathophysiology of heart failure (HF) has led to the development of new therapeutic options such as gene therapy and the use of adeno-associated viral (AAV) vectors. Despite the promising results in early clinical trials of gene therapy for HF, various obstacles have been faced, such as the presence of neutralizing antibodies (NAbs) against the capsid vectors. NAb activity limits vector transduction levels and therefore diminishes the final therapeutic response. Recent studies evaluating the prevalence of NAbs in various populations found considerable geographic variability for each AAV serotype. However, the levels of NAbs in Latin American populations are unknown, becoming a limiting factor to conducting AAV vector therapeutic trials in this population. Objective The goal of this study is to determine for the first time, the prevalence of anti-AAV NAbs for the serotypes 1, 2, and 9 in HF patients from the city of Bucaramanga, Colombia, using the in vitro transduction inhibition assay. Methods We will conduct a cross-sectional study with patients who periodically attend the HF clinic of the Cardiovascular Foundation of Colombia and healthy volunteers matched for age and sex. For all participants, we will evaluate the NAb levels against serotypes AAV1, AAV2, and AAV9. We will determine NAb levels using the in vitro transduction inhibition assay. In addition, participants will answer a survey to evaluate their epidemiological and socioeconomic variables. Participation in the study will be voluntary and all participants will sign an informed consent document before any intervention. Results The project is in the first phase: elaboration of case report forms and the informed consent form, and design of the recruitment strategy. Patient recruitment is expected to begin in the spring of 2016. We expect to have preliminary results, including the titer of the viral vectors, multiplicity of infections that we will use for each serotype

Natural antibodies to glycans.

PubMed

Bovin, N V

2013-07-01

A wide variety of so-called natural antibodies (nAbs), i.e. immunoglobulins generated by B-1 cells, are directed to glycans. nAbs to glycans can be divided in three groups: 1) conservative nAbs, i.e. practically the same in all healthy donors with respect to their epitope specificity and level in blood; 2) allo-antibodies to blood group antigens; 3) plastic antibodies related to the first or the second group but discussed separately because their level changes considerably during diseases and some temporary conditions, in particular inflammation and pregnancy. Antibodies from the third group proved to be prospective markers of a number of diseases, whereas their unusual level (below or above the norm) is not necessarily the consequence of disease/state. Modern microarrays allowed the determination of the human repertoire, which proved to be unexpectedly broad. It was observed that the content of some nAbs reaches about 0.1% of total immunoglobulins. Immunoglobulins of M class dominate for most nAbs, constituting up to 80-90%. Their affinity (to a monovalent glycan, in KD terms) were found to be within the range 10(-4)-10(-6) M. Antibodies to Galβ1-3GlcNAc (Le(C)), 4-HSO3Galβ1-4GalNAc (4'-O-SuLN), Fucα1-3GlcNAc, Fucα1-4GlcNAc, GalNAcα1-3Gal (Adi), Galα1-4Galβ1-4Glc (P(k)), Galα1-4Galβ1-4GlcNAc (P1), GlcNAcα-terminated glycans, and hyaluronic acid should be noted among the nAbs revealed and studied during the last decade. At the same time, a kind of "taboo" is observed for a number of glycans: antibodies to Le(X) and Le(Y), and almost all gangliosides have not been observed in healthy persons. Many of the revealed nAbs were directed to constrained inner (core) part of glycan, directly adjoined to lipid of cell membrane or protein. The biological function of these nAbs remains unclear; for anti-core antibodies, a role of surveillance on appearance of aberrant, especially cancer, antigens is supposed. The first data related to oncodiagnostics based on

Population-based study of invasive disease due to beta-hemolytic streptococci of groups other than A and B.

PubMed

Broyles, Laura N; Van Beneden, Chris; Beall, Bernard; Facklam, Richard; Shewmaker, P Lynn; Malpiedi, Paul; Daily, Pamala; Reingold, Arthur; Farley, Monica M

2009-03-15

Beta-hemolytic streptococci of groups other than A and B (NABS) are increasingly recognized as causes of clinically significant disease, but precise information about this heterogeneous group is lacking. We report the incidence of NABS infection and describe the epidemiologic and clinical characteristics. Active, population-based surveillance for invasive NABS was performed over a 2-year period in the 8-county metropolitan Atlanta, Georgia, area and the 3-county San Francisco Bay, California, area. Clinical records were reviewed, and available isolates were sent to the Centers for Disease Control and Prevention (Atlanta) for additional microbiologic characterization. Incidences were calculated using year-appropriate US Census Bureau data. A total of 489 cases of invasive NABS infection were identified (3.2 cases per 100,000 population). The median age of patients was 55 years; 64% of patients were males, and 87% had underlying diseases. The incidence was higher among black persons than white persons (4.0 vs. 2.5 cases per 100,000 population; P < .01) and increased with age among all races. Infections were community acquired in 416 cases (85%). Among the 450 patients (94%) with NABS infection who were hospitalized, 55 (12%) died. Of 266 isolates (54%) speciated at the Centers for Disease Control and Prevention, 212 (80%) were Streptococcus dysgalactiae subspecies equisimilis; 46 (17%) were members of the Streptococcus anginosus group. S. dysgalactiae subspecies equisimilis primarily presented as skin and soft-tissue infection in older patients, whereas individuals with invasive S. anginosus group infections were more likely to be younger patients with intra-abdominal infections. NABS comprise multiple distinct species that cause a significant number of community-acquired invasive infections. Clinical manifestations differ by species. Thus, speciation of invasive NABS may be warranted in clinical settings.

Breadth of neutralizing antibodies elicited by stable, homogeneous clade A and clade C HIV-1 gp140 envelope trimers in guinea pigs.

PubMed

Nkolola, Joseph P; Peng, Hanqin; Settembre, Ethan C; Freeman, Michael; Grandpre, Lauren E; Devoy, Colleen; Lynch, Diana M; La Porte, Annalena; Simmons, Nathaniel L; Bradley, Ritu; Montefiori, David C; Seaman, Michael S; Chen, Bing; Barouch, Dan H

2010-04-01

The native envelope (Env) spike on the surface of human immunodeficiency virus type 1 (HIV-1) is trimeric, and thus trimeric Env vaccine immunogens are currently being explored in preclinical immunogenicity studies. Key challenges have included the production and purification of biochemically homogeneous and stable trimers and the evaluation of these immunogens utilizing standardized virus panels for neutralization assays. Here we report the binding and neutralizing antibody (NAb) responses elicited by clade A (92UG037.8) and clade C (CZA97.012) Env gp140 trimer immunogens in guinea pigs. These trimers have been selected and engineered for optimal biochemical stability and have defined antigenic properties. Purified gp140 trimers with Ribi adjuvant elicited potent, cross-clade NAb responses against tier 1 viruses as well as detectable but low-titer NAb responses against select tier 2 viruses from clades A, B, and C. In particular, the clade C trimer elicited NAbs that neutralized 27%, 20%, and 47% of tier 2 viruses from clades A, B, and C, respectively. Heterologous DNA prime, protein boost as well as DNA prime, recombinant adenovirus boost regimens expressing these antigens, however, did not result in an increased magnitude or breadth of NAb responses in this system. These data demonstrate the immunogenicity of stable, homogeneous clade A and clade C gp140 trimers and exemplify the utility of standardized tier 1 and tier 2 virus panels for assessing the NAb responses of candidate HIV-1 Env immunogens.

Reliability of Pseudotyped Influenza Viral Particles in Neutralizing Antibody Detection

PubMed Central

Yang, Jinghui; Li, Weidong; Long, Yunfeng; Song, Shaohui; Liu, Jing; Zhang, Xinwen; Wang, Xiaoguang; Jiang, Shude; Liao, Guoyang

2014-01-01

Background Current influenza control strategies require an active surveillance system. Pseudotyped viral particles (pp) together with the evaluation of pre-existing immunity in a population might satisfy this requirement. However, the reliability of using pp in neutralizing antibody (nAb) detection are undefined. Methodology/Principal Findings Pseudotyped particles of A(H1N1)pmd09 (A/California/7/2009) and HPAI H5N1 (A/Anhui/1/2005), as well as their reassortants, were generated. The reliability of using these pp in nAb detection were compared concurrently with the corresponding viruses by a hemagglutination inhibition test, as well as ELISA-, cytopathic effect-, and fluorescence-based microneutralization assays. In the qualitative detection on nAbs, the pp and their corresponding viruses were in complete agreement, with an R2 value equal to or near 1 in two different populations. In the quantitative detection on nAbs, although the geometric mean titers (95% confidence interval) differed between the pp and viruses, no significant difference was observed. Furthermore, humoral immunity against the reassortants was evaluated; our results indicated strong consistency between the nAbs against reassortant pp and those against naïve pp harboring the same hemagglutinin. Conclusion/Significance The pp displayed high reliability in influenza virus nAb detection. The use of reassortant pp is a safe and convenient strategy for characterizing emerging influenza viruses and surveying the disease burden. PMID:25436460

The nuclear F-actin interactome of Xenopus oocytes reveals an actin-bundling kinesin that is essential for meiotic cytokinesis

PubMed Central

Samwer, Matthias; Dehne, Heinz-Jürgen; Spira, Felix; Kollmar, Martin; Gerlich, Daniel W; Urlaub, Henning; Görlich, Dirk

2013-01-01

Nuclei of Xenopus laevis oocytes grow 100 000-fold larger in volume than a typical somatic nucleus and require an unusual intranuclear F-actin scaffold for mechanical stability. We now developed a method for mapping F-actin interactomes and identified a comprehensive set of F-actin binders from the oocyte nuclei. Unexpectedly, the most prominent interactor was a novel kinesin termed NabKin (Nuclear and meiotic actin-bundling Kinesin). NabKin not only binds microtubules but also F-actin structures, such as the intranuclear actin bundles in prophase and the contractile actomyosin ring during cytokinesis. The interaction between NabKin and F-actin is negatively regulated by Importin-β and is responsive to spatial information provided by RanGTP. Disconnecting NabKin from F-actin during meiosis caused cytokinesis failure and egg polyploidy. We also found actin-bundling activity in Nabkin's somatic paralogue KIF14, which was previously shown to be essential for somatic cell division. Our data are consistent with the notion that NabKin/KIF14 directly link microtubules with F-actin and that such link is essential for cytokinesis. PMID:23727888

Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans

PubMed Central

Chou, Meng-Yun; Fogelstrand, Linda; Hartvigsen, Karsten; Hansen, Lotte F.; Woelkers, Douglas; Shaw, Peter X.; Choi, Jeomil; Perkmann, Thomas; Bäckhed, Fredrik; Miller, Yury I.; Hörkkö, Sohvi; Corr, Maripat; Witztum, Joseph L.; Binder, Christoph J.

2009-01-01

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of oxidized lipoproteins and apoptotic cells. Adaptive immune responses to various oxidation-specific epitopes play an important role in atherogenesis. However, accumulating evidence suggests that these epitopes are also recognized by innate receptors, such as scavenger receptors on macrophages, and plasma proteins, such as C-reactive protein (CRP). Here, we provide multiple lines of evidence that oxidation-specific epitopes constitute a dominant, previously unrecognized target of natural Abs (NAbs) in both mice and humans. Using reconstituted mice expressing solely IgM NAbs, we have shown that approximately 30% of all NAbs bound to model oxidation-specific epitopes, as well as to atherosclerotic lesions and apoptotic cells. Because oxidative processes are ubiquitous, we hypothesized that these epitopes exert selective pressure to expand NAbs, which in turn play an important role in mediating homeostatic functions consequent to inflammation and cell death, as demonstrated by their ability to facilitate apoptotic cell clearance. These findings provide novel insights into the functions of NAbs in mediating host homeostasis and into their roles in health and diseases, such as chronic inflammatory diseases and atherosclerosis. PMID:19363291

FUNDAMENTAL DIFFERENCES BETWEEN NATURAL ANTIBODIES AND POLYREACTIVE IMMUNOGLOBULINS.

PubMed

Bobrovnik, S A; Demchenko, M A; Komisarenko, S V

2015-01-01

A problem of similarity and differences between so-called polyreactive immunoglobulins (PRIGs) and natural antibodies (NAbs), capable of cross-reacting with some structurally dissimilar antigens, has been considered. The analysis of mechanisms of an unspecific interaction between PRIGs or NAbs and antigens evidences for the fact that essential differences exist between these substances. These differences permit classifying the abovementioned substances as different types of immunoglobulin molecules. The major difference between PRIGs and NAbs may include both the mechanisms of the above mentioned immunoglobulin molecules binding to antigens and their interaction affinity, as well as an absolutely different influence of some low-molecular substances on the efficiency of the interaction with antigens. Relying on the obtained data it can be assumed that, since PRIGs and NAbs have fundamental differences, they may perform not only similar but also different functions of the immune system.

Development of cement solidification process for sodium borate waste generated from PWR plants

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hirofumi Okabe; Tatsuaki Sato; Yuichi Shoji

2013-07-01

A cement solidification process for treating sodium borate waste produced in pressurized water reactor (PWR) plants was studied. To obtain high volume reduction and high mechanical strength of the waste, simulated concentrated borate liquid waste with a sodium / boron (Na/B) mole ratio of 0.27 was dehydrated and powdered by using a wiped film evaporator. To investigate the effect of the Na/B mole ratio on the solidification process, a sodium tetraborate decahydrate reagent with a Na/B mole ratio of 0.5 was also used. Ordinary portland cement (OPC) and some additives were used for the solidification. Solidified cement prepared from powderedmore » waste with a Na/B mole ratio 0.24 and having a high silica sand content (silica sand/cement>2) showed to improved uniaxial compressive strength. (authors)« less

Immunoglobulin with High-Titer In Vitro Cross-Neutralizing Hepatitis C Virus Antibodies Passively Protects Chimpanzees from Homologous, but Not Heterologous, Challenge

PubMed Central

Engle, Ronald E.; Faulk, Kristina; Wang, Richard Y.; Farci, Patrizia; Alter, Harvey J.; Purcell, Robert H.

2015-01-01

The importance of neutralizing antibodies (NAbs) in protection against hepatitis C virus (HCV) remains controversial. We infused a chimpanzee with H06 immunoglobulin from a genotype 1a HCV-infected patient and challenged with genotype strains efficiently neutralized by H06 in vitro. Genotype 1a NAbs afforded no protection against genotype 4a or 5a. Protection against homologous 1a lasted 18 weeks, but infection emerged when NAb titers waned. However, 6a infection was prevented. The differential in vivo neutralization patterns have implications for HCV vaccine development. PMID:26085160

Contributions of Science Principles to Teaching: How Science Principles Can Be Used

ERIC Educational Resources Information Center

Henson, Kenneth T.

1974-01-01

Describes the steps involved in using the "principles" approach in teaching science, illustrates the process of using science principles with an example relating to rock formation, and discusses the relevance of this approach to contemporary trends in science teaching. (JR)

Performance measurement for case management: principles and objectives for developing standard measures.

PubMed

Howe, Rufus

2005-01-01

Developing standardized performance measurements for case management (CM) has become the holy grail of the field. The Council for Case Management Accountability (CCMA), a leadership committee of the Case Management Society of America (CMSA), has been grappling with the concept since early 2003. This article lays out a theoretical framework for performance measurement and then outlines the progress on a specific initiative begun by CCMA to correlate CM practices with improved outcome measures.

Instructors' Use of the Principles of Teaching and Learning during College Class Sessions

ERIC Educational Resources Information Center

Foster, Daniel D.; Whittington, M. Susie

2017-01-01

The purpose of this study was to measure the frequency of utilization of the Principles of Teaching and Learning (Newcomb, McCracken, Warmbrod, & Whittington, 2004) during college class sessions. Process-product research was implemented (Gage, 1972; Rosenshine & Furst, 1973) using the Principles of Teaching and Learning Assessment (PTLA)…

Applying the four principles

PubMed Central

Macklin, R

2003-01-01

Gillon is correct that the four principles provide a sound and useful way of analysing moral dilemmas. As he observes, the approach using these principles does not provide a unique solution to dilemmas. This can be illustrated by alternatives to Gillon's own analysis of the four case scenarios. In the first scenario, a different set of factual assumptions could yield a different conclusion about what is required by the principle of beneficence. In the second scenario, although Gillon's conclusion is correct, what is open to question is his claim that what society regards as the child's best interest determines what really is in the child's best interest. The third scenario shows how it may be reasonable for the principle of beneficence to take precedence over autonomy in certain circumstances, yet like the first scenario, the ethical conclusion relies on a set of empirical assumptions and predictions of what is likely to occur. The fourth scenario illustrates how one can draw different conclusions based on the importance given to the precautionary principle. PMID:14519836

Applying the four principles.

PubMed

Macklin, R

2003-10-01

Gillon is correct that the four principles provide a sound and useful way of analysing moral dilemmas. As he observes, the approach using these principles does not provide a unique solution to dilemmas. This can be illustrated by alternatives to Gillon's own analysis of the four case scenarios. In the first scenario, a different set of factual assumptions could yield a different conclusion about what is required by the principle of beneficence. In the second scenario, although Gillon's conclusion is correct, what is open to question is his claim that what society regards as the child's best interest determines what really is in the child's best interest. The third scenario shows how it may be reasonable for the principle of beneficence to take precedence over autonomy in certain circumstances, yet like the first scenario, the ethical conclusion relies on a set of empirical assumptions and predictions of what is likely to occur. The fourth scenario illustrates how one can draw different conclusions based on the importance given to the precautionary principle.

The precautionary principle: is it safe.

PubMed

Gignon, Maxime; Ganry, Olivier; Jardé, Olivier; Manaouil, Cécile

2013-06-01

The precautionary principle is generally acknowledged to be a powerful tool for protecting health but it was originally invoked by policy makers for dealing with environmental issues. In the 1990s, the principle was incorporated into many legislative and regulatory texts in international law. One can consider that the precautionary principle has turned into "precautionism" necessary to prove to the people, taking account of risk in decisions. There is now a risk that these abuses will deprive the principle of its meaning and value. When pushed to its limits, the precautionary principle can even be dangerous when applied to the healthcare field. This is why a critical analysis of the principle is necessary. Through the literature, it sometimes seems to deviate somehow from the essence of the precautionary principle as it is commonly used in relation to health. We believe that educational work is necessary to familiarize professionals, policy makers and public opinion of the precautionary principle and avoid confusion. We propose a critical analysis of the use and misuse of the precautionary principle.

Crosscheck Principle in Pediatric Audiology Today: A 40-Year Perspective

PubMed Central

2016-01-01

The crosscheck principle is just as important in pediatric audiology as it was when first described 40 years ago. That is, no auditory test result should be accepted and used in the diagnosis of hearing loss until it is confirmed or crosschecked by one or more independent measures. Exclusive reliance on only one or two tests, even objective auditory measures, may result in a auditory diagnosis that is not clear or perhaps incorrect. On the other hand, close and careful analysis of findings for a test battery consisting of objective procedures and behavioral tests whenever feasible usually leads to prompt and accurate diagnosis of auditory dysfunction. This paper provides a concise review of the crosscheck principle from its introduction to its clinical application today. The review concludes with a description of a modern test battery for pediatric hearing assessment that supplements traditional behavioral tests with a variety of independent objective procedures including aural immittance measures, otoacoustic emissions, and auditory evoked responses. PMID:27626077

Crosscheck Principle in Pediatric Audiology Today: A 40-Year Perspective.

PubMed

Hall, James W

2016-09-01

The crosscheck principle is just as important in pediatric audiology as it was when first described 40 years ago. That is, no auditory test result should be accepted and used in the diagnosis of hearing loss until it is confirmed or crosschecked by one or more independent measures. Exclusive reliance on only one or two tests, even objective auditory measures, may result in a auditory diagnosis that is not clear or perhaps incorrect. On the other hand, close and careful analysis of findings for a test battery consisting of objective procedures and behavioral tests whenever feasible usually leads to prompt and accurate diagnosis of auditory dysfunction. This paper provides a concise review of the crosscheck principle from its introduction to its clinical application today. The review concludes with a description of a modern test battery for pediatric hearing assessment that supplements traditional behavioral tests with a variety of independent objective procedures including aural immittance measures, otoacoustic emissions, and auditory evoked responses.

Patterns of Hierarchy in Formal and Principled Moral Reasoning.

ERIC Educational Resources Information Center

Zeidler, Dana Lewis

Measurements of formal reasoning and principled moral reasoning ability were obtained from a sample of 99 tenth grade students. Specific modes of formal reasoning (proportional reasoning, controlling variables, probabilistic, correlational and combinatorial reasoning) were first examined. Findings support the notion of hierarchical relationships…

Basic principles of stability.

PubMed

Egan, William; Schofield, Timothy

2009-11-01

An understanding of the principles of degradation, as well as the statistical tools for measuring product stability, is essential to management of product quality. Key to this is management of vaccine potency. Vaccine shelf life is best managed through determination of a minimum potency release requirement, which helps assure adequate potency throughout expiry. Use of statistical tools such a least squares regression analysis should be employed to model potency decay. The use of such tools provides incentive to properly design vaccine stability studies, while holding stability measurements to specification presents a disincentive for collecting valuable data. The laws of kinetics such as Arrhenius behavior help practitioners design effective accelerated stability programs, which can be utilized to manage stability after a process change. Design of stability studies should be carefully considered, with an eye to minimizing the variability of the stability parameter. In the case of measuring the degradation rate, testing at the beginning and the end of the study improves the precision of this estimate. Additional design considerations such as bracketing and matrixing improve the efficiency of stability evaluation of vaccines.

48 CFR 49.113 - Cost principles.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 1 2010-10-01 2010-10-01 false Cost principles. 49.113 Section 49.113 Federal Acquisition Regulations System FEDERAL ACQUISITION REGULATION CONTRACT MANAGEMENT TERMINATION OF CONTRACTS General Principles 49.113 Cost principles. The cost principles and procedures in the...

Sustained Antibody Responses 6 Years Following 1, 2, or 3 Doses of Quadrivalent Human Papillomavirus (HPV) Vaccine in Adolescent Fijian Girls, and Subsequent Responses to a Single Dose of Bivalent HPV Vaccine: A Prospective Cohort Study.

PubMed

Toh, Zheng Quan; Russell, Fiona M; Reyburn, Rita; Fong, James; Tuivaga, Evelyn; Ratu, Tupou; Nguyen, Cattram D; Devi, Rachel; Kama, Mike; Matanitobua, Silivia; Tabrizi, Sepehr N; Garland, Suzanne M; Sinha, Rohit; Frazer, Ian; Tikoduadua, Lisi; Kado, Joseph; Rafai, Eric; Mulholland, Edward K; Licciardi, Paul V

2017-04-01

The duration of antibody response following reduced human papillomavirus (HPV) vaccine doses has not been determined. We compared the antibody responses in girls previously vaccinated with zero, 1, 2, or 3 doses of quadrivalent HPV vaccine (4vHPV; Gardasil, Merck) 6 years previously. A prospective cohort study was undertaken in 200 Fijian girls 15-19 years of age. Approximately equal numbers of girls from 2 main ethnic groups (Fijians of Indian descent [FID] and Indigenous Fijians [iTaukei]) in Fiji were recruited for each dosage groups. Blood was drawn before and 28 days following a single dose of bivalent HPV vaccine (2vHPV; Cervarix, GlaxoSmithKline). We measured neutralizing antibodies (NAb) against HPV-6, -11, -16, and -18 using the pseudovirion-based neutralization assay. After 6 years (before a dose of 2vHPV was given), the geometric mean NAb titers for all 4 HPV types were not statistically different between 2-dose (2D) and 3-dose (3D) recipients: HPV-6 (3D: 2216 [95% confidence interval {CI},1695-2896]; 2D: 1476 [95% CI, 1019-2137]; P = .07), HPV-11 (3D: 4431 [95% CI, 3396-5783]; 2D: 2951 [95% CI, 1984-4390]; P = .09), HPV-16 (3D: 3373 [95% CI, 2511-4530]; 2D: 3275 [95% CI, 2452-4373]; P = .89); HPV-18 (3D: 628 [95% CI: 445-888]; 2D: 606 [95% CI, 462-862]; P = .89), and were higher in FID than iTaukei girls. Although 1-dose recipients had significantly lower NAb titers than 2-/3-dose recipients, their NAb titers were 5- to 30-fold higher than unvaccinated girls. Post-2vHPV NAb titers against HPV-16 and -18 were not statistically different between girls who received 1, 2, or 3 doses of 4vHPV previously. Two doses of 4vHPV provide similar NAb titers as 3 doses for 6 years, although the clinical significance is unknown. A single dose of 4vHPV elicits antibodies that persisted for at least 6 years, and induced immune memory, suggesting possible protection against HPV vaccine types after a single dose of 4vHPV. © The Author 2016. Published by Oxford University

Principles of project management

NASA Technical Reports Server (NTRS)

1982-01-01

The basic principles of project management as practiced by NASA management personnel are presented. These principles are given as ground rules and guidelines to be used in the performance of research, development, construction or operational assignments.

A comparative genomics perspective on the genetic content of the alkaliphilic haloarchaeon Natrialba magadii ATCC 43099T

PubMed Central

2012-01-01

Background Natrialba magadii is an aerobic chemoorganotrophic member of the Euryarchaeota and is a dual extremophile requiring alkaline conditions and hypersalinity for optimal growth. The genome sequence of Nab. magadii type strain ATCC 43099 was deciphered to obtain a comprehensive insight into the genetic content of this haloarchaeon and to understand the basis of some of the cellular functions necessary for its survival. Results The genome of Nab. magadii consists of four replicons with a total sequence of 4,443,643 bp and encodes 4,212 putative proteins, some of which contain peptide repeats of various lengths. Comparative genome analyses facilitated the identification of genes encoding putative proteins involved in adaptation to hypersalinity, stress response, glycosylation, and polysaccharide biosynthesis. A proton-driven ATP synthase and a variety of putative cytochromes and other proteins supporting aerobic respiration and electron transfer were encoded by one or more of Nab. magadii replicons. The genome encodes a number of putative proteases/peptidases as well as protein secretion functions. Genes encoding putative transcriptional regulators, basal transcription factors, signal perception/transduction proteins, and chemotaxis/phototaxis proteins were abundant in the genome. Pathways for the biosynthesis of thiamine, riboflavin, heme, cobalamin, coenzyme F420 and other essential co-factors were deduced by in depth sequence analyses. However, approximately 36% of Nab. magadii protein coding genes could not be assigned a function based on Blast analysis and have been annotated as encoding hypothetical or conserved hypothetical proteins. Furthermore, despite extensive comparative genomic analyses, genes necessary for survival in alkaline conditions could not be identified in Nab. magadii. Conclusions Based on genomic analyses, Nab. magadii is predicted to be metabolically versatile and it could use different carbon and energy sources to sustain growth. Nab

Guiding Restoration Principles

DTIC Science & Technology

2004-12-01

novaeangliae). Rapid, unexplained declines in the populations of the southern pod of resident Puget Sound orcas (Orcinus orca ), groundfi sh such as...Guiding Restoration Principles 1 Technical Report 2004-03 Guiding Restoration Principles Prepared in support of the Puget Sound ...Kurt Fresh, Tom Mumford and Miles Logsdon Puget Sound Nearshore Partnership WDFW - P.O. Box 43145, Olympia Washington 98504-3145 U.S. Army Corps of

A review of the generalized uncertainty principle.

PubMed

Tawfik, Abdel Nasser; Diab, Abdel Magied

2015-12-01

Based on string theory, black hole physics, doubly special relativity and some 'thought' experiments, minimal distance and/or maximum momentum are proposed. As alternatives to the generalized uncertainty principle (GUP), the modified dispersion relation, the space noncommutativity, the Lorentz invariance violation, and the quantum-gravity-induced birefringence effects are summarized. The origin of minimal measurable quantities and the different GUP approaches are reviewed and the corresponding observations are analysed. Bounds on the GUP parameter are discussed and implemented in the understanding of recent PLANCK observations of cosmic inflation. The higher-order GUP approaches predict minimal length uncertainty with and without maximum momenta. Possible arguments against the GUP are discussed; for instance, the concern about its compatibility with the equivalence principles, the universality of gravitational redshift and the free fall and law of reciprocal action are addressed.

32 CFR 203.6 - Cost principles.

Code of Federal Regulations, 2010 CFR

2010-07-01

... 32 National Defense 2 2010-07-01 2010-07-01 false Cost principles. 203.6 Section 203.6 National... Cost principles. (a) Non-profit contractors must comply with the cost principles in OMB Circular A-122...) For-profit contractors and subcontractors must comply with the cost principles in the FAR (48 CFR part...

Positron Emission Tomography: Principles, Technology, and Recent Developments

NASA Astrophysics Data System (ADS)

Ziegler, Sibylle I.

2005-04-01

Positron emission tomography (PET) is a nuclear medical imaging technique for quantitative measurement of physiologic parameters in vivo (an overview of principles and applications can be found in [P.E. Valk, et al., eds. Positron Emission Tomography. Basic Science and Clinical Practice. 2003, Springer: Heidelberg]), based on the detection of small amounts of posi-tron-emitter-labelled biologic molecules. Various radiotracers are available for neuro-logical, cardiological, and oncological applications in the clinic and in research proto-cols. This overview describes the basic principles, technology, and recent develop-ments in PET, followed by a section on the development of a tomograph with ava-lanche photodiodes dedicated for small animal imaging as an example of efforts in the domain of high resolution tomographs.

Principles for School Drug Education

ERIC Educational Resources Information Center

Meyer, Lois

2004-01-01

This document presents a revised set of principles for school drug education. The principles for drug education in schools comprise an evolving framework that has proved useful over a number of decades in guiding the development of effective drug education. The first edition of "Principles for Drug Education in Schools" (Ballard et al.…

The exosome component Rrp6 is required for RNA polymerase II termination at specific targets of the Nrd1-Nab3 pathway.

PubMed

Fox, Melanie J; Gao, Hongyu; Smith-Kinnaman, Whitney R; Liu, Yunlong; Mosley, Amber L

2015-01-01

The exosome and its nuclear specific subunit Rrp6 form a 3'-5' exonuclease complex that regulates diverse aspects of RNA biology including 3' end processing and degradation of a variety of noncoding RNAs (ncRNAs) and unstable transcripts. Known targets of the nuclear exosome include short (<1000 bp) RNAPII transcripts such as small noncoding RNAs (snRNAs), cryptic unstable transcripts (CUTs), and some stable unannotated transcripts (SUTs) that are terminated by an Nrd1, Nab3, and Sen1 (NNS) dependent mechanism. NNS-dependent termination is coupled to RNA 3' end processing and/or degradation by the Rrp6/exosome in yeast. Recent work suggests Nrd1 is necessary for transcriptome surveillance, regulating promoter directionality and suppressing antisense transcription independently of, or prior to, Rrp6 activity. It remains unclear whether Rrp6 is directly involved in termination; however, Rrp6 has been implicated in the 3' end processing and degradation of ncRNA transcripts including CUTs. To determine the role of Rrp6 in NNS termination globally, we performed RNA sequencing (RNA-Seq) on total RNA and perform ChIP-exo analysis of RNA Polymerase II (RNAPII) localization. Deletion of RRP6 promotes hyper-elongation of multiple NNS-dependent transcripts resulting from both improperly processed 3' RNA ends and faulty transcript termination at specific target genes. The defects in RNAPII termination cause transcriptome-wide changes in mRNA expression through transcription interference and/or antisense repression, similar to previously reported effects of depleting Nrd1 from the nucleus. Elongated transcripts were identified within all classes of known NNS targets with the largest changes in transcription termination occurring at CUTs. Interestingly, the extended transcripts that we have detected in our studies show remarkable similarity to Nrd1-unterminated transcripts at many locations, suggesting that Rrp6 acts with the NNS complex globally to promote transcription

Availability of Care Concordant With Patient-centered Medical Home Principles Among Those With Chronic Conditions: Measuring Care Outcomes.

PubMed

Pourat, Nadereh; Charles, Shana A; Snyder, Sophie

2016-03-01

Care delivery redesign in the form of patient-centered medical home (PCMH) is considered as a potential solution to improve patient outcomes and reduce costs, particularly for patients with chronic conditions. But studies of prevalence or impact at the population level are rare. We aimed to assess whether desired outcomes indicating better care delivery and patient-centeredness were associated with receipt of care according to 3 important PCMH principles. We analyzed data from a representative population survey in California in 2009, focusing on a population with chronic condition who had a usual source of care. We used bivariate, logistic, and negative-binomial regressions. The indicators of PCMH concordant care included continuity of care (personal doctor), care coordination, and care management (individual treatment plan). Outcomes included flu shots, count of outpatient visits, any emergency department visit, timely provider communication, and confidence in self-care. We found that patients whose care was concordant with all 3 PCMH principles were more likely to receive flu shots, more outpatient care, and timely response from providers. Concordance with 2 principles led to some desired outcomes. Concordance with only 1 principle was not associated with desired outcomes. Patients who received care that met 3 key aspects of PCMH: coordination, continuity, and management, had better quality of care and more efficient use of the health care system.

Developmental Principles: Fact or Fiction

PubMed Central

Durston, A. J.

2012-01-01

While still at school, most of us are deeply impressed by the underlying principles that so beautifully explain why the chemical elements are ordered as they are in the periodic table, and may wonder, with the theoretician Brian Goodwin, “whether there might be equally powerful principles that account for the awe-inspiring diversity of body forms in the living realm”. We have considered the arguments for developmental principles, conclude that they do exist and have specifically identified features that may generate principles associated with Hox patterning of the main body axis in bilaterian metazoa in general and in the vertebrates in particular. We wonder whether this exercise serves any purpose. The features we discuss were already known to us as parts of developmental mechanisms and defining developmental principles (how, and at which level?) adds no insight. We also see little profit in the proposal by Goodwin that there are principles outside the emerging genetic mechanisms that need to be taken into account. The emerging developmental genetic hierarchies already reveal a wealth of interesting phenomena, whatever we choose to call them. PMID:22489210

Developmental principles: fact or fiction.

PubMed

Durston, A J

2012-01-01

While still at school, most of us are deeply impressed by the underlying principles that so beautifully explain why the chemical elements are ordered as they are in the periodic table, and may wonder, with the theoretician Brian Goodwin, "whether there might be equally powerful principles that account for the awe-inspiring diversity of body forms in the living realm". We have considered the arguments for developmental principles, conclude that they do exist and have specifically identified features that may generate principles associated with Hox patterning of the main body axis in bilaterian metazoa in general and in the vertebrates in particular. We wonder whether this exercise serves any purpose. The features we discuss were already known to us as parts of developmental mechanisms and defining developmental principles (how, and at which level?) adds no insight. We also see little profit in the proposal by Goodwin that there are principles outside the emerging genetic mechanisms that need to be taken into account. The emerging developmental genetic hierarchies already reveal a wealth of interesting phenomena, whatever we choose to call them.

Multiple human papillomavirus infections and type-competition in women from a clinic attendee population in China.

PubMed

Nie, Jianhui; Liu, Jianhua; Xie, Hui; Sun, Zhengrong; Zhao, Juan; Chen, Qingqing; Liu, Yangyang; Huang, Weijin; Ruan, Qiang; Wang, Youchun

2016-11-01

To investigate the multi-infection patterns and type competition for human papillomavirus (HPV) in Chinese clinic attending women and evaluate the association between the infection status and cancer risk. Three hundred and thirty-two HPV-DNA-positive samples were genotyped for 21 HPVs and tested for 13 types of HPV neutralizing antibody using pseudoviron-based assay. Odds ratios (ORs) were calculated to evaluate the coinfection patterns for both DNA and neutralizing antibody (NAb), and the associations of HSIL+ with HPV DNA and NAb. Of the 332 HPV-DNA-positive subjects, 279 (84.0%) were detected as NAb positive. Multi-positive results were identified in 23.2% (77/332) HPV DNA tests and 60.2% (168/279) HPV NAb assays. The NAb titers for the multiple-positive samples (geometric mean 214) were significantly higher than the single-positive samples (geometric mean 114) (P < 0.01). HPV16-HPV52 was identified as a type-competition pair for both HPV DNA (OR = 0.09; 95%CI = 0.02-0.42) and NAb (OR = 0.27; 95%CI = 0.11-0.69) data. Compared to other types, HPV16 DNA was associated significantly with high risk of HSIL+ (OR = 2.57; 95%CI = 1.23-5.38). HPV16-HPV52 was identified as a potential type-competition pair, which might result in the type modulation with the implementation of the approved bi- or quadri-valent vaccines. J. Med. Virol. 88:1989-1998, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The neural circuits for arithmetic principles.

PubMed

Liu, Jie; Zhang, Han; Chen, Chuansheng; Chen, Hui; Cui, Jiaxin; Zhou, Xinlin

2017-02-15

Arithmetic principles are the regularities underlying arithmetic computation. Little is known about how the brain supports the processing of arithmetic principles. The current fMRI study examined neural activation and functional connectivity during the processing of verbalized arithmetic principles, as compared to numerical computation and general language processing. As expected, arithmetic principles elicited stronger activation in bilateral horizontal intraparietal sulcus and right supramarginal gyrus than did language processing, and stronger activation in left middle temporal lobe and left orbital part of inferior frontal gyrus than did computation. In contrast, computation elicited greater activation in bilateral horizontal intraparietal sulcus (extending to posterior superior parietal lobule) than did either arithmetic principles or language processing. Functional connectivity analysis with the psychophysiological interaction approach (PPI) showed that left temporal-parietal (MTG-HIPS) connectivity was stronger during the processing of arithmetic principle and language than during computation, whereas parietal-occipital connectivities were stronger during computation than during the processing of arithmetic principles and language. Additionally, the left fronto-parietal (orbital IFG-HIPS) connectivity was stronger during the processing of arithmetic principles than during computation. The results suggest that verbalized arithmetic principles engage a neural network that overlaps but is distinct from the networks for computation and language processing. Copyright © 2016 Elsevier Inc. All rights reserved.

Archimedes' Principle in General Coordinates

ERIC Educational Resources Information Center

Ridgely, Charles T.

2010-01-01

Archimedes' principle is well known to state that a body submerged in a fluid is buoyed up by a force equal to the weight of the fluid displaced by the body. Herein, Archimedes' principle is derived from first principles by using conservation of the stress-energy-momentum tensor in general coordinates. The resulting expression for the force is…

75 FR 9878 - Draft Principles and Standards Sections of the “Economic and Environmental Principles and...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-04

... COUNCIL ON ENVIRONMENTAL QUALITY Draft Principles and Standards Sections of the ``Economic and Environmental Principles and Guidelines for Water and Related Land Resources Implementation Studies... the ``Economic and Environmental Principles and Guidelines for Water and Related Land Resources...

Exploring Cramming: Student Behaviors, Beliefs, and Learning Retention in the Principles of Marketing Course

ERIC Educational Resources Information Center

McIntyre, Shelby H.; Munson, J. Michael

2008-01-01

Cramming for finals is common on college campuses, and many students seem to cram for their final in the Principles of Marketing course. This article addresses the question of defining and measuring a "cramming study strategy." Scales are developed to assess (a) cramming for courses in general and (b) cramming specifically in the Principles of…

Endorsement of universal health coverage financial principles in Burkina Faso.

PubMed

Agier, Isabelle; Ly, Antarou; Kadio, Kadidiatou; Kouanda, Seni; Ridde, Valéry

2016-02-01

In West Africa, health system funding rarely involves cross-subsidization among population segments. In some countries, a few community-based or professional health insurance programs are present, but coverage is very low. The financial principles underlying universal health coverage (UHC) sustainability and solidarity are threefold: 1) anticipation of potential health risks; 2) risk sharing and; 3) socio-economic status solidarity. In Burkina Faso, where decision-makers are favorable to national health insurance, we measured endorsement of these principles and discerned which management configurations would achieve the greatest adherence. We used a sequential exploratory design. In a qualitative step (9 interviews, 12 focus groups), we adapted an instrument proposed by Goudge et al. (2012) to the local context and addressed desirability bias. Then, in a quantitative step (1255 respondents from the general population), we measured endorsement. Thematic analysis (qualitative) and logistic regressions (quantitative) were used. High levels of endorsement were found for each principle. Actual practices showed that anticipation and risk sharing were not only intentions. Preferences were given to solidarity between socio-economic status (SES) levels and progressivity. Although respondents seemed to prefer the national level for implementation, their current solidarity practices were mainly focused on close family. Thus, contribution levels should be set so that the entire family benefits from healthcare. Some critical conditions must be met to make UHC financial principles a reality through health insurance in Burkina Faso: trust, fair and mandatory contributions, and education. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

A Free Energy Principle for Biological Systems

PubMed Central

Karl, Friston

2012-01-01

This paper describes a free energy principle that tries to explain the ability of biological systems to resist a natural tendency to disorder. It appeals to circular causality of the sort found in synergetic formulations of self-organization (e.g., the slaving principle) and models of coupled dynamical systems, using nonlinear Fokker Planck equations. Here, circular causality is induced by separating the states of a random dynamical system into external and internal states, where external states are subject to random fluctuations and internal states are not. This reduces the problem to finding some (deterministic) dynamics of the internal states that ensure the system visits a limited number of external states; in other words, the measure of its (random) attracting set, or the Shannon entropy of the external states is small. We motivate a solution using a principle of least action based on variational free energy (from statistical physics) and establish the conditions under which it is formally equivalent to the information bottleneck method. This approach has proved useful in understanding the functional architecture of the brain. The generality of variational free energy minimisation and corresponding information theoretic formulations may speak to interesting applications beyond the neurosciences; e.g., in molecular or evolutionary biology. PMID:23204829

The Effect of Economic Interdependence on Foreign Relations: Implications for Linkage Diplomacy

DTIC Science & Technology

1980-08-01

each member of a dyad, nAB and nBA , or the dyadic interaction eZasticity, n., is proportional to the change 1 in intensity that is attributable to...these few successes were soon reversed as a result of Congressional dis- pleasure with Soviet domestic policies. As a case in point, he cites the...3.18) flT t ex I ( i,t nAB + i,t) nBA ’ or (3.19) I’n ex In. t’ where t 1, (3.20) n. t i,t + i,t 1, nAB nBA . (3.21) n. t is then the

Global ethics and principlism.

PubMed

Gordon, John-Stewart

2011-09-01

This article examines the special relation between common morality and particular moralities in the four-principles approach and its use for global ethics. It is argued that the special dialectical relation between common morality and particular moralities is the key to bridging the gap between ethical universalism and relativism. The four-principles approach is a good model for a global bioethics by virtue of its ability to mediate successfully between universal demands and cultural diversity. The principle of autonomy (i.e., the idea of individual informed consent), however, does need to be revised so as to make it compatible with alternatives such as family- or community-informed consent. The upshot is that the contribution of the four-principles approach to global ethics lies in the so-called dialectical process and its power to deal with cross-cultural issues against the background of universal demands by joining them together.

First-Principles pH Theory

NASA Astrophysics Data System (ADS)

Kim, Yong-Hyun; Zhang, S. B.

2006-03-01

Despite being one of the most important macroscopic measures and a long history even before the quantum mechanics, the concept of pH has rarely been mentioned in microscopic theories, nor being incorporated computationally into first-principles theory of aqueous solutions. Here, we formulate a theory for the pH dependence of solution formation energy by introducing the proton chemical potential as the microscopic counterpart of pH in atomistic solution models. Within the theory, the general acid-base chemistry can be cast in a simple pictorial representation. We adopt density-functional molecular dynamics to demonstrate the usefulness of the method by studying a number of solution systems including water, small solute molecules such as NH3 and HCOOH, and more complex amino acids with several functional groups. For pure water, we calculated the auto- ionization constant to be 13.2 with a 95 % accuracy. For other solutes, the calculated dissociation constants, i.e., the so- called pKa, are also in reasonable agreement with experiments. Our first-principles pH theory can be readily applied to broad solution chemistry problems such as redox reactions.

[Microbiota of lower urine tract and genital organs of healthy men and in infertility].

PubMed

Naboka, Iu L; Kogan, M I; Gudima, I A; Ibishev, Kh S; Pasechnik, D G; Logvinov, A K; Ilmdarov, Sh B

2015-01-01

Study microflora of urine, ejaculate, urethra scrape in normal state and infertility. 2 groups of men were examined: I (28)--control, conditionally healthy men (20 - 25 years of age), II (26)--infertile patients (25 - 35 years of age). Middle portion of morning urine, ejaculate, urethra scrape were studied in group I, in II--ejaculate. Bacteriologic study of urine and ejaculate was carried out in an extended kit of nutrient media (HiMedia) for facultative- anaerobic (FAB) and non-clostridia anaerobic bacteria (NAB). Urethra scrape and ejaculate were studied by PCR in group I. In urethra scrape and ejaculate a wide spectrum of FAB and NAB was detected in group I. Corynebacterium spp. and coagulase-negative staphylococci (67.9% each) were the dominant cluster of FAB. Eubacterium spp.--in NAB. Bacteriologic study of ejaculate corresponded in PCR with similar results of dominating bacteria. Among FAB the same clusters dominated during bacteriologic study of ejaculate from group II patients, among NAB--Propionibacterium spp., Peptococcus spp. and Peptostreptococcus spp. Quantitative characteristics of ejaculate of group I and II differed insignificantly. The frequency of detection of certain genera of FAB and NAB was significantly higher in patients with infertility than in conditionally healthy men, however quantitative parameters of the isolated microorganisms practically did not differ between groups.

Arenavirus Glycan Shield Promotes Neutralizing Antibody Evasion and Protracted Infection

PubMed Central

Malinge, Pauline; Magistrelli, Giovanni; Fischer, Nicolas; Sahin, Mehmet; Bergthaler, Andreas; Igonet, Sebastien; ter Meulen, Jan; Rigo, Dorothée; Meda, Paolo; Rabah, Nadia; Coutard, Bruno; Bowden, Thomas A.; Lambert, Paul-Henri; Siegrist, Claire-Anne; Pinschewer, Daniel D.

2015-01-01

Arenaviruses such as Lassa virus (LASV) can cause severe hemorrhagic fever in humans. As a major impediment to vaccine development, delayed and weak neutralizing antibody (nAb) responses represent a unifying characteristic of both natural infection and all vaccine candidates tested to date. To investigate the mechanisms underlying arenavirus nAb evasion we engineered several arenavirus envelope-chimeric viruses and glycan-deficient variants thereof. We performed neutralization tests with sera from experimentally infected mice and from LASV-convalescent human patients. NAb response kinetics in mice correlated inversely with the N-linked glycan density in the arenavirus envelope protein’s globular head. Additionally and most intriguingly, infection with fully glycosylated viruses elicited antibodies, which neutralized predominantly their glycan-deficient variants, both in mice and humans. Binding studies with monoclonal antibodies indicated that envelope glycans reduced nAb on-rate, occupancy and thereby counteracted virus neutralization. In infected mice, the envelope glycan shield promoted protracted viral infection by preventing its timely elimination by the ensuing antibody response. Thus, arenavirus envelope glycosylation impairs the protective efficacy rather than the induction of nAbs, and thereby prevents efficient antibody-mediated virus control. This immune evasion mechanism imposes limitations on antibody-based vaccination and convalescent serum therapy. PMID:26587982

HIV-1 Cross-Reactive Primary Virus Neutralizing Antibody Response Elicited by Immunization in Nonhuman Primates

PubMed Central

Wang, Yimeng; O'Dell, Sijy; Turner, Hannah L.; Chiang, Chi-I; Lei, Lin; Guenaga, Javier; Wilson, Richard; Martinez-Murillo, Paola; Doria-Rose, Nicole; Ward, Andrew B.; Mascola, John R.; Wyatt, Richard T.; Karlsson Hedestam, Gunilla B.

2017-01-01

ABSTRACT Elicitation of broadly neutralizing antibody (bNAb) responses is a major goal for the development of an HIV-1 vaccine. Current HIV-1 envelope glycoprotein (Env) vaccine candidates elicit predominantly tier 1 and/or autologous tier 2 virus neutralizing antibody (NAb) responses, as well as weak and/or sporadic cross-reactive tier 2 virus NAb responses with unknown specificity. To delineate the specificity of vaccine-elicited cross-reactive tier 2 virus NAb responses, we performed single memory B cell sorting from the peripheral blood of a rhesus macaque immunized with YU2gp140-F trimers in adjuvant, using JR-FL SOSIP.664, a native Env trimer mimetic, as a sorting probe to isolate monoclonal Abs (MAbs). We found striking genetic and functional convergence of the SOSIP-sorted Ig repertoire, with predominant VH4 or VH5 gene family usage and Env V3 specificity. Of these vaccine-elicited V3-specific MAbs, nearly 20% (6/33) displayed cross-reactive tier 2 virus neutralization, which recapitulated the serum neutralization capacity. Substantial similarities in binding specificity, neutralization breadth and potency, and sequence/structural homology were observed between selected macaque cross-reactive V3 NAbs elicited by vaccination and prototypic V3 NAbs derived from natural infections in humans, highlighting the convergence of this subset of primate V3-specific B cell repertories. Our study demonstrated that cross-reactive primary virus neutralizing B cell lineages could be elicited by vaccination as detected using a standardized panel of tier 2 viruses. Whether these lineages could be expanded to acquire increased breadth and potency of neutralization merits further investigation. IMPORTANCE Elicitation of antibody responses capable of neutralizing diverse HIV-1 primary virus isolates (designated broadly neutralizing antibodies [bNAbs]) remains a high priority for the vaccine field. bNAb responses were so far observed only in response to natural infection within

The accentuation principle of figure-ground segregation and the downbeat illusion.

PubMed

Pinna, Baingio; Sirigu, Luca

2016-10-01

Pinna and Sirigu (2011) demonstrated a new principle of grouping, called the accentuation principle, stating that, all else being equal, elements tend to group in the same oriented direction of the discontinuous element placed within a whole set of continuous/homogeneous components. The discontinuous element behaves like an accent, i.e. a visual emphasis within the wholeness of components as shown in the next section. In this work, the accentuation principle has been extended to new visual domains. In particular, it is shown how this principle affects shape perception. Moreover several visual object attributes are also highlighted, among which orientation, spatial position, inner dynamics and apparent motion that determine the so-called organic segmentation and furthermore tend to induce figure-ground segregation. On the basis of the results of experimental phenomenology, the accentuation can be considered as a complex principle ruling grouping, figure-ground segregation, shape and meaning formation. Through a new musical illusion of downbeat, it is also demonstrated that this principle influences perceptual organization not only in space but also in time and, thus, in both visual and musical domains. This illusion can be heard in eight measures of Pagodes, a solo piano music by Claude Debussy (1862-1918), where a strong physical-perceptual discrepancy in terms of upbeats and downbeats inversion is strongly perceived in both staves. Copyright © 2016 Elsevier B.V. All rights reserved.

Other ways of measuring `Big G'

NASA Astrophysics Data System (ADS)

Rothleitner, Christian

2016-03-01

In 1798, the British scientist Henry Cavendish performed the first laboratory experiment to determine the gravitational force between two massive bodies. From his result, Newton's gravitational constant, G, was calculated. Cavendish's measurement principle was the torsion balance invented by John Michell some 15 years before. During the following two centuries, more than 300 new measurements followed. Although technology - and physics - developed rapidly during this time, surprisingly, most experiments were still based on the same principle. In fact, the most accurate determination of G to date is a measurement based on the torsion balance principle. Despite the fact that G was one of the first fundamental physical constants ever measured, and despite the huge number of experiments performed on it to this day, its CODATA recommended value still has the highest standard measurement uncertainty when compared to other fundamental physical constants. Even more serious is the fact that even measurements based on the same principle often do not overlap within their attributed standard uncertainties. It must be assumed that various experiments are subject to one or more unknown biases. In this talk I will present some alternative experimental setups to the torsion balance which have been performed or proposed to measure G. Although their estimated uncertainties are often higher than most torsion balance experiments, revisiting such ideas is worthwhile. Advances in technology could offer solutions to problems which were previously insurmountable, these solutions could result in lower measurement uncertainties. New measurement principles could also help to uncover hidden systematic effects.

Disordered crystals from first principles I: Quantifying the configuration space

NASA Astrophysics Data System (ADS)

Kühne, Thomas D.; Prodan, Emil

2018-04-01

This work represents the first chapter of a project on the foundations of first-principle calculations of the electron transport in crystals at finite temperatures. We are interested in the range of temperatures, where most electronic components operate, that is, room temperature and above. The aim is a predictive first-principle formalism that combines ab-initio molecular dynamics and a finite-temperature Kubo-formula for homogeneous thermodynamic phases. The input for this formula is the ergodic dynamical system (Ω , G , dP) defining the thermodynamic crystalline phase, where Ω is the configuration space for the atomic degrees of freedom, G is the space group acting on Ω and dP is the ergodic Gibbs measure relative to the G-action. The present work develops an algorithmic method for quantifying (Ω , G , dP) from first principles. Using the silicon crystal as a working example, we find the Gibbs measure to be extremely well characterized by a multivariate normal distribution, which can be quantified using a small number of parameters. The latter are computed at various temperatures and communicated in the form of a table. Using this table, one can generate large and accurate thermally-disordered atomic configurations to serve, for example, as input for subsequent simulations of the electronic degrees of freedom.

A Principle of Intentionality.

PubMed

Turner, Charles K

2017-01-01

The mainstream theories and models of the physical sciences, including neuroscience, are all consistent with the principle of causality. Wholly causal explanations make sense of how things go, but are inherently value-neutral, providing no objective basis for true beliefs being better than false beliefs, nor for it being better to intend wisely than foolishly. Dennett (1987) makes a related point in calling the brain a syntactic (procedure-based) engine. He says that you cannot get to a semantic (meaning-based) engine from there. He suggests that folk psychology revolves around an intentional stance that is independent of the causal theories of the brain, and accounts for constructs such as meanings, agency, true belief, and wise desire. Dennett proposes that the intentional stance is so powerful that it can be developed into a valid intentional theory. This article expands Dennett's model into a principle of intentionality that revolves around the construct of objective wisdom. This principle provides a structure that can account for all mental processes, and for the scientific understanding of objective value. It is suggested that science can develop a far more complete worldview with a combination of the principles of causality and intentionality than would be possible with scientific theories that are consistent with the principle of causality alone.

A Principle of Intentionality

PubMed Central

Turner, Charles K.

2017-01-01

The mainstream theories and models of the physical sciences, including neuroscience, are all consistent with the principle of causality. Wholly causal explanations make sense of how things go, but are inherently value-neutral, providing no objective basis for true beliefs being better than false beliefs, nor for it being better to intend wisely than foolishly. Dennett (1987) makes a related point in calling the brain a syntactic (procedure-based) engine. He says that you cannot get to a semantic (meaning-based) engine from there. He suggests that folk psychology revolves around an intentional stance that is independent of the causal theories of the brain, and accounts for constructs such as meanings, agency, true belief, and wise desire. Dennett proposes that the intentional stance is so powerful that it can be developed into a valid intentional theory. This article expands Dennett’s model into a principle of intentionality that revolves around the construct of objective wisdom. This principle provides a structure that can account for all mental processes, and for the scientific understanding of objective value. It is suggested that science can develop a far more complete worldview with a combination of the principles of causality and intentionality than would be possible with scientific theories that are consistent with the principle of causality alone. PMID:28223954

Evaluation of the effect of compression therapy using surgical gloves on nanoparticle albumin-bound paclitaxel-induced peripheral neuropathy: a phase II multicenter study by the Kamigata Breast Cancer Study Group.

PubMed

Tsuyuki, Shigeru; Senda, Noriko; Kanng, Yookija; Yamaguchi, Ayane; Yoshibayashi, Hiroshi; Kikawa, Yuichiro; Katakami, Nobuyuki; Kato, Hironori; Hashimoto, Takashi; Okuno, Toshitaka; Yamauchi, Akira; Inamoto, Takashi

2016-11-01

To investigate the efficacy of using surgical glove (SG) compression therapy to prevent nanoparticle albumin-bound paclitaxel (nab-PTX)-induced peripheral neuropathy. Patients with primary and recurrent breast cancer who received 260 mg/m 2 of nab-PTX were eligible for this case-control study. Patients wore two SGs of the same size, i.e., one size smaller than the size that fit their dominant hand, for only 90 min. They did not wear two SGs on the non-dominant hand, which served as the control hand. Peripheral neuropathy was evaluated at each treatment cycle using common terminology criteria for adverse events (CTCAE) version 4.0 and the Patient Neurotoxicity Questionnaire. The temperature of each fingertip of the compression SG-protected hand and control hand was measured using thermography. Between August 2013 and January 2016, 43 patients were enrolled and 42 were evaluated. The occurrence rates of CTCAE grade 2 or higher sensory and motor peripheral neuropathies were significantly lower for SG-protected hands than for control hands (sensory neuropathy 21.4 vs. 76.1 %; motor neuropathy 26.2 vs. 57.1 %). No patients withdrew from this study because they could not tolerate the compression from the SGs. SG compression therapy significantly decreased the temperature of each fingertip by 1.6-2.2 °C as compared with the temperature before chemotherapy (p < 0.0001). SG compression therapy is effective for reducing nab-PTX-induced peripheral neuropathy. The nab-PTX exposure to the peripheral nerve may be decreased because the SG decreases microvascular flow to the fingertip.

A Canadian framework for applying the precautionary principle to public health issues.

PubMed

Weir, Erica; Schabas, Richard; Wilson, Kumanan; Mackie, Chris

2010-01-01

The precautionary principle has influenced environmental and public health policy. It essentially states that complete evidence of a potential risk is not required before action is taken to mitigate the effects of the potential risk. The application of precaution to public health issues is not straightforward and could paradoxically cause harm to the public's health when applied inappropriately. To avoid this, we propose a framework for applying the precautionary principle to potential public health risks. The framework consists of ten guiding questions to help establish whether a proposed application of the precautionary principle on a public health matter is based on adequacy of the evidence of causation, severity of harm and acceptability of the precautionary measures.

Constraining the generalized uncertainty principle with the atomic weak-equivalence-principle test

NASA Astrophysics Data System (ADS)

Gao, Dongfeng; Wang, Jin; Zhan, Mingsheng

2017-04-01

Various models of quantum gravity imply the Planck-scale modifications of Heisenberg's uncertainty principle into a so-called generalized uncertainty principle (GUP). The GUP effects on high-energy physics, cosmology, and astrophysics have been extensively studied. Here, we focus on the weak-equivalence-principle (WEP) violation induced by the GUP. Results from the WEP test with the 85Rb-87Rb dual-species atom interferometer are used to set upper bounds on parameters in two GUP proposals. A 1045-level bound on the Kempf-Mangano-Mann proposal and a 1027-level bound on Maggiore's proposal, which are consistent with bounds from other experiments, are obtained. All these bounds have huge room for improvement in the future.

Applying multimedia design principles enhances learning in medical education.

PubMed

Issa, Nabil; Schuller, Mary; Santacaterina, Susan; Shapiro, Michael; Wang, Edward; Mayer, Richard E; DaRosa, Debra A

2011-08-01

The Association of American Medical Colleges' Institute for Improving Medical Education's report entitled 'Effective Use of Educational Technology' called on researchers to study the effectiveness of multimedia design principles. These principles were empirically shown to result in superior learning when used with college students in laboratory studies, but have not been studied with undergraduate medical students as participants. A pre-test/post-test control group design was used, in which the traditional-learning group received a lecture on shock using traditionally designed slides and the modified-design group received the same lecture using slides modified in accord with Mayer's principles of multimedia design. Participants included Year 3 medical students at a private, midwestern medical school progressing through their surgery clerkship during the academic year 2009-2010. The medical school divides students into four groups; each group attends the surgery clerkship during one of the four quarters of the academic year. Students in the second and third quarters served as the modified-design group (n=91) and students in the fourth-quarter clerkship served as the traditional-design group (n=39). Both student cohorts had similar levels of pre-lecture knowledge. Both groups showed significant improvements in retention (p<0.0001), transfer (p<0.05) and total scores (p<0.0001) between the pre- and post-tests. Repeated-measures anova analysis showed statistically significant greater improvements in retention (F=10.2, p=0.0016) and total scores (F=7.13, p=0.0081) for those students instructed using principles of multimedia design compared with those instructed using the traditional design. Multimedia design principles are easy to implement and result in improved short-term retention among medical students, but empirical research is still needed to determine how these principles affect transfer of learning. Further research on applying the principles of multimedia

Evaluation of Calibration Laboratories Performance

NASA Astrophysics Data System (ADS)

Filipe, Eduarda

2011-12-01

One of the main goals of interlaboratory comparisons (ILCs) is the evaluation of the laboratories performance for the routine calibrations they perform for the clients. In the frame of Accreditation of Laboratories, the national accreditation boards (NABs) in collaboration with the national metrology institutes (NMIs) organize the ILCs needed to comply with the requirements of the international accreditation organizations. In order that an ILC is a reliable tool for a laboratory to validate its best measurement capability (BMC), it is needed that the NMI (reference laboratory) provides a better traveling standard—in terms of accuracy class or uncertainty—than the laboratories BMCs. Although this is the general situation, there are cases where the NABs ask the NMIs to evaluate the performance of the accredited laboratories when calibrating industrial measuring instruments. The aim of this article is to discuss the existing approaches for the evaluation of ILCs and propose a basis for the validation of the laboratories measurement capabilities. An example is drafted with the evaluation of the results of mercury-in-glass thermometers ILC with 12 participant laboratories.

Babinet's principle in the Fresnel regime studied using ultrasound

NASA Astrophysics Data System (ADS)

Hitachi, Akira; Takata, Momo

2010-07-01

The diffraction of ultrasound by a circular disk and an aperture of the same size has been investigated as a demonstration of Babinet's principle in the Fresnel regime. The amplitude and the phase of the diffracted ultrasonic waves are measured and a graphical treatment of the results is performed by drawing vectors in the complex plane. The results verify Babinet's principle. It is also found that the incident wave is π /2 behind the phase of the wave passing through on the central axis of a circular aperture. Because both waves travel the same path and the same distance, they should be in phase. This paradox has previously been regarded as a defect of Fresnel's theory.

Approaches to Foster Transfer of Formal Principles: Which Route to Take?

PubMed

Schalk, Lennart; Saalbach, Henrik; Stern, Elsbeth

2016-01-01

Enabling learners to transfer knowledge about formal principles to new problems is a major aim of science and mathematics education, which, however, is notoriously difficult to reach. Previous research advocates different approaches of how to introduce principles to foster the transfer of knowledge about formal principles. One approach suggests teaching a generic formalism of the principles. Another approach suggests presenting (at least) two concrete cases instantiating the principle. A third approach suggests presenting a generic formalism accompanied by a case. As yet, though, empirical results regarding the transfer potential of these approaches are mixed and difficult to integrate as the three approaches have rarely been tested competitively. Furthermore, the approaches have been evaluated in relation to different control conditions, and they have been assessed using varying transfer measures. In the present experiment, we introduced undergraduates to the formal principles of propositional logic with the aim to systematically compare the transfer potential of the different approaches in relation to each other and to a common control condition by using various learning and transfer tasks. Results indicate that all approaches supported successful learning and transfer of the principles, but also caused systematic differences in the magnitude of transfer. Results indicate that the combination of a generic formalism with a case was surprisingly unsuccessful while learners who compared two cases outperformed the control condition. We discuss how the simultaneous assessment of the different approaches allows to more precisely capture the underlying learning mechanisms and to advance theory on how these mechanisms contribute to transfer performance.

Approaches to Foster Transfer of Formal Principles: Which Route to Take?

PubMed Central

Schalk, Lennart; Saalbach, Henrik; Stern, Elsbeth

2016-01-01

Enabling learners to transfer knowledge about formal principles to new problems is a major aim of science and mathematics education, which, however, is notoriously difficult to reach. Previous research advocates different approaches of how to introduce principles to foster the transfer of knowledge about formal principles. One approach suggests teaching a generic formalism of the principles. Another approach suggests presenting (at least) two concrete cases instantiating the principle. A third approach suggests presenting a generic formalism accompanied by a case. As yet, though, empirical results regarding the transfer potential of these approaches are mixed and difficult to integrate as the three approaches have rarely been tested competitively. Furthermore, the approaches have been evaluated in relation to different control conditions, and they have been assessed using varying transfer measures. In the present experiment, we introduced undergraduates to the formal principles of propositional logic with the aim to systematically compare the transfer potential of the different approaches in relation to each other and to a common control condition by using various learning and transfer tasks. Results indicate that all approaches supported successful learning and transfer of the principles, but also caused systematic differences in the magnitude of transfer. Results indicate that the combination of a generic formalism with a case was surprisingly unsuccessful while learners who compared two cases outperformed the control condition. We discuss how the simultaneous assessment of the different approaches allows to more precisely capture the underlying learning mechanisms and to advance theory on how these mechanisms contribute to transfer performance. PMID:26871902

A polyvalent inactivated rhinovirus vaccine is broadly immunogenic in rhesus macaques

PubMed Central

Lee, Sujin; Nguyen, Minh Trang; Currier, Michael G.; Jenkins, Joe B.; Strobert, Elizabeth A.; Kajon, Adriana E.; Madan-Lala, Ranjna; Bochkov, Yury A.; Gern, James E.; Roy, Krishnendu; Lu, Xiaoyan; Erdman, Dean D.; Spearman, Paul; Moore, Martin L.

2016-01-01

As the predominant aetiological agent of the common cold, human rhinovirus (HRV) is the leading cause of human infectious disease. Early studies showed that a monovalent formalin-inactivated HRV vaccine can be protective, and virus-neutralizing antibodies (nAb) correlated with protection. However, co-circulation of many HRV types discouraged further vaccine efforts. Here, we test the hypothesis that increasing virus input titres in polyvalent inactivated HRV vaccine may result in broad nAb responses. We show that serum nAb against many rhinovirus types can be induced by polyvalent, inactivated HRVs plus alhydrogel (alum) adjuvant. Using formulations up to 25-valent in mice and 50-valent in rhesus macaques, HRV vaccine immunogenicity was related to sufficient quantity of input antigens, and valency was not a major factor for potency or breadth of the response. Thus, we have generated a vaccine capable of inducing nAb responses to numerous and diverse HRV types. PMID:27653379

Serotype-Specific Neutralizing Antibody Epitopes of Human Adenovirus Type 3 (HAdV-3) and HAdV-7 Reside in Multiple Hexon Hypervariable Regions

PubMed Central

Qiu, Hongling; Li, Xiao; Tian, Xingui; Zhou, Zhichao; Xing, Ke; Li, Haitao; Tang, Ni; Liu, Wenkuan; Bai, Peisheng

2012-01-01

Human adenovirus types 3 and 7 (HAdV-3 and HAdV-7) occur epidemically and contribute greatly to respiratory diseases, but there is no currently available licensed recombinant HAdV-3/HAdV-7 bivalent vaccine. Identification of serotype-specific neutralizing antibody (NAb) epitopes for HAdV-3 and HAdV-7 will be beneficial for development of recombinant HAdV-3/HAdV-7 bivalent vaccines. In this study, four NAb epitopes within hexon hypervariable regions (HVRs) were predicted for HAdV-3 and HAdV-7, respectively, by using bioinformatics. Eight hexon chimeric adenovirus vectors with the alternation of only one predicted neutralizing epitope were constructed. Further in vitro and in vivo neutralization assays indicated that E2 (residing in HVR2) and E3 (residing in HVR5) are NAb epitopes for HAdV-7, and E3 plays a more important role in generating NAb responses. Cross-neutralization assays indicated that all four predicted epitopes, R1 to R4, are NAb epitopes for HAdV-3, and R1 (residing in HVR1) plays the most important role in generating NAb responses. Humoral immune responses elicited by the recombinant rAdH7R1 (containing the R1 epitope) were significantly and durably suppressed by HAdV-3-specific NAbs. Surprisingly, the rAdΔE3GFP-specific neutralizing epitope responses induced by rAdMHE3 (R3 replaced by E3) and rAdMHE4 (R4 replaced by E4) were weaker than those of rAdMHE1 (R1 replaced by E1) or rAdMHE2 (R2 relaced by E2) in vitro and in vivo. Furthermore, rAdMHE4 replicated more slowly in HEp-2 cells, and the final yield was about 10-fold lower than that of rAdΔE3GFP. The current findings contribute not only to the development of new adenovirus vaccine candidates, but also to the construction of new gene delivery vectors. PMID:22623776

Exposure to histone deacetylase inhibitors during Pavlovian conditioning enhances subsequent cue-induced reinstatement of operant behavior.

PubMed

Ploense, Kyle L; Kerstetter, Kerry A; Wade, Matthew A; Woodward, Nicholas C; Maliniak, Dan; Reyes, Michael; Uchizono, Russell S; Bredy, Timothy W; Kippin, Tod E

2013-06-01

Histone deacetylase inhibitors (HDACIs) strengthen memory following fear conditioning and cocaine-induced conditioned place preference. Here, we examined the effects of two nonspecific HDACIs, valproic acid (VPA) and sodium butyrate (NaB), on appetitive learning measured by conditioned stimulus (CS)-induced reinstatement of operant responding. Rats were trained to lever press for food reinforcement and then injected with VPA (50-200 mg/kg, i.p.), NaB (250-1000 mg/kg, i.p.), or saline vehicle (1.0 ml/kg), 2 h before receiving pairings of noncontingent presentation of food pellets preceded by a tone+light cue CS. Rats next underwent extinction of operant responding followed by response-contingent re-exposure to the CS. Rats receiving VPA (100 mg/kg) or NaB (1000 mg/kg) before conditioning displayed significantly higher cue-induced reinstatement than did saline controls. Rats that received either vehicle or VPA (100 mg/kg) before a conditioning session with a randomized relation between presentation of food pellets and the CS failed to show subsequent cue-induced reinstatement with no difference between the two groups. These findings indicate that, under certain contexts, HDACIs strengthen memory formation by specifically increasing the associative strength of the CS, not through an increasing motivation to seek reinforcement. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Exposure to histone deacetylase inhibitors during Pavlovian conditioning enhances subsequent cue-induced reinstatement of operant behavior

PubMed Central

Ploense, Kyle L.; Kerstetter, Kerry A.; Wade, Matthew A.; Woodward, Nicholas C.; Maliniak, Dan; Reyes, Michael; Uchizono, Russell S.; Bredy, Timothy W.; Kippin, Tod E.

2014-01-01

Histone deacetylase inhibitors (HDACIs) strengthen memory following fear conditioning and cocaine-induced conditioned place preference. Here, we examined the effects of two non-specific HDACIs, valproic acid (VPA) and sodium butyrate (NaB), on appetitive learning measured via conditioned stimulus (CS)-induced reinstatement of operant responding. Rats were trained to lever press for food reinforcement and then injected with VPA (50–200 mg/kg, i.p.), NaB (250–1000 mg/kg, i.p.), or saline vehicle (1.0 ml/kg), 2h before receiving pairings of noncontingent presentation of food pellets preceded by a tone+light cue CS. Rats next underwent extinction of operant responding followed by response-contingent re-exposure to the CS. Rats receiving VPA (100 mg/kg) or NaB (1000 mg/kg) prior to conditioning displayed significantly higher cue-induced reinstatement than did saline controls. Rats that receiving either vehicle or VPA (100 mg/kg) prior to a conditioning session with a randomized relation between presentation of food pellets and the CS failed to show subsequent cue-induced reinstatement with no difference between the two groups. These findings indicate that, under certain contexts, HDACIs strengthen memory formation by specifically increasing the associative strength of the CS, not through an increasing motivation to seek reinforcement. PMID:23604166

Rigorous force field optimization principles based on statistical distance minimization

DOE PAGES

Vlcek, Lukas; Chialvo, Ariel A.

2015-10-12

We use the concept of statistical distance to define a measure of distinguishability between a pair of statistical mechanical systems, i.e., a model and its target, and show that its minimization leads to general convergence of the model’s static measurable properties to those of the target. Here we exploit this feature to define a rigorous basis for the development of accurate and robust effective molecular force fields that are inherently compatible with coarse-grained experimental data. The new model optimization principles and their efficient implementation are illustrated through selected examples, whose outcome demonstrates the higher robustness and predictive accuracy of themore » approach compared to other currently used methods, such as force matching and relative entropy minimization. We also discuss relations between the newly developed principles and established thermodynamic concepts, which include the Gibbs-Bogoliubov inequality and the thermodynamic length.« less

The Suspension of the National Association of Broadcasters' Code and Its Effects on the Regulation of Advertising.

ERIC Educational Resources Information Center

Maddox, Lynda M.; Zanot, Eric J.

After a federal judge ruled in 1982 that some stipulations of the National Association of Broadcasters' (NAB) Television Code were violating antitrust laws, the NAB responded by suspending all code operations. Effects of the suspension on network advertising included (1) the disappearance of preclearance for commercials about cholesterol-related…

Acoustic levitation and the Boltzmann-Ehrenfest principle

NASA Technical Reports Server (NTRS)

Putterman, S.; Rudnick, Joseph; Barmatz, M.

1989-01-01

The Boltzmann-Ehrenfest principle of adiabatic invariance relates the acoustic potential acting on a sample positioned in a single-mode cavity to the shift in resonant frequency caused by the presence of this sample. This general and simple relation applies to samples and cavities of arbitrary shape, dimension, and compressibility. Positioning forces and torques can, therefore, be determined from straightforward measurements of frequency shifts. Applications to the Rayleigh disk phenomenon and levitated cylinders are presented.

Fundamental Tactical Principles of Soccer: A Comparison of Different Age Groups.

PubMed

Borges, Paulo Henrique; Guilherme, José; Rechenchosky, Leandro; da Costa, Luciane Cristina Arantes; Rinadi, Wilson

2017-09-01

The fundamental tactical principles of the game of soccer represent a set of action rules that guide behaviours related to the management of game space. The aim of this study was to compare the performance of fundamental offensive and defensive tactical principles among youth soccer players from 12 to 17 years old. The sample consisted of 3689 tactical actions performed by 48 soccer players in three age categories: under 13 (U-13), under 15 (U-15), and under 17 (U-17). Tactical performance was measured using the System of Tactical Assessment in Soccer (FUT-SAT). The Kruskal Wallis, Mann-Whitney U, Friedman, Wilcoxon, and Cohen's Kappa tests were used in the study analysis. The results showed that the principles of "offensive coverage" (p = 0.01) and "concentration" (p = 0.04) were performed more frequently by the U-17 players than the U-13 players. The tactical principles "width and length" (p < 0.05) and "defensive unit" (p < 0.05) were executed more frequently by younger soccer players. It can be concluded that the frequency with which fundamental tactical principles are performed varies between the gaming categories, which implies that there is valuation of defensive security and a progressive increase in "offensive coverage" caused by increased confidence and security in offensive actions.

AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges

PubMed Central

Gardner, Matthew R.; Kattenhorn, Lisa M.; Kondur, Hema R.; von Schaewen, Markus; Dorfman, Tatyana; Chiang, Jessica J.; Haworth, Kevin G.; Decker, Julie M.; Alpert, Michael D.; Bailey, Charles C.; Neale, Ernest S.; Fellinger, Christoph H.; Joshi, Vinita R.; Fuchs, Sebastian P.; Martinez-Navio, Jose M.; Quinlan, Brian D.; Yao, Annie Y.; Mouquet, Hugo; Gorman, Jason; Zhang, Baoshan; Poignard, Pascal; Nussenzweig, Michel C.; Burton, Dennis R.; Kwong, Peter D.; Piatak, Michael; Lifson, Jeffrey D.; Gao, Guangping; Desrosiers, Ronald C.; Evans, David T.; Hahn, Beatrice H.; Ploss, Alexander; Cannon, Paula M.; Seaman, Michael S.; Farzan, Michael

2015-01-01

Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs)1,2. However even the best bNAbs neutralize 10–50% of HIV-1 isolates inefficiently (IC80 > 5 μg/ml), suggesting that high concentrations of these antibodies would be necessary to achieve general protection3–6. Here we show that eCD4-Ig, a fusion of CD4-Ig with a small CCR5-mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean IC50 < 0.05 μg/ml). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2, and SIV isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46, and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17 to 77 μg/ml of fully functional rhesus eCD4-Ig for 40 weeks, and these macaques were protected from multiple infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine. PMID:25707797

Early Growth Response-1 Induces and Enhances Vascular Endothelial Growth Factor-A Expression in Lung Cancer Cells

PubMed Central

Shimoyamada, Hiroaki; Yazawa, Takuya; Sato, Hanako; Okudela, Koji; Ishii, Jun; Sakaeda, Masashi; Kashiwagi, Korehito; Suzuki, Takehisa; Mitsui, Hideaki; Woo, Tetsukan; Tajiri, Michihiko; Ohmori, Takahiro; Ogura, Takashi; Masuda, Munetaka; Oshiro, Hisashi; Kitamura, Hitoshi

2010-01-01

Vascular endothelial growth factor-A (VEGF-A) is crucial for angiogenesis, vascular permeability, and metastasis during tumor development. We demonstrate here that early growth response-1 (EGR-1), which is induced by the extracellular signal–regulated kinase (ERK) pathway activation, activates VEGF-A in lung cancer cells. Increased EGR-1 expression was found in adenocarcinoma cells carrying mutant K-RAS or EGFR genes. Hypoxic culture, siRNA experiment, luciferase assays, chromatin immunoprecipitation, electrophoretic mobility shift assays, and quantitative RT-PCR using EGR-1–inducible lung cancer cells demonstrated that EGR-1 binds to the proximal region of the VEGF-A promoter, activates VEGF-A expression, and enhances hypoxia inducible factor 1α (HIF-1α)-mediated VEGF-A expression. The EGR-1 modulator, NAB-2, was rapidly induced by increased levels of EGR-1. Pathology samples of human lung adenocarcinomas revealed correlations between EGR-1/HIF-1α and VEGF-A expressions and relative elevation of EGR-1 and VEGF-A expression in mutant K-RAS- or EGFR-carrying adenocarcinomas. Both EGR-1 and VEGF-A expression increased as tumors dedifferentiated, whereas HIF-1α expression did not. Although weak correlation was found between EGR-1 and NAB-2 expressions on the whole, NAB-2 expression decreased as tumors dedifferentiated, and inhibition of DNA methyltransferase/histone deacetylase increased NAB-2 expression in lung cancer cells despite no epigenetic alteration in the NAB-2 promoter. These findings suggest that EGR-1 plays important roles on VEGF-A expression in lung cancer cells, and epigenetic silencing of transactivator(s) associated with NAB-2 expression might also contribute to upregulate VEGF-A expression. PMID:20489156

Determination of ranges for reporting pollen aeroallergen levels in the Washington, DC, metropolitan area.

PubMed

Kosisky, Susan E; Marks, Mariko S; Yacovone, Margaret A; Nelson, Michael R

2011-09-01

Local aeroallergen monitoring provides useful information for the atopic patient and medical community. Currently, National Allergy Bureau (NAB) ranges are used for reporting pollen count levels in the Washington, DC, area. To determine standard range criteria (low, moderate, high, and very high) for the reporting of specific tree, grass, and weed aeroallergens representative of the Washington, DC, metropolitan region. Atmospheric sampling for pollen aeroallergens was performed using a volumetric rotating-arm impaction sampler (model 40 Rotorod, SDI Company, Plymouth Meeting, PA). The cumulative pollen count, over a 12-year period (1998-2009), was determined for specific pollen aeroallergens. Local ranges were developed using methodology previously employed to determine NAB ranges. A comparison was made between NAB and Washington, DC, area ranges. The local median count, and low and moderate range criteria, are markedly lower than NAB range counts for tree, grass, and weed pollen. The NAB 99th percentile (high) count is significantly higher for grass and weed pollen but lower for tree pollen. Using new local range criteria, an increase was seen in the number of high days recorded for weed pollen (1,300%), grass pollen (258.6%), and tree pollen (11.8%). Previously, using NAB range criteria, no very high days were reported for grass and weed pollen over the 12-year period. Washington, DC, ranges establish more relevant reporting standards for our local patient population and will allow for comparison with reporting levels developed for sampling locations nationwide as well as with other regional sites. Copyright © 2011 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

Priority-setting in New Zealand: translating principles into practice.

PubMed

Ashton, T; Cumming, J; Devlin, N

2000-07-01

In May 1998 the New Zealand Health Funding Authority released a discussion paper which proposed a principles-based approach to setting purchasing priorities that incorporates the economic methods of programme budgeting and marginal analysis, and cost-utility analysis. The principles upon which the process was to be based are effectiveness, cost, equity of health outcomes, Maori health and acceptability. This essay describes and critiques issues associated with translating the principles into practice, most particularly the proposed methods for evaluating the effectiveness and measuring the cost of services. It is argued that the proposals make an important contribution towards the development of a method for prioritizing services which challenges our thinking about those services and their goals, and which is systematic, explicit, and transparent. The shift towards 'thinking at the margin' and systematically reviewing the value for money of competing claims on resources is likely to improve the quality of decision-making compared with the status quo. This does not imply that prioritization can, or should, be undertaken by means of any simple formula. Any prioritization process should always be guided by informed judgement. The approach is more appropriate for some services than for others. Key methodological issues that need further consideration include the choice of instrument for measuring health gains, the identification of marginal services, how to combine qualitative and quantitative information, and how to ensure consistency across different levels of decision-making.

7 CFR 3430.31 - Guiding principles.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 7 Agriculture 15 2010-01-01 2010-01-01 false Guiding principles. 3430.31 Section 3430.31 Agriculture Regulations of the Department of Agriculture (Continued) COOPERATIVE STATE RESEARCH, EDUCATION... § 3430.31 Guiding principles. The guiding principle for Federal assistance application review and...

The Principle-Based Method of Practical Ethics.

PubMed

Spielthenner, Georg

2017-09-01

This paper is about the methodology of doing practical ethics. There is a variety of methods employed in ethics. One of them is the principle-based approach, which has an established place in ethical reasoning. In everyday life, we often judge the rightness and wrongness of actions by their conformity to principles, and the appeal to principles plays a significant role in practical ethics, too. In this paper, I try to provide a better understanding of the nature of principle-based reasoning. To accomplish this, I show in the first section that these principles can be applied to cases in a meaningful and sufficiently precise way. The second section discusses the question how relevant applying principles is to the resolution of ethical issues. This depends on their nature. I argue that the principles under consideration in this paper should be interpreted as presumptive principles and I conclude that although they cannot be expected to bear the weight of definitely resolving ethical problems, these principles can nevertheless play a considerable role in ethical research.

Satellite Test of the Equivalence Principle as a Probe of Modified Newtonian Dynamics.

PubMed

Pereira, Jonas P; Overduin, James M; Poyneer, Alexander J

2016-08-12

The proposed satellite test of the equivalence principle (STEP) will detect possible violations of the weak equivalence principle by measuring relative accelerations between test masses of different composition with a precision of one part in 10^{18}. A serendipitous by-product of the experimental design is that the absolute or common-mode acceleration of the test masses is also measured to high precision as they oscillate along a common axis under the influence of restoring forces produced by the position sensor currents, which in drag-free mode lead to Newtonian accelerations as small as 10^{-14}  g. This is deep inside the low-acceleration regime where modified Newtonian dynamics (MOND) diverges strongly from the Newtonian limit of general relativity. We show that MOND theories (including those based on the widely used "n family" of interpolating functions as well as the covariant tensor-vector-scalar formulation) predict an easily detectable increase in the frequency of oscillations of the STEP test masses if the strong equivalence principle holds. If it does not hold, MOND predicts a cumulative increase in oscillation amplitude which is also detectable. STEP thus provides a new and potentially decisive test of Newton's law of inertia, as well as the equivalence principle in both its strong and weak forms.

Meta-analyses of seven of the National Institute on Drug Abuse's principles of drug addiction treatment.

PubMed

Pearson, Frank S; Prendergast, Michael L; Podus, Deborah; Vazan, Peter; Greenwell, Lisa; Hamilton, Zachary

2012-07-01

Of the 13 principles of drug addiction treatment disseminated by the National Institute on Drug Abuse (NIDA), 7 were meta-analyzed as part of the Evidence-based Principles of Treatment (EPT) project. By averaging outcomes over the diverse programs included in the EPT, we found that 5 of the NIDA principles examined are supported: matching treatment to the client's needs, attending to the multiple needs of clients, behavioral counseling interventions, treatment plan reassessment, and counseling to reduce risk of HIV. Two of the NIDA principles are not supported: remaining in treatment for an adequate period and frequency of testing for drug use. These weak effects could be the result of the principles being stated too generally to apply to the diverse interventions and programs that exist or unmeasured moderator variables being confounded with the moderators that measured the principles. Meta-analysis should be a standard tool for developing principles of effective treatment for substance use disorders. Copyright © 2012 Elsevier Inc. All rights reserved.

Characterization of the Neutralizing Antibody Response in a Case of Genetically Linked HIV Superinfection.

PubMed

Ssemwanga, Deogratius; Doria-Rose, Nicole A; Redd, Andrew D; Shiakolas, Andrea R; Longosz, Andrew F; Nsubuga, Rebecca N; Mayanja, Billy N; Asiki, Gershim; Seeley, Janet; Kamali, Anatoli; Ransier, Amy; Darko, Samuel; Walker, Michael P; Bruno, Daniel; Martens, Craig; Douek, Daniel; Porcella, Stephen F; Quinn, Thomas C; Mascola, John R; Kaleebu, Pontiano

2018-04-23

This report describes the identification of a genetically confirmed linked heterosexual human immunodeficiency virus (HIV) superinfection (HIV-SI) in a woman with chronic HIV infection who acquired a second strain of the virus from her husband. Serum neutralizing antibody (NAb) responses against their homologous and heterologous viruses, including the superinfecting strain, in the woman and her husband were examined before and after onset of HIV-SI. The woman displayed a moderately potent and broad anti-HIV NAb response prior to superinfection but did not possess NAb activity against the superinfecting strain. This case highlights the unique potential of linked HIV-SI studies to examine natural protection from HIV infection.

Ethical principles and concepts in medicine.

PubMed

Taylor, Robert M

2013-01-01

Clinical ethics is the application of ethical theories, principles, rules, and guidelines to clinical situations in medicine. Therefore, clinical ethics is analogous to clinical medicine in that general principles and concepts must be applied intelligently and thoughtfully to unique clinical circumstances. The three major ethical theories are consequentialism, whereby the consequences of an action determine whether it is ethical; deontology, whereby to be ethical is to do one's duty, and virtue ethics, whereby ethics is a matter of cultivating appropriate virtues. In the real world of medicine, most people find that all three perspectives offer useful insights and are complementary rather than contradictory. The most common approach to clinical ethical analysis is principlism. According to principlism, the medical practitioner must attempt to uphold four important principles: respect for patient autonomy, beneficence, nonmaleficence, and justice. When these principles conflict, resolving them depends on the details of the case. Alternative approaches to medical ethics, including the primacy of beneficence, care-based ethics, feminist ethics, and narrative ethics, help to define the limitations of principlism and provide a broader perspective on medical ethics. © 2013 Elsevier B.V. All rights reserved.

How Many Principles for Public Health Ethics?

PubMed Central

Coughlin, Steven S.

2009-01-01

General moral (ethical) principles play a prominent role in certain methods of moral reasoning and ethical decision-making in bioethics and public health. Examples include the principles of respect for autonomy, beneficence, nonmaleficence, and justice. Some accounts of ethics in public health have pointed to additional principles related to social and environmental concerns, such as the precautionary principle and principles of solidarity or social cohesion. This article provides an overview of principle-based methods of moral reasoning as they apply to public health ethics including a summary of advantages and disadvantages of methods of moral reasoning that rely upon general principles of moral reasoning. Drawing upon the literature on public health ethics, examples are provided of additional principles, obligations, and rules that may be useful for analyzing complex ethical issues in public health. A framework is outlined that takes into consideration the interplay of ethical principles and rules at individual, community, national, and global levels. Concepts such as the precautionary principle and solidarity are shown to be useful to public health ethics to the extent that they can be shown to provide worthwhile guidance and information above and beyond principles of beneficence, nonmaleficence, and justice, and the clusters of rules and maxims that are linked to these moral principles. Future directions likely to be productive include further work on areas of public health ethics such as public trust, community empowerment, the rights of individuals who are targeted (or not targeted) by public health interventions, individual and community resilience and wellbeing, and further clarification of principles, obligations, and rules in public health disciplines such as environmental science, prevention and control of chronic and infectious diseases, genomics, and global health. PMID:20072707

Developing a policy for paediatric biobanks: principles for good practice

PubMed Central

Hens, Kristien; Van El, Carla E; Borry, Pascal; Cambon-Thomsen, Anne; Cornel, Martina C; Forzano, Francesca; Lucassen, Anneke; Patch, Christine; Tranebjaerg, Lisbeth; Vermeulen, Eric; Salvaterra, Elena; Tibben, Aad; Dierickx, Kris

2013-01-01

The participation of minors in biobank research can offer great benefits for science and health care. However, as minors are a vulnerable population they are also in need of adequate protective measures when they are enrolled in research. Research using biobanked biological samples from children poses additional ethical issues to those raised by research using adult biobanks. For example, small children have only limited capacity, if any, to understand the meaning and implications of the research and to give a documented agreement to it. Older minors are gradually acquiring this capacity. We describe principles for good practice related to the inclusion of minors in biobank research, focusing on issues related to benefits and subsidiarity, consent, proportionality and return of results. Some of these issues are currently heavily debated, and we conclude by providing principles for good practice for policy makers of biobanks, researchers and anyone involved in dealing with stored tissue samples from children. Actual implementation of the principles will vary according to different jurisdictions. PMID:22713814

Spaceborne receivers: Basic principles

NASA Technical Reports Server (NTRS)

Stacey, J. M.

1984-01-01

The underlying principles of operation of microwave receivers for space observations of planetary surfaces were examined. The design philosophy of the receiver as it is applied to operate functionally as an efficient receiving system, the principle of operation of the key components of the receiver, and the important differences among receiver types are explained. The operating performance and the sensitivity expectations for both the modulated and total power receiver configurations are outlined. The expressions are derived from first principles and are developed through the important intermediate stages to form practicle and easily applied equations. The transfer of thermodynamic energy from point to point within the receiver is illustrated. The language of microwave receivers is applied statistics.

New algorithms for motion error detection of numerical control machine tool by laser tracking measurement on the basis of GPS principle.

PubMed

Wang, Jindong; Chen, Peng; Deng, Yufen; Guo, Junjie

2018-01-01

As a three-dimensional measuring instrument, the laser tracker is widely used in industrial measurement. To avoid the influence of angle measurement error on the overall measurement accuracy, the multi-station and time-sharing measurement with a laser tracker is introduced on the basis of the global positioning system (GPS) principle in this paper. For the proposed method, how to accurately determine the coordinates of each measuring point by using a large amount of measured data is a critical issue. Taking detecting motion error of a numerical control machine tool, for example, the corresponding measurement algorithms are investigated thoroughly. By establishing the mathematical model of detecting motion error of a machine tool with this method, the analytical algorithm concerning on base station calibration and measuring point determination is deduced without selecting the initial iterative value in calculation. However, when the motion area of the machine tool is in a 2D plane, the coefficient matrix of base station calibration is singular, which generates a distortion result. In order to overcome the limitation of the original algorithm, an improved analytical algorithm is also derived. Meanwhile, the calibration accuracy of the base station with the improved algorithm is compared with that with the original analytical algorithm and some iterative algorithms, such as the Gauss-Newton algorithm and Levenberg-Marquardt algorithm. The experiment further verifies the feasibility and effectiveness of the improved algorithm. In addition, the different motion areas of the machine tool have certain influence on the calibration accuracy of the base station, and the corresponding influence of measurement error on the calibration result of the base station depending on the condition number of coefficient matrix are analyzed.

New algorithms for motion error detection of numerical control machine tool by laser tracking measurement on the basis of GPS principle

NASA Astrophysics Data System (ADS)

Wang, Jindong; Chen, Peng; Deng, Yufen; Guo, Junjie

2018-01-01

As a three-dimensional measuring instrument, the laser tracker is widely used in industrial measurement. To avoid the influence of angle measurement error on the overall measurement accuracy, the multi-station and time-sharing measurement with a laser tracker is introduced on the basis of the global positioning system (GPS) principle in this paper. For the proposed method, how to accurately determine the coordinates of each measuring point by using a large amount of measured data is a critical issue. Taking detecting motion error of a numerical control machine tool, for example, the corresponding measurement algorithms are investigated thoroughly. By establishing the mathematical model of detecting motion error of a machine tool with this method, the analytical algorithm concerning on base station calibration and measuring point determination is deduced without selecting the initial iterative value in calculation. However, when the motion area of the machine tool is in a 2D plane, the coefficient matrix of base station calibration is singular, which generates a distortion result. In order to overcome the limitation of the original algorithm, an improved analytical algorithm is also derived. Meanwhile, the calibration accuracy of the base station with the improved algorithm is compared with that with the original analytical algorithm and some iterative algorithms, such as the Gauss-Newton algorithm and Levenberg-Marquardt algorithm. The experiment further verifies the feasibility and effectiveness of the improved algorithm. In addition, the different motion areas of the machine tool have certain influence on the calibration accuracy of the base station, and the corresponding influence of measurement error on the calibration result of the base station depending on the condition number of coefficient matrix are analyzed.

Use of flow cytometry, fluorescence microscopy, and PCR-based techniques to assess intraspecific and interspecific matings of Armillaria species

Treesearch

Mee-Sook Kim; Ned B. Klopfenstein; Geral I. McDonald; Kathiravetpillai Arumuganathan

2001-01-01

For assessments of intraspecific mating using flow cytometry and fluorescence microscopy, two compatible basidiospore-derived isolates were selected from each of four parental basidiomata of North American Biological Species (NABS) X. The nuclear status in NABS X varied with basidiospore-derived isolates. Nuclei within basidiospore-derived isolates existed as haploids...

Operationalizing Principle-Based Standards for Animal Welfare-Indicators for Climate Problems in Pig Houses.

PubMed

Vermeer, Herman M; Hopster, Hans

2018-03-23

The Dutch animal welfare law includes so-called principle-based standards. This means that the objective is described in abstract terms, enabling farmers to comply with the law in their own way. Principle-based standards are, however, difficult for the inspection agency to enforce because strict limits are missing. This pilot project aimed at developing indicators (measurements) to assess the climate in pig houses, thus enabling the enforcement of principle-based standards. In total, 64 farms with weaners and 32 farms with growing-finishing pigs were visited. On each farm, a set of climate-related measurements was collected in six pens. For each of these measurements, a threshold value was set, and exceeding this threshold indicated a welfare risk. Farm inspections were carried out during winter and spring, thus excluding situations with heat stress. Assessment of the variation and correlation between measurements reduced the dataset from 39 to 12 measurements. Using a principal components analysis helped to select five major measurements as warning signals. The number of exceeded thresholds per pen and per farm was calculated for both the large (12) and small (five) sets of measurements. CO₂ and NH₃ concentrations were related to the outside temperature. On colder days, there was less ventilation, and thus CO₂ and NH₃ concentrations increased. Air quality, reflected in the CO₂ and NH₃ concentrations, was associated with respiratory problems. Eye scores were positively correlated with both pig and pen fouling, and pig and pen fouling were closely related. We selected five signal indicators: CO₂, NH₃, and tail and eye score for weaners and finishers, and added ear score for weaners and pig fouling for growing-finishing pigs. The results indicate that pig farms can be ranked based on five signal indicators related to reduced animal welfare caused by climatic conditions. This approach could be adopted to other principle-based standards for pigs as well

Hamilton's Principle for Beginners

ERIC Educational Resources Information Center

Brun, J. L.

2007-01-01

I find that students have difficulty with Hamilton's principle, at least the first time they come into contact with it, and therefore it is worth designing some examples to help students grasp its complex meaning. This paper supplies the simplest example to consolidate the learning of the quoted principle: that of a free particle moving along a…

A NEW PRINCIPLE FOR ELECTROMAGNETIC CATHETER FLOW METERS*

PubMed Central

Kolin, Alexander

1969-01-01

An electromagnetic catheter flow meter is described in which the magnetic field is generated by two parallel bundles of wire carrying equal currents in opposite directions. The electrodes are fixed centrally to the insulated wire bundles that generate the magnetic field. The flow sensor is flexible, resembling a split catheter. The flow transducer is designed to constrict as it is introduced through a branch artery and to expand in the main artery over the span of its diameter. The principle is suitable for branch flow measurement as well as for measurement of flow in a major artery or vein by the same transducer. A special method of guiding the electrode wires results in a zero base line at zero flow for the entire range of diameters accommodating the field generating coil. The electrodes could be used in this configuration with a magnetic field generated by coils external to the patient for blood flow measurements with a catheter of reduced gauge. The transducer can be made smaller in circumference than those employed in other electromagnetic flow measuring catheter devices. This feature is of special value for envisaged clinical uses (percutaneous introduction) to minimize surgical intervention. The velocity sensitivity of the flow transducer is a logarithmic function of the tube diameter. The flow throughout the entire tube cross section contributes to the flow signal. It is sufficient to calibrate the transducer by one measurement in a dielectric conduit of less than maximum diameter. The sensitivity at other diameters follows from a logarithmic plot. The diameter of the blood vessel is outlined by the transducer in radiograms, thus obviating the need for radiopaque materials. The principle was demonstrated by measurements in vitro. Experiments in vivo, derivation of equations, and construction details will be published elsewhere. Images PMID:5257127

Principle component analyses of questionnaires measuring individual differences in synaesthetic phenomenology.

PubMed

Anderson, Hazel P; Ward, Jamie

2015-05-01

Questionnaires have been developed for categorising grapheme-colour synaesthetes into two sub-types based on phenomenology: associators and projectors. The general approach has been to assume a priori the existence of two sub-types on a single dimension (with endpoints as projector and associator) rather than explore, in a data-driven fashion, other possible models. We collected responses from 175 grapheme-colour synaesthetes on two questionnaires, the Illustrated Synaesthetic Experience Questionnaire (Skelton, Ludwig, & Mohr, 2009) and Rouw and Scholte's (2007) Projector-Associator Questionnaire. After Principle Component Analysis both questionnaires were comprised of two factors which coincide with the projector/associator distinction. This suggests that projectors and associators are not opposites of each other, but separate dimensions of experience (e.g. some synaesthetes claim to be both, others claim to be neither). The revised questionnaires provide a useful tool for researchers and insights into the phenomenology of synaesthesia. Copyright © 2015 Elsevier Inc. All rights reserved.

24 CFR 3282.402 - General principles.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 24 Housing and Urban Development 5 2010-04-01 2010-04-01 false General principles. 3282.402... and Remedial Actions § 3282.402 General principles. (a) Nothing in this subpart or in these... manufactured home manufacturers to provide remedial actions under this subpart is limited by the principle that...

Software for Fermat's Principle and Lenses

ERIC Educational Resources Information Center

Mihas, Pavlos

2012-01-01

Fermat's principle is considered as a unifying concept. It is usually presented erroneously as a "least time principle". In this paper we present some software that shows cases of maxima and minima and the application of Fermat's principle to the problem of focusing in lenses. (Contains 12 figures.)

Extrema principles of entrophy production and energy dissipation in fluid mechanics

NASA Technical Reports Server (NTRS)

Horne, W. Clifton; Karamcheti, Krishnamurty

1988-01-01

A survey is presented of several extrema principles of energy dissipation as applied to problems in fluid mechanics. An exact equation is derived for the dissipation function of a homogeneous, isotropic, Newtonian fluid, with terms associated with irreversible compression or expansion, wave radiation, and the square of the vorticity. By using entropy extrema principles, simple flows such as the incompressible channel flow and the cylindrical vortex are identified as minimal dissipative distributions. The principal notions of stability of parallel shear flows appears to be associated with a maximum dissipation condition. These different conditions are consistent with Prigogine's classification of thermodynamic states into categories of equilibrium, linear nonequilibrium, and nonlinear nonequilibrium thermodynamics; vortices and acoustic waves appear as examples of dissipative structures. The measurements of a typical periodic shear flow, the rectangular wall jet, show that direct measurements of the dissipative terms are possible.

Genetic and Non-Genetic Inheritance of Natural Antibodies Binding Keyhole Limpet Hemocyanin in a Purebred Layer Chicken Line

PubMed Central

Berghof, T. V. L.; van der Klein, S. A. S.; Arts, J. A. J.; Parmentier, H. K.; van der Poel, J. J.; Bovenhuis, H.

2015-01-01

Natural antibodies (NAb) are defined as antibodies present in individuals without known antigenic challenge. Levels of NAb binding keyhole limpet hemocyanin (KLH) in chickens were earlier shown to be heritable, and to be associated with survival. Selective breeding may thus provide a strategy to improve natural disease resistance. We phenotyped 3,689 white purebred laying chickens for KLH binding NAb of different isotypes around 16 weeks of age. Heritabilities of 0.12 for the titers of total antibodies (IgT), 0.14 for IgM, 0.10 for IgA, and 0.07 for IgG were estimated. We also estimated high, positive genetic, and moderate to high, positive phenotypic correlations of IgT, IgM, IgA, and IgG, suggesting that selective breeding for NAb can be done on all antibody isotypes simultaneously. In addition, a relatively substantial non-genetic maternal environmental effect of 0.06 was detected for IgM, which may reflect a transgenerational effect. This suggests that not only the genes of the mother, but also the maternal environment affects the immune system of the offspring. Breaking strength and early eggshell whiteness of the mother’s eggs were predictive for IgM levels in the offspring, and partly explained the observed maternal environmental effects. The present results confirm that NAb are heritable, however maternal effects should be taken into account. PMID:26114750

Interactions between HIV-1 Neutralizing Antibodies and Model Lipid Membranes imaged with AFM

NASA Astrophysics Data System (ADS)

Zauscher, Stefan; Hardy, Gregory; Alam, Munir; Shapter, Joseph

2012-02-01

Lipid membrane interactions with rare, broadly neutralizing antibodies (NAbs), 2F5 and 4E10, play a critical role in HIV-1 neutralization. Our research is motivated by recent immunization studies that have shown that induction of antibodies that avidly bind the gp41-MPER antigen is not sufficient for neutralization. Rather, it is required that antigen designs induce polyreactive antibodies that recognize MPER antigens as well as the viral lipid membrane. However, the mechanistic details of how membrane properties influence NAb-lipid and NAb-antigen interactions remain unknown. Furthermore, it is well established that the native viral membrane is heterogeneous, representing a mosaic of lipid rafts and protein clustering. However, the size, physical properties, and dynamics of these regions are poorly characterized and their potential roles in HIV-1 neutralization are also unknown. To understand how membrane properties contribute to 2F5/4E10 membrane interactions, we have engineered biomimetic supported lipid bilayers (SLBs) and use atomic force microscopy to visualize membrane domains, antigen clustering, and antibody-membrane interactions at sub-nanometer z-resolution. Our results show that localized binding of HIV-1 antigens and NAbs occur preferentially with the most fluid membrane domain. This supports the theory that NAbs may interact with regions of low lateral lipid forces that allow antibody insertion into the bilayer.

The principle of proportionality revisited: interpretations and applications.

PubMed

Hermerén, Göran

2012-11-01

The principle of proportionality is used in many different contexts. Some of these uses and contexts are first briefly indicated. This paper focusses on the use of this principle as a moral principle. I argue that under certain conditions the principle of proportionality is helpful as a guide in decision-making. But it needs to be clarified and to be used with some flexibility as a context-dependent principle. Several interpretations of the principle are distinguished, using three conditions as a starting point: importance of objective, relevance of means, and most favourable option. The principle is then tested against an example, which suggests that a fourth condition, focusing on non-excessiveness, needs to be added. I will distinguish between three main interpretations of the principle, some primarily with uses in research ethics, others with uses in other areas of bioethics, for instance in comparisons of therapeutic means and ends. The relations between the principle of proportionality and the precautionary principle are explored in the following section. It is concluded that the principles are different and may even clash. In the next section the principle of proportionality is applied to some medical examples drawn from research ethics and bioethics. In concluding, the status of the principle of proportionality as a moral principle is discussed. What has been achieved so far and what remains to be done is finally summarized.

Patient safety principles in family medicine residency accreditation standards and curriculum objectives

PubMed Central

Kassam, Aliya; Sharma, Nishan; Harvie, Margot; O’Beirne, Maeve; Topps, Maureen

2016-01-01

Abstract Objective To conduct a thematic analysis of the College of Family Physicians of Canada’s (CFPC’s) Red Book accreditation standards and the Triple C Competency-based Curriculum objectives with respect to patient safety principles. Design Thematic content analysis of the CFPC’s Red Book accreditation standards and the Triple C curriculum. Setting Canada. Main outcome measures Coding frequency of the patient safety principles (ie, patient engagement; respectful, transparent relationships; complex systems; a just and trusting culture; responsibility and accountability for actions; and continuous learning and improvement) found in the analyzed CFPC documents. Results Within the analyzed CFPC documents, the most commonly found patient safety principle was patient engagement (n = 51 coding references); the least commonly found patient safety principles were a just and trusting culture (n = 5 coding references) and complex systems (n = 5 coding references). Other patient safety principles that were uncommon included responsibility and accountability for actions (n = 7 coding references) and continuous learning and improvement (n = 12 coding references). Conclusion Explicit inclusion of patient safety content such as the use of patient safety principles is needed for residency training programs across Canada to ensure the full spectrum of care is addressed, from community-based care to acute hospital-based care. This will ensure a patient safety culture can be cultivated from residency and sustained into primary care practice. PMID:27965349

Cooperative Learning Principles Enhance Online Interaction

ERIC Educational Resources Information Center

Jacobs, George; Seow, Peter

2014-01-01

This paper describes eight principles that can be used to promote cooperative interactions among students working in online environments. The principles derive from a well-established approach to education, known variously as cooperative learning and collaborative learning. Each principle is explained as to what it means, why it is important and…

20 CFR 401.140 - General principles.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 20 Employees' Benefits 2 2010-04-01 2010-04-01 false General principles. 401.140 Section 401.140... INFORMATION Disclosure of Official Records and Information § 401.140 General principles. When no law... follow FOIA principles to resolve that question. We do this to insure uniform treatment in all situations...

Conceptual Principles of Quality of Life: An Empirical Exploration

ERIC Educational Resources Information Center

Bramston, P.; Chipuer, H.; Pretty, G.

2005-01-01

Background: Quality of life is a popular measure of outcomes and its widespread use has led to recent calls for a better understanding of the construct, emphasizing the need to build a substantial body of knowledge around what determines perceptions of life quality. Three widely reported and used conceptual principles are examined in this study.…

16 CFR 260.6 - General principles.

Code of Federal Regulations, 2010 CFR

2010-01-01

... ENVIRONMENTAL MARKETING CLAIMS § 260.6 General principles. The following general principles apply to all environmental marketing claims, including, but not limited to, those described in § 260.7. In addition, § 260.7... 16 Commercial Practices 1 2010-01-01 2010-01-01 false General principles. 260.6 Section 260.6...

The harm principle as a mid-level principle?: three problems from the context of infectious disease control.

PubMed

Krom, André

2011-10-01

Effective infectious disease control may require states to restrict the liberty of individuals. Since preventing harm to others is almost universally accepted as a legitimate (prima facie) reason for restricting the liberty of individuals, it seems plausible to employ a mid-level harm principle in infectious disease control. Moral practices like infectious disease control support - or even require - a certain level of theory-modesty. However, employing a mid-level harm principle in infectious disease control faces at least three problems. First, it is unclear what we gain by attaining convergence on a specific formulation of the harm principle. Likely candidates for convergence, a harm principle aimed at preventing harmful conduct, supplemented by considerations of effectiveness and always choosing the least intrusive means still leave ample room for normative disagreement. Second, while mid-level principles are sometimes put forward in response to the problem of normative theories attaching different weight to moral principles, employing a mid-level harm principle completely leaves open how to determine what weight to attach to it in application. Third, there appears to be a trade-off between attaining convergence and finding a formulation of the harm principle that can justify liberty-restrictions in all situations of contagion, including interventions that are commonly allowed. These are not reasons to abandon mid-level theorizing altogether. But there is no reason to be too theory-modest in applied ethics. Morally justifying e.g. if a liberty-restriction in infectious disease control is proportional to the aim of harm-prevention, promptly requires moving beyond the mid-level harm principle. © 2011 Blackwell Publishing Ltd.

Acceptability of Behavioral Treatments: Influence of Knowledge of Behavioral Principles.

ERIC Educational Resources Information Center

Rasnake, L. Kaye; And Others

1993-01-01

Fifty-seven direct care staff members from an intermediate care facility for adults with mental retardation rated the acceptability of interventions used for self-injurious behavior and completed a measure of knowledge about behavioral principles. Results indicated that staff age and educational attainment were related to knowledge scores, but…

Gamma-Ray Telescope and Uncertainty Principle

ERIC Educational Resources Information Center

Shivalingaswamy, T.; Kagali, B. A.

2012-01-01

Heisenberg's Uncertainty Principle is one of the important basic principles of quantum mechanics. In most of the books on quantum mechanics, this uncertainty principle is generally illustrated with the help of a gamma ray microscope, wherein neither the image formation criterion nor the lens properties are taken into account. Thus a better…

Le Chatelier's principle in replicator dynamics

NASA Astrophysics Data System (ADS)

Allahverdyan, Armen E.; Galstyan, Aram

2011-10-01

The Le Chatelier principle states that physical equilibria are not only stable, but they also resist external perturbations via short-time negative-feedback mechanisms: a perturbation induces processes tending to diminish its results. The principle has deep roots, e.g., in thermodynamics it is closely related to the second law and the positivity of the entropy production. Here we study the applicability of the Le Chatelier principle to evolutionary game theory, i.e., to perturbations of a Nash equilibrium within the replicator dynamics. We show that the principle can be reformulated as a majorization relation. This defines a stability notion that generalizes the concept of evolutionary stability. We determine criteria for a Nash equilibrium to satisfy the Le Chatelier principle and relate them to mutualistic interactions (game-theoretical anticoordination) showing in which sense mutualistic replicators can be more stable than (say) competing ones. There are globally stable Nash equilibria, where the Le Chatelier principle is violated even locally: in contrast to the thermodynamic equilibrium a Nash equilibrium can amplify small perturbations, though both types of equilibria satisfy the detailed balance condition.

Le Chatelier's principle in replicator dynamics.

PubMed

Allahverdyan, Armen E; Galstyan, Aram

2011-10-01

The Le Chatelier principle states that physical equilibria are not only stable, but they also resist external perturbations via short-time negative-feedback mechanisms: a perturbation induces processes tending to diminish its results. The principle has deep roots, e.g., in thermodynamics it is closely related to the second law and the positivity of the entropy production. Here we study the applicability of the Le Chatelier principle to evolutionary game theory, i.e., to perturbations of a Nash equilibrium within the replicator dynamics. We show that the principle can be reformulated as a majorization relation. This defines a stability notion that generalizes the concept of evolutionary stability. We determine criteria for a Nash equilibrium to satisfy the Le Chatelier principle and relate them to mutualistic interactions (game-theoretical anticoordination) showing in which sense mutualistic replicators can be more stable than (say) competing ones. There are globally stable Nash equilibria, where the Le Chatelier principle is violated even locally: in contrast to the thermodynamic equilibrium a Nash equilibrium can amplify small perturbations, though both types of equilibria satisfy the detailed balance condition.

Fundamental Tactical Principles of Soccer: A Comparison of Different Age Groups

PubMed Central

Guilherme, José; Rechenchosky, Leandro; da Costa, Luciane Cristina Arantes; Rinadi, Wilson

2017-01-01

Abstract The fundamental tactical principles of the game of soccer represent a set of action rules that guide behaviours related to the management of game space. The aim of this study was to compare the performance of fundamental offensive and defensive tactical principles among youth soccer players from 12 to 17 years old. The sample consisted of 3689 tactical actions performed by 48 soccer players in three age categories: under 13 (U-13), under 15 (U-15), and under 17 (U-17). Tactical performance was measured using the System of Tactical Assessment in Soccer (FUT-SAT). The Kruskal Wallis, Mann-Whitney U, Friedman, Wilcoxon, and Cohen’s Kappa tests were used in the study analysis. The results showed that the principles of “offensive coverage” (p = 0.01) and “concentration” (p = 0.04) were performed more frequently by the U-17 players than the U-13 players. The tactical principles “width and length” (p < 0.05) and “defensive unit” (p < 0.05) were executed more frequently by younger soccer players. It can be concluded that the frequency with which fundamental tactical principles are performed varies between the gaming categories, which implies that there is valuation of defensive security and a progressive increase in “offensive coverage” caused by increased confidence and security in offensive actions. PMID:28828091

GUIDING PRINCIPLES FOR GOOD PRACTICES IN HOSPITAL-BASED HEALTH TECHNOLOGY ASSESSMENT UNITS.

PubMed

Sampietro-Colom, Laura; Lach, Krzysztof; Pasternack, Iris; Wasserfallen, Jean-Blaise; Cicchetti, Americo; Marchetti, Marco; Kidholm, Kristian; Arentz-Hansen, Helene; Rosenmöller, Magdalene; Wild, Claudia; Kahveci, Rabia; Ulst, Margus

2015-01-01

Health technology assessment (HTA) carried out for policy decision making has well-established principles unlike hospital-based HTA (HB-HTA), which differs from the former in the context characteristics and ways of operation. This study proposes principles for good practices in HB-HTA units. A framework for good practice criteria was built inspired by the EFQM excellence business model and information from six literature reviews, 107 face-to-face interviews, forty case studies, large-scale survey, focus group, Delphi survey, as well as local and international validation. In total, 385 people from twenty countries have participated in defining the principles for good practices in HB-HTA units. Fifteen guiding principles for good practices in HB-HTA units are grouped in four dimensions. Dimension 1 deals with principles of the assessment process aimed at providing contextualized information for hospital decision makers. Dimension 2 describes leadership, strategy and partnerships of HB-HTA units which govern and facilitate the assessment process. Dimension 3 focuses on adequate resources that ensure the operation of HB-HTA units. Dimension 4 deals with measuring the short- and long-term impact of the overall performance of HB-HTA units. Finally, nine core guiding principles were selected as essential requirements for HB-HTA units based on the expertise of the HB-HTA units participating in the project. Guiding principles for good practices set up a benchmark for HB-HTA because they represent the ideal performance of HB-HTA units; nevertheless, when performing HTA at hospital level, context also matters; therefore, they should be adapted to ensure their applicability in the local context.

Heisenberg's observability principle

NASA Astrophysics Data System (ADS)

Wolff, Johanna

2014-02-01

Werner Heisenberg's 1925 paper 'Quantum-theoretical re-interpretation of kinematic and mechanical relations' marks the beginning of quantum mechanics. Heisenberg famously claims that the paper is based on the idea that the new quantum mechanics should be 'founded exclusively upon relationships between quantities which in principle are observable'. My paper is an attempt to understand this observability principle, and to see whether its employment is philosophically defensible. Against interpretations of 'observability' along empiricist or positivist lines I argue that such readings are philosophically unsatisfying. Moreover, a careful comparison of Heisenberg's reinterpretation of classical kinematics with Einstein's argument against absolute simultaneity reveals that the positivist reading does not fit with Heisenberg's strategy in the paper. Instead the appeal to observability should be understood as a specific criticism of the causal inefficacy of orbital electron motion in Bohr's atomic model. I conclude that the tacit philosophical principle behind Heisenberg's argument is not a positivistic connection between observability and meaning, but the idea that a theory should not contain causally idle wheels.

A non-randomized multicentre trial of human immune plasma for treatment of hantavirus cardiopulmonary syndrome caused by Andes virus.

PubMed

Vial, Pablo A; Valdivieso, Francisca; Calvo, Mario; Rioseco, M Luisa; Riquelme, Raul; Araneda, Andres; Tomicic, Vinko; Graf, Jerónimo; Paredes, Laura; Florenzano, Matias; Bidart, Teresa; Cuiza, Analia; Marco, Claudia; Hjelle, Brian; Ye, Chunyan; Hanfelt-Goade, Diane; Vial, Cecilia; Rivera, Juan C; Delgado, Iris; Mertz, Gregory J

2015-01-01

In Chile, Andes virus (ANDV) is the sole aetiological agent of hantavirus cardiopulmonary syndrome (HCPS) with mean annual incidence of 55 cases, 32% case fatality rate (CFR) and no specific treatment. Neutralizing antibody (NAb) titres at hospital admission correlate inversely with HCPS severity. We designed an open trial to explore safety and efficacy and evaluate pharmacokinetics of immune plasma as a treatment strategy for this disease. We performed plasmapheresis on donors at least 6 months after HCPS and measured NAb titres through a focus-reduction neutralization test. Subjects admitted to 10 study sites with suspected/confirmed HCPS were eligible for treatment with immune plasma by intravenous infusion at an ANDV NAb dose of 5,000 U/kg. HCPS was confirmed through immunoglobulin M serology or reverse transcriptase-PCR. The main outcome was mortality within 30 days. From 2008-2012, we enrolled and treated 32 cases and confirmed HCPS in 29. CFR of hantavirus plasma-treated cases was 4/29 (14%); CFR of non-treated cases in the same period in Chile was 63/199 (32%; P=0.049, OR=0.35, CI=0.12, 0.99); CFR of non-treated cases at the same study sites between 2005-2012 was 18/66 (27%; (P=0.15, OR=0.43, CI=0.14, 1.34) and CFR in a previous methylprednisolone treatment study was 20/60 (33%; P=0.052, OR=0.32, CI=0.10, 1.00). We detected no serious adverse events associated to plasma infusion. Plasma NAb titres reached in recipients were variable and viral load remained stable. Human ANDV immune plasma infusion appears safe for HCPS. We observed a decrease in CFR in treated cases with borderline significance that will require further studies for confirmation.

Principles and the search for moral certainty.

PubMed

Churchill, L R; Simán, J J

1986-01-01

In medical ethics, principles have an important but frequently overextended role. The need for exact answers and moral formulae sometimes leads to the misuse of principles, such that they usurp the central place of persons and become ends in themselves. The Baby Jane Doe case is discussed as a prominent instance of both the proper uses and abuses of principles. A more fitting role for principles is described and illustrated, stressing the use of principles as tools of moral discernment and the time-laden character of moral judgments.

Principles of Burn Pain Management.

PubMed

James, Dominika Lipowska; Jowza, Maryam

2017-10-01

This article describes pathophysiology of burn injury-related pain and the basic principles of burn pain management. The focus is on concepts of perioperative and periprocedural pain management with extensive discussion of opioid-based analgesia, including patient-controlled analgesia, challenges of effective opioid therapy in opioid-tolerant patients, and opioid-induced hyperalgesia. The principles of multimodal pain management are discussed, including the importance of psychological counseling, perioperative interventional pain procedures, and alternative pain management options. A brief synopsis of the principles of outpatient pain management is provided. Copyright © 2017 Elsevier Inc. All rights reserved.

Negligible effects of tryptophan on the aflatoxin adsorption of sodium bentonite.

PubMed

Magnoli, A P; Copia, P; Monge, M P; Magnoli, C E; Dalcero, A M; Chiacchiera, S M

2014-01-01

The main objective of this study was to determine if the competitive adsorption of tryptophan (Trp) and aflatoxin B₁ (AFB₁) could potentially affect the ability of a sodium bentonite (NaB) to prevent aflatoxicosis in monogastric animals. The adsorption of Trp and AFB₁ on this adsorbent is fast and could be operating on the same time-scale making competition feasible. In vitro competitive adsorption experiments under simulated gastrointestinal conditions were performed. A high affinity of the clay for Trp and NaB was observed. The effect of an excess of KCl to mimic the ionic strength of the physiological conditions were also investigated. A six-times decrease in the Trp surface excess at saturation was observed. A similar behaviour was previously found for AFB₁ adsorption. Taking into account the amount of Trp adsorbed by the clay and the usual adsorbent supplementation level in diets, a decrease in Trp bioavailability is not expected to occur. Tryptophan adsorption isotherms on NaB were 'S'-shaped and were adjusted by the Frumkin-Fowler-Guggenheim model. The reversibility of the adsorption processes was investigated in order to check a potential decrease in the ability of NaB to protect birds against chronic aflatoxicoses. Adsorption processes were completely reversible for Trp, while almost irreversible for AFB₁. In spite of the high affinity of the NaB for Trp, probably due to the reversible character of Trp adsorption, no changes in the AFB₁ adsorption isotherm were observed when an excess of the amino acid was added to the adsorption medium. As a consequence of the preferential and irreversible AFB₁ adsorption and the reversible weak binding of Trp to the NaB, no changes in the aflatoxin sorption ability of the clay are expected to occur in the gastrointestinal tract of birds.

Core principles of evolutionary medicine: A Delphi study.

PubMed

Grunspan, Daniel Z; Nesse, Randolph M; Barnes, M Elizabeth; Brownell, Sara E

2018-01-01

Evolutionary medicine is a rapidly growing field that uses the principles of evolutionary biology to better understand, prevent and treat disease, and that uses studies of disease to advance basic knowledge in evolutionary biology. Over-arching principles of evolutionary medicine have been described in publications, but our study is the first to systematically elicit core principles from a diverse panel of experts in evolutionary medicine. These principles should be useful to advance recent recommendations made by The Association of American Medical Colleges and the Howard Hughes Medical Institute to make evolutionary thinking a core competency for pre-medical education. The Delphi method was used to elicit and validate a list of core principles for evolutionary medicine. The study included four surveys administered in sequence to 56 expert panelists. The initial open-ended survey created a list of possible core principles; the three subsequent surveys winnowed the list and assessed the accuracy and importance of each principle. Fourteen core principles elicited at least 80% of the panelists to agree or strongly agree that they were important core principles for evolutionary medicine. These principles over-lapped with concepts discussed in other articles discussing key concepts in evolutionary medicine. This set of core principles will be helpful for researchers and instructors in evolutionary medicine. We recommend that evolutionary medicine instructors use the list of core principles to construct learning goals. Evolutionary medicine is a young field, so this list of core principles will likely change as the field develops further.

Boosting of HIV-1 Neutralizing Antibody Responses by a Distally Related Retroviral Envelope Protein

PubMed Central

Uchtenhagen, Hannes; Schiffner, Torben; Bowles, Emma; Heyndrickx, Leo; LaBranche, Celia; Applequist, Steven E.; Jansson, Marianne; De Silva, Thushan; Back, Jaap Willem; Achour, Adnane; Scarlatti, Gabriella; Fomsgaard, Anders; Montefiori, David; Stewart-Jones, Guillaume; Spetz, Anna-Lena

2014-01-01

Our knowledge of the binding sites for neutralizing antibodies (NAbs) that recognize a broad range of HIV-1 strains (bNAb) has substantially increased in recent years. However, gaps remain in our understanding of how to focus B-cell responses to vulnerable conserved sites within the HIV-1 envelope glycoprotein (Env). Here we report an immunization strategy composed of a trivalent HIV-1 (clade B envs) DNA prime, followed by a SIVmac239 gp140 Env protein boost that aimed to focus the immune response to structurally conserved parts of the HIV-1 and SIV Envs. Heterologous NAb titres, primarily to tier 1 HIV-1 isolates, elicited during the trivalent HIV-1 env prime, were significantly increased by the SIVmac239 gp140 protein boost in rabbits. Epitope mapping of antibody binding reactivity revealed preferential recognition of the C1, C2, V2, V3 and V5 regions. These results provide a proof of concept that a distally related retroviral SIV Env protein boost can increase pre-existing NAb responses against HIV-1. PMID:24829409

Structural constraints determine the glycosylation of HIV-1 envelope trimers

PubMed Central

Pritchard, Laura K.; Vasiljevic, Snezana; Ozorowski, Gabriel; Seabright, Gemma E.; Cupo, Albert; Ringe, Rajesh; Kim, Helen J.; Sanders, Rogier W.; Doores, Katie J.; Burton, Dennis R.; Wilson, Ian A.; Ward, Andrew B.; Moore, John P.; Crispin, Max

2015-01-01

A highly glycosylated, trimeric envelope glycoprotein (Env) mediates HIV-1 cell entry. The high density and heterogeneity of the glycans shield Env from recognition by the immune system but, paradoxically, many potent broadly neutralizing antibodies (bNAbs) recognize epitopes involving this glycan shield. To better understand Env glycosylation and its role in bNAb recognition, we characterized a soluble, cleaved recombinant trimer (BG505 SOSIP.664) that is a close structural and antigenic mimic of native Env. Large, unprocessed oligomannose-type structures (Man8-9GlcNAc2) are notably prevalent on the gp120 components of the trimer, irrespective of the mammalian cell expression system or the bNAb used for affinity-purification. In contrast, gp41 subunits carry more highly processed glycans. The glycans on uncleaved, non-native oligomeric gp140 proteins are also highly processed. A homogeneous, oligomannose-dominated glycan profile is therefore a hallmark of a native Env conformation and a potential Achilles’ heel that can be exploited for bNAb recognition and vaccine design. PMID:26051934

Teaching/learning principles

NASA Technical Reports Server (NTRS)

Hankins, D. B.; Wake, W. H.

1981-01-01

The potential remote sensing user community is enormous, and the teaching and training tasks are even larger; however, some underlying principles may be synthesized and applied at all levels from elementary school children to sophisticated and knowledgeable adults. The basic rules applying to each of the six major elements of any training course and the underlying principle involved in each rule are summarized. The six identified major elements are: (1) field sites for problems and practice; (2) lectures and inside study; (3) learning materials and resources (the kit); (4) the field experience; (5) laboratory sessions; and (6) testing and evaluation.

Teaching the foundational principles of rehabilitation psychology.

PubMed

Stiers, William

2016-02-01

Wright (1983) described 20 "value-laden beliefs and principles" that form the foundational principles of rehabilitation psychology, and the education and training of rehabilitation psychologists necessitates that they acquire the specialty-specific knowledge and attitudes/values related to these principles. This article addresses 2 questions about how these principles can be taught in rehabilitation psychology training: (a) What are the core theories and evidence supporting these foundational principles, and what should be the content of a "core curriculum" for teaching these?; and (b) What is known about the most effective methods for teaching these foundational principles, including questions of how to teach values? The foundational principles were grouped into 3 categories: individual psychological processes, social psychological processes, and values related to social integration. A literature review was conducted in these 3 categories, and the results are summarized and discussed. A core curriculum is discussed for teaching about disability-specific individual psychological processes, social psychological processes, and values related to social integration, including methods to reduce group prejudice and promote values relevant to the foundational principles. Specific suggestions for training program content and methods are provided. It is hoped that effective teaching of Wright's (1983) value-laden beliefs and principles will help rehabilitation psychology trainers and trainees focus on the key knowledge and attitude-value competencies that are to be acquired in training. (c) 2016 APA, all rights reserved).

Hubble Nabs Space Invaders?

NASA Image and Video Library

2017-12-08

The gravitational field surrounding this massive cluster of galaxies, Abell 68, acts as a natural lens in space to brighten and magnify the light coming from very distant background galaxies. Like a fun house mirror, lensing creates a fantasy landscape of arc-like images and mirror images of background galaxies. The foreground cluster is 2 billion light-years away, and the lensed images come from galaxies far behind it. In this photo, the image of a spiral galaxy at upper left has been stretched and mirrored into a shape similar to that of a simulated alien from the classic 1970s computer game "Space Invaders!" A second, less distorted image of the same galaxy appears to the left of the large, bright elliptical galaxy. In the upper right of the photo is another striking feature of the image that is unrelated to gravitational lensing. What appears to be purple liquid dripping from a galaxy is a phenomenon called ram-pressure stripping. The gas clouds within the galaxy are being stripped out and heated up as the galaxy passes through a region of denser intergalactic gas. This image was taken in infrared light by Hubble’s Wide Field Camera 3, and combined with near-infrared observations from Hubble’s Advanced Camera for Surveys. The image is based in part on data spotted by Nick Rose in the Hubble’s Hidden Treasures image processing competition. The Hubble Space Telescope is a project of international cooperation between NASA and the European Space Agency. NASA's Goddard Space Flight Center in Greenbelt, Md., manages the telescope. The Space Telescope Science Institute (STScI) in Baltimore, Md., conducts Hubble science operations. STScI is operated by the Association of Universities for Research in Astronomy, Inc., in Washington. Credit: NASA and ESA Acknowledgement: N. Rose For image files and more information about Abell 68, visit: hubblesite.org/news/2013/09 www.spacetelescope.org/news/heic04 heritage.stsci.edu/2013/09 www.spacetelescope.org/projects/hiddentreasures/ NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

Hubble Nabs Space Invaders?

NASA Image and Video Library

2017-12-08

The gravitational field surrounding this massive cluster of galaxies, Abell 68, acts as a natural lens in space to brighten and magnify the light coming from very distant background galaxies. Like a fun house mirror, lensing creates a fantasy landscape of arc-like images and mirror images of background galaxies. The foreground cluster is 2 billion light-years away, and the lensed images come from galaxies far behind it. In this photo, the image of a spiral galaxy at upper left has been stretched and mirrored into a shape similar to that of a simulated alien from the classic 1970s computer game "Space Invaders!" A second, less distorted image of the same galaxy appears to the left of the large, bright elliptical galaxy. In the upper right of the photo is another striking feature of the image that is unrelated to gravitational lensing. What appears to be purple liquid dripping from a galaxy is a phenomenon called ram-pressure stripping. The gas clouds within the galaxy are being stripped out and heated up as the galaxy passes through a region of denser intergalactic gas. This image was taken in infrared light by Hubble’s Wide Field Camera 3, and combined with near-infrared observations from Hubble’s Advanced Camera for Surveys. The image is based in part on data spotted by Nick Rose in the Hubble’s Hidden Treasures image processing competition. The Hubble Space Telescope is a project of international cooperation between NASA and the European Space Agency. NASA's Goddard Space Flight Center in Greenbelt, Md., manages the telescope. The Space Telescope Science Institute (STScI) in Baltimore, Md., conducts Hubble science operations. STScI is operated by the Association of Universities for Research in Astronomy, Inc., in Washington. To read more go to: 1.usa.gov/Z6uDUp Credit: NASA and ESA Acknowledgement: N. Rose For image files and more information about Abell 68, visit: hubblesite.org/news/2013/09 www.spacetelescope.org/news/heic04 heritage.stsci.edu/2013/09 www.spacetelescope.org/projects/hiddentreasures/ NASA image use policy. NASA Goddard Space Flight Center enables NASA’s mission through four scientific endeavors: Earth Science, Heliophysics, Solar System Exploration, and Astrophysics. Goddard plays a leading role in NASA’s accomplishments by contributing compelling scientific knowledge to advance the Agency’s mission. Follow us on Twitter Like us on Facebook Find us on Instagram

Towards HIV-1 remission: potential roles for broadly neutralizing antibodies.

PubMed

Halper-Stromberg, Ariel; Nussenzweig, Michel C

2016-02-01

Current antiretroviral drug therapies do not cure HIV-1 because they do not eliminate a pool of long-lived cells harboring immunologically silent but replication-competent proviruses - termed the latent reservoir. Eliminating this reservoir and stimulating the immune response to control infection in the absence of therapy remain important but unsolved goals of HIV-1 cure research. Recently discovered broadly neutralizing antibodies (bNAbs) exhibit remarkable breadth and potency in their ability to neutralize HIV-1 in vitro, and recent studies have demonstrated new therapeutic applications for passively administered bNAbs in vivo. This Review discusses the roles bNAbs might play in HIV-1 treatment regimens, including prevention, therapy, and cure.

Principles of Need and the Aggregation Thesis.

PubMed

Gustavsson, Erik; Juth, Niklas

2017-09-02

Principles of need are constantly referred to in health care priority setting. The common denominator for any principle of need is that it will ascribe some kind of special normative weight to people being worse off. However, this common ground does not answer the question how a plausible principle of need should relate to the aggregation of benefits across individuals. Principles of need are sometimes stated as being incompatible with aggregation and sometimes characterized as accepting aggregation in much the same way as utilitarians do. In this paper we argue that if one wants to take principles of need seriously both of these positions have unreasonable implications. We then characterize and defend a principle of need consisting of sufficientarian elements as well as prioritarian which avoids these unreasonable implications.

Improved Bounds on Violation of the Strong Equivalence Principle

NASA Technical Reports Server (NTRS)

Arzoumanian, Z.

2002-01-01

I describe a unique, 20-year-long timing program for the binary pulsar B0655+64, the stalwart control experiment for measurements of gravitational radiation damping in relativistic neutron-star binaries. Observed limits on evolution of the B0655+64 orbit provide new bounds on the existence of dipolar gravitational radiation, and hence on violation of the Strong Equivalence Principle.

Ensuring the reliability of stable isotope ratio data--beyond the principle of identical treatment.

PubMed

Carter, J F; Fry, B

2013-03-01

The need for inter-laboratory comparability is crucial to facilitate the globalisation of scientific networks and the development of international databases to support scientific and criminal investigations. This article considers what lessons can be learned from a series of inter-laboratory comparison exercises organised by the Forensic Isotope Ratio Mass Spectrometry (FIRMS) network in terms of reference materials (RMs), the management of data quality, and technical limitations. The results showed that within-laboratory precision (repeatability) was generally good but between-laboratory accuracy (reproducibility) called for improvements. This review considers how stable isotope laboratories can establish a system of quality control (QC) and quality assurance (QA), emphasising issues of repeatability and reproducibility. For results to be comparable between laboratories, measurements must be traceable to the international δ-scales and, because isotope ratio measurements are reported relative to standards, a key aspect is the correct selection, calibration, and use of international and in-house RMs. The authors identify four principles which promote good laboratory practice. The principle of identical treatment by which samples and RMs are processed in an identical manner and which incorporates three further principles; the principle of identical correction (by which necessary corrections are identified and evenly applied), the principle of identical scaling (by which data are shifted and stretched to the international δ-scales), and the principle of error detection by which QC and QA results are monitored and acted upon. To achieve both good repeatability and good reproducibility it is essential to obtain RMs with internationally agreed δ-values. These RMs will act as the basis for QC and can be used to calibrate further in-house QC RMs tailored to the activities of specific laboratories. In-house QA standards must also be developed to ensure that QC

Grounding principles for inferring agency: Two cultural perspectives.

PubMed

Ojalehto, Bethany L; Medin, Douglas L; García, Salino G

2017-06-01

The present research investigates cultural variation in grounding principles for inferring agency in order to address an important theoretical debate: does cultural diversity in agency concepts reflect an animistic overextension of (universal) folkpsychology, as many have argued, or an alternative theory of folkcommunication based on relational principles? In two experiments, mind perception measures were adapted to assess beliefs concerning the agency of non-animal kinds (plants, abiotic kinds, complex artifacts) among Indigenous Ngöbe adults in Panama and US college students. Agency attributions varied systematically, with Ngöbe ascribing greater agency to non-animal natural kinds and US college participants ascribing greater agency to complex artifacts. Analysis of explanations revealed divergent interpretations of agency as a prototypically human capacity requiring consciousness (US), versus a relational capacity expressed in directed interactions (Ngöbe). Converging measures further illuminated the inferential principles underlying these agency attributions. (1) An experimental relational framing of agency probes facilitated Ngöbe but not US agency attributions. (2) Further analysis showed that three key dimensions of agency attribution (experience, cognition, animacy) are organized differently across cultures. (3) A Bayesian approach to cultural consensus modeling confirmed the presence of two distinct consensus models rather than variations on a single (universal) model. Together, these results indicate that conceptual frameworks for agency differ across US college and Ngöbe communities. We conclude that Ngöbe concepts of agency derive from a distinct theory of folkcommunication based on an ecocentric prototype rather than overextensions of an anthropocentric folkpsychology. These observations suggest that folkpsychology and mind perception represent culture specific frameworks for agency, with significant implications for domain-specificity theory and

National Principles of War: Guiding National Power to Victory

DTIC Science & Technology

2006-05-26

label the principles as more Principles of Battle7 than Principles of War. As John I. Alger remarked in his book on the history of the Principles of War...better suited to be Principles of Military Operations than National Principles of War. In his The Quest for Victory, John I. Alger recognizes three...mentioned work, John Alger discusses same those principles but adds the principle unity of command. Not only was this a crucial time for the development of

Humoral response and protection from experimental challenge following vaccination of raccoon pups with a modified-live canine distemper virus vaccine.

PubMed

Paré, J A; Barker, I K; Crawshaw, G J; McEwen, S A; Carman, P S; Johnson, R P

1999-07-01

Eight 8-wk-old raccoon pups (Procyon lotor) with maternal canine distemper virus (CDV) neutralizing antibodies (NAb) and 24 8-wk-old seronegative pups were administered a commercial modified-live CDV vaccine (Galaxy, D, Solvay Animal Health, Inc., Kitchener, Ontario, Canada). All 24 seronegative raccoons had detectable serum CDV NAb titers 14 days after the initial dose. Titers rose to maximum levels 4 wk post-vaccination. Mean titers for groups of vaccinated seronegative pups were maintained between 1:256 and 1:2,048 for the remainder of the 3 mo observation period. Geometric means of the serum CDV NAb titer of eight seronegative pups given a single vaccine dose at 8 wk of age did not differ significantly from those of eight pups that were given serial doses at 8, 12, and 16 wk of age, or from those of eight pups vaccinated once at 16 wk of age. Seven unvaccinated 8-wk-old raccoon pups used as controls remained seronegative throughout the trial. Seven out of eight 8-wk-old pups with maternal antibodies, vaccinated at 8, 12, and 16 wk of age, failed to develop a rise in their CDV NAb titers until at least 18 wk of age, 2 wk after the third vaccination. Titers in eight unvaccinated raccoons with maternal antibodies declined steadily to undetectable levels at 20 wk of age. A half-life of 10.55 days was calculated for maternally-derived CDV NAb in raccoon pups. Sixteen vaccinated raccoons were protected from clinical disease following experimental oronasal challenge with a virulent raccoon strain of CDV, 13 to 23 wk after vaccination. Serum CDV NAb titers at the time of challenge ranged from 1:12 to 1:384 and increased during the period of observation. Three of four unvaccinated seronegative raccoons used as controls failed to mount any detectable CDV NAb and were euthanatized after developing clinical signs of canine distemper 26, 29, and 30 days post-challenge (PC). Necropsies confirmed the diagnosis. The fourth control raccoon exhibited transient equivocal clinical

Ten financial management principles for survival.

PubMed

Cleverley, W O

1988-03-01

Financial insolvency is the primary cause of hospital failure. Managers may analyze a hospital's financial statements to anticipate and prevent fiscal problems. Ten measures of fiscal status may be used to evaluate the following: operating profitability nonoperating income equity growth liquidity debt capacity age of facilities revenue generation replacement funds receivables survivability Based on data from the Financial Analysis Service, Catholic hospitals are doing better than other U.S. hospitals in some areas of financial preparedness. In most areas, however, all hospitals suffer by comparison with manufacturers. The 10 principles of solvent and successful operations can help hospitals improve financial resiliency.

Introduction: Principles of quantum gravity

NASA Astrophysics Data System (ADS)

Crowther, Karen; Rickles, Dean

2014-05-01

In this introduction, we describe the rationale behind this special issue on Principles of Quantum Gravity. We explain what we mean by 'principles' and relate this to the various contributions. Finally, we draw out some general themes that can be found running throughout these contributions.

Harm reduction principles for healthcare settings.

PubMed

Hawk, Mary; Coulter, Robert W S; Egan, James E; Fisk, Stuart; Reuel Friedman, M; Tula, Monique; Kinsky, Suzanne

2017-10-24

Harm reduction refers to interventions aimed at reducing the negative effects of health behaviors without necessarily extinguishing the problematic health behaviors completely. The vast majority of the harm reduction literature focuses on the harms of drug use and on specific harm reduction strategies, such as syringe exchange, rather than on the harm reduction philosophy as a whole. Given that a harm reduction approach can address other risk behaviors that often occur alongside drug use and that harm reduction principles have been applied to harms such as sex work, eating disorders, and tobacco use, a natural evolution of the harm reduction philosophy is to extend it to other health risk behaviors and to a broader healthcare audience. Building on the extant literature, we used data from in-depth qualitative interviews with 23 patients and 17 staff members from an HIV clinic in the USA to describe harm reduction principles for use in healthcare settings. We defined six principles of harm reduction and generalized them for use in healthcare settings with patients beyond those who use illicit substances. The principles include humanism, pragmatism, individualism, autonomy, incrementalism, and accountability without termination. For each of these principles, we present a definition, a description of how healthcare providers can deliver interventions informed by the principle, and examples of how each principle may be applied in the healthcare setting. This paper is one of the firsts to provide a comprehensive set of principles for universal harm reduction as a conceptual approach for healthcare provision. Applying harm reduction principles in healthcare settings may improve clinical care outcomes given that the quality of the provider-patient relationship is known to impact health outcomes and treatment adherence. Harm reduction can be a universal precaution applied to all individuals regardless of their disclosure of negative health behaviors, given that health

Multimedia Principle in Teaching Lessons

ERIC Educational Resources Information Center

Kari Jabbour, Khayrazad

2012-01-01

Multimedia learning principle occurs when we create mental representations from combining text and relevant graphics into lessons. This article discusses the learning advantages that result from adding multimedia learning principle into instructions; and how to select graphics that support learning. There is a balance that instructional designers…

Measurement Invariance: A Foundational Principle for Quantitative Theory Building

ERIC Educational Resources Information Center

Nimon, Kim; Reio, Thomas G., Jr.

2011-01-01

This article describes why measurement invariance is a critical issue to quantitative theory building within the field of human resource development. Readers will learn what measurement invariance is and how to test for its presence using techniques that are accessible to applied researchers. Using data from a LibQUAL+[TM] study of user…

Phenotypical and molecular distinctness of sinonasal haemangiopericytoma compared to solitary fibrous tumour of the sinonasal tract.

PubMed

Agaimy, Abbas; Barthelmeß, Sarah; Geddert, Helene; Boltze, Carsten; Moskalev, Evgeny A; Koch, Michael; Wiemann, Stefan; Hartmann, Arndt; Haller, Florian

2014-11-01

Sinonasal haemangiopericytoma (SN-HPC) is a rare sinonasal mesenchymal neoplasm of perivascular myoid cell origin. Solitary fibrous tumour (SFT) occurs only very rarely in the sinonasal tract. SFT and soft tissue HPC have been considered a single entity. Recently, recurrent gene fusions involving NAB2-STAT6 resulting in differential expression of STAT6 were characterized as central molecular events in SFT. However, no data exist for NAB2-STAT6 status or STAT6 expression in SN-HPC. We examined six SN-HPCs and two sinonasal SFTs by immunohistochemistry and RT-PCR for NAB2-STAT6 fusions. SN-HPC affected three females and three males (mean age: 72 years). They expressed smooth muscle actin, lacked strong CD34 reactivity and were negative for nuclear STAT6 expression. RT-PCR analysis confirmed the absence of NAB2-STAT6 fusions in all cases. Conversely, both sinonasal SFTs (in males aged 39 and 52 years) displayed classical features of pleuropulmonary and soft-tissue SFTs (uniformly CD34-positive with strong nuclear expression of STAT6). RT-PCR revealed NAB2-STAT6 fusions in both cases. These findings confirm the molecular and phenotypical distinctness of these two entities. While SN-HPC is a site-specific sinonasal neoplasm of as yet unknown molecular pathogenesis, sinonasal SFTs show phenotypical and molecular identity to their pleural/extrapleural counterparts. © 2014 John Wiley & Sons Ltd.

HIV-specific Fc effector function early in infection predicts the development of broadly neutralizing antibodies.

PubMed

Richardson, Simone I; Chung, Amy W; Natarajan, Harini; Mabvakure, Batsirai; Mkhize, Nonhlanhla N; Garrett, Nigel; Abdool Karim, Salim; Moore, Penny L; Ackerman, Margaret E; Alter, Galit; Morris, Lynn

2018-04-01

While the induction of broadly neutralizing antibodies (bNAbs) is a major goal of HIV vaccination strategies, there is mounting evidence to suggest that antibodies with Fc effector function also contribute to protection against HIV infection. Here we investigated Fc effector functionality of HIV-specific IgG plasma antibodies over 3 years of infection in 23 individuals, 13 of whom developed bNAbs. Antibody-dependent cellular phagocytosis (ADCP), complement deposition (ADCD), cellular cytotoxicity (ADCC) and cellular trogocytosis (ADCT) were detected in almost all individuals with levels of activity increasing over time. At 6 months post-infection, individuals with bNAbs had significantly higher levels of ADCD and ADCT that correlated with antibody binding to C1q and FcγRIIa respectively. In addition, antibodies from individuals with bNAbs showed more IgG subclass diversity to multiple HIV antigens which also correlated with Fc polyfunctionality. Germinal center activity represented by CXCL13 levels and expression of activation-induced cytidine deaminase (AID) was found to be associated with neutralization breadth, Fc polyfunctionality and IgG subclass diversity. Overall, multivariate analysis by random forest classification was able to group bNAb individuals with 85% sensitivity and 80% specificity based on the properties of their antibody Fc early in HIV infection. Thus, the Fc effector function profile predicted the development of neutralization breadth in this cohort, suggesting that intrinsic immune factors within the germinal center provide a mechanistic link between the Fc and Fab of HIV-specific antibodies.

TrkB blockade in the hippocampus after training or retrieval impairs memory: protection from consolidation impairment by histone deacetylase inhibition.

PubMed

Blank, Martina; Petry, Fernanda S; Lichtenfels, Martina; Valiati, Fernanda E; Dornelles, Arethuza S; Roesler, Rafael

2016-03-01

Relatively little is known about the requirement of signaling initiated by brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), in the early phases of memory consolidation, as well as about its possible functional interactions with epigenetic mechanisms. Here we show that blocking TrkB in the dorsal hippocampus after learning or retrieval impairs retention of memory for inhibitory avoidance (IA). More importantly, the impairing effect of TrkB antagonism on consolidation was completely prevented by the histone deacetylase (HDAC) inhibitor sodium butyrate (NaB). Male Wistar rats were given an intrahippocampal infusion of saline (SAL) or NaB before training, followed by an infusion of either vehicle (VEH) or the selective TrkB antagonist ANA-12 immediately after training. In a second experiment, the infusions were administered before and after retrieval. ANA-12 after either training or retrieval produced a significant impairment in a subsequent memory retention test. Pretraining administration of NaB prevented the effect of ANA-12, although NaB given before retrieval did not alter the impairment resulting from TrkB blockade. The results indicate that inhibition of BDNF/TrkB in the hippocampus can hinder consolidation and reconsolidation of IA memory. However, TrkB activity is not required for consolidation in the presence of NaB, suggesting that a dysfunction in BDNF/TrkB signaling can be fully compensated by HDAC inhibition to allow hippocampal memory formation.

Structure-based Design of Cyclically Permuted HIV-1 gp120 Trimers That Elicit Neutralizing Antibodies*

PubMed Central

Kesavardhana, Sannula; Das, Raksha; Citron, Michael; Datta, Rohini; Ecto, Linda; Srilatha, Nonavinakere Seetharam; DiStefano, Daniel; Swoyer, Ryan; Joyce, Joseph G.; Dutta, Somnath; LaBranche, Celia C.; Montefiori, David C.; Flynn, Jessica A.; Varadarajan, Raghavan

2017-01-01

A major goal for HIV-1 vaccine development is an ability to elicit strong and durable broadly neutralizing antibody (bNAb) responses. The trimeric envelope glycoprotein (Env) spikes on HIV-1 are known to contain multiple epitopes that are susceptible to bNAbs isolated from infected individuals. Nonetheless, all trimeric and monomeric Env immunogens designed to date have failed to elicit such antibodies. We report the structure-guided design of HIV-1 cyclically permuted gp120 that forms homogeneous, stable trimers, and displays enhanced binding to multiple bNAbs, including VRC01, VRC03, VRC-PG04, PGT128, and the quaternary epitope-specific bNAbs PGT145 and PGDM1400. Constructs that were cyclically permuted in the V1 loop region and contained an N-terminal trimerization domain to stabilize V1V2-mediated quaternary interactions, showed the highest homogeneity and the best antigenic characteristics. In guinea pigs, a DNA prime-protein boost regimen with these new gp120 trimer immunogens elicited potent neutralizing antibody responses against highly sensitive Tier 1A isolates and weaker neutralizing antibody responses with an average titer of about 115 against a panel of heterologous Tier 2 isolates. A modest fraction of the Tier 2 virus neutralizing activity appeared to target the CD4 binding site on gp120. These results suggest that cyclically permuted HIV-1 gp120 trimers represent a viable platform in which further modifications may be made to eventually achieve protective bNAb responses. PMID:27879316

Principles of Optics

NASA Astrophysics Data System (ADS)

Born, Max; Wolf, Emil

1999-10-01

Principles of Optics is one of the classic science books of the twentieth century, and probably the most influential book in optics published in the past forty years. This edition has been thoroughly revised and updated, with new material covering the CAT scan, interference with broad-band light and the so-called Rayleigh-Sommerfeld diffraction theory. This edition also details scattering from inhomogeneous media and presents an account of the principles of diffraction tomography to which Emil Wolf has made a basic contribution. Several new appendices are also included. This new edition will be invaluable to advanced undergraduates, graduate students and researchers working in most areas of optics.

Ethical principles of informed consent: exploring nurses' dual role of care provider and researcher.

PubMed

Judkins-Cohn, Tanya M; Kielwasser-Withrow, Kiersten; Owen, Melissa; Ward, Jessica

2014-01-01

This article describes the ethical principles of autonomy, beneficence, and justice within the nurse researcher-participant relationship as these principles relate to the informed consent process for research. Within this process, the nurse is confronted with a dual role. This article describes how nurses, who are in the dual role of care provider and researcher, can apply these ethical principles to their practice in conjunction with the American Nurses Association's code of ethics for nurses. This article also describes, as an element of ethical practice, the importance of using participant-centered quality measures to aid informed decision making of participants in research. In addition, the article provides strategies for improving the informed consent process in nursing research. Finally, case scenarios are discussed, along with the application of ethical principles within the awareness of the dual role of the nurse as care provider and researcher. Copyright 2014, SLACK Incorporated.

49 CFR 236.786 - Principle, closed circuit.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 49 Transportation 4 2010-10-01 2010-10-01 false Principle, closed circuit. 236.786 Section 236.786 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION... Principle, closed circuit. The principle of circuit design where a normally energized electric circuit which...

The Effect of Principle-Procedure and Procedure-Principle Sequencing on Learning Outcomes. IDD&E Working Paper No. 19.

ERIC Educational Resources Information Center

Lim-Quek, Muriel; And Others

This study tested the effects of two instructional sequences--principle-procedure and procedure-principle--on the application and transfer of learning. It was hypothesized that a principle-procedure sequence would result in better near-transfer and far-transfer and that students would prefer this sequence. The 38 freshmen enrolled in a business…

[General principles of urban ecological land classification and planning].

PubMed

Deng, Xiaowen; Sun, Yichao; Han, Shijie

2005-10-01

Urban ecological land planning is a difficult and urgent task in city layout. This paper presented the definition of urban ecological land, and according the definition, divided the urban ecological land into two groups, i. e., ecological land for service, and ecological land for functioning. Based on the principles of city layout, some measures to plan these two urban ecological land groups were proposed.

18 CFR 725.6 - Principles, standards and procedures.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Principles, standards... Responsibilities § 725.6 Principles, standards and procedures. The Principles, Standards and Procedures established... Orders. These Principles, Standards and Procedures are found in 18 CFR parts 710 through 717. ...

Sensor of total hip arthoplasty wear designed on principle of scanning profilometry

NASA Astrophysics Data System (ADS)

Rössler, Tomas; Mandat, Dusan; Gallo, Jiri; Hrabovsky, Miroslav; Pochmon, Michal; Havranek, Vitezslav

2008-12-01

Total hip arthroplasty significantly improves the quality of life in majority of patients with osteoarthritis. However, prosthetic wear is a problem because of inducing the development of aseptic loosening and periprosthetic osteolysis which needs the revision surgery. Thus, the polyethylene wear measurement is the central to contemporary orthopaedics and this interesting has encouraged the development and improvement of both radiologic (in vivo) and non-radiologic (in vitro) methods for polyethylene wear quantification. The principles of polyethylene liner wear measurements are predominantly geometric; nevertheless, the realization of individual types of in vivo measurements brings with it the necessity of many simplifications and compromising steps to acquire approximately accurate values. In fact, the volumetric wear can be obtained by mathematical conversion based on the most linear shift of femoral head in the cup. However, such approach is understood to be somewhat insufficient. Our ongoing research pointed to the development of optical non-contact method for wear measurement and its results are introduced in this paper including the methodology designed for the usability validation of the method for the given purpose and the description of sensor, its principle, technical realization, design and parameters.

System level electrochemical principles

NASA Technical Reports Server (NTRS)

Thaller, L. H.

1985-01-01

The traditional electrochemical storage concepts are difficult to translate into high power, high voltage multikilowatt storage systems. The increased use of electronics, and the use of electrochemical couples that minimize the difficulties associated with the corrective measures to reduce the cell to cell capacity dispersion were adopted by battery technology. Actively cooled bipolar concepts are described which represent some attractive alternative system concepts. They are projected to have higher energy densities lower volumes than current concepts. They should be easier to scale from one capacity to another and have a closer cell to cell capacity balance. These newer storage system concepts are easier to manage since they are designed to be a fully integrated battery. These ideas are referred to as system level electrochemistry. The hydrogen-oxygen regenerative fuel cells (RFC) is probably the best example of the integrated use of these principles.

Gravitational Lagrangians, Mach's Principle, and the Equivalence Principle in an Expanding Universe

NASA Astrophysics Data System (ADS)

Essén, Hanno

2014-08-01

Gravitational Lagrangians as derived by Fock for the Einstein-Infeld-Hoffmann approach, and by Kennedy assuming only a fourth rank tensor interaction, contain long range interactions. Here we investigate how these affect the local dynamics when integrated over an expanding universe out to the Hubble radius. Taking the cosmic expansion velocity into account in a heuristic manner it is found that these long range interactions imply Mach's principle, provided the universe has the critical density, and that mass is renormalized. Suitable higher order additions to the Lagrangians make the formalism consistent with the equivalence principle.

Combination of confocal principle and aperture stop separation improves suppression of crystalline lens fluorescence in an eye model.

PubMed

Klemm, Matthias; Blum, Johannes; Link, Dietmar; Hammer, Martin; Haueisen, Jens; Schweitzer, Dietrich

2016-09-01

Fluorescence lifetime imaging ophthalmoscopy (FLIO) is a new technique to detect changes in the human retina. The autofluorescence decay over time, generated by endogenous fluorophores, is measured in vivo. The strong autofluorescence of the crystalline lens, however, superimposes the intensity decay of the retina fluorescence, as the confocal principle is not able to suppress it sufficiently. Thus, the crystalline lens autofluorescence causes artifacts in the retinal fluorescence lifetimes determined from the intensity decays. Here, we present a new technique to suppress the autofluorescence of the crystalline lens by introducing an annular stop into the detection light path, which we call Schweitzer's principle. The efficacy of annular stops with an outer diameter of 7 mm and inner diameters of 1 to 5 mm are analyzed in an experimental setup using a model eye based on fluorescent dyes. Compared to the confocal principle, Schweitzer's principle with an inner diameter of 3 mm is able to reduce the simulated crystalline lens fluorescence to 4%, while 42% of the simulated retina fluorescence is preserved. Thus, we recommend the implementation of Schweitzer's principle in scanning laser ophthalmoscopes used for fundus autofluorescence measurements, especially the FLIO device, for improved image quality.

Phonon-defect scattering and thermal transport in semiconductors: developing guiding principles

NASA Astrophysics Data System (ADS)

Polanco, Carlos; Lindsay, Lucas

First principles calculations of thermal conductivity have shown remarkable agreement with measurements for high-quality crystals. Nevertheless, most materials contain defects that provide significant extrinsic resistance and lower the conductivity from that of a perfect sample. This effect is usually accounted for with simplified analytical models that neglect the atomistic details of the defect and the exact dynamical properties of the system, which limits prediction capabilities. Recently, a method based on Greens functions was developed to calculate the phonon-defect scattering rates from first principles. This method has shown the important role of point defects in determining thermal transport in diamond and boron arsenide, two competitors for the highest bulk thermal conductivity. Here, we study the role of point defects on other relatively high thermal conductivity semiconductors, e.g., BN, BeSe, SiC, GaN and Si. We compare their first principles defect-phonon scattering rates and effects on transport properties with those from simplified models and explore common principles that determine these. Efforts will focus on basic vibrational properties that vary from system to system, such as density of states, interatomic force constants and defect deformation. Research supported by the U.S. Department of Energy, Basic Energy Sciences, Materials Sciences and Engineering Division.

The Virtue of Principle Ethics.

ERIC Educational Resources Information Center

Bersoff, Donald N.

1996-01-01

Presents arguments against adopting virtue ethics as a guiding concept in developing counseling guidelines: (1) virtue ethics is irrelevant in the resolution of most ethics cases; (2) virtue and principle ethics overlap; (3) principle ethics are more suited to acting and deciding; (4) the emphasis on virtue ethics increases the possibility of…

The Aristotelian Principle and Education.

ERIC Educational Resources Information Center

Pekarsky, Daniel

1980-01-01

For the Aristotelian principle to become operative, certain principles must be met. Individuals should be free from anxiety about satisfying basic needs. They cannot enjoy complexity in their lives beyond a certain point. To have satisfying lives, individuals should engage in both passive and active enjoyments, leading from a lower to a higher…

An Empirical Investigation of Clicker Technology in Financial Accounting Principles

ERIC Educational Resources Information Center

Marshall, Leisa L.; Varnon, Anthony W.

2012-01-01

The effects of clicker-use and active learning classroom activities on student performance in financial accounting principles were examined. A repeated measure design was used to compare performance on four exams between a clicker group and a non-clicker group, after controlling for GPA and age. A matched-pairs t-test was used to compare the…

Research on the parallel load sharing principle of a novel self-decoupled piezoelectric six-dimensional force sensor.

PubMed

Li, Ying-Jun; Yang, Cong; Wang, Gui-Cong; Zhang, Hui; Cui, Huan-Yong; Zhang, Yong-Liang

2017-09-01

This paper presents a novel integrated piezoelectric six-dimensional force sensor which can realize dynamic measurement of multi-dimensional space load. Firstly, the composition of the sensor, the spatial layout of force-sensitive components, and measurement principle are analyzed and designed. There is no interference of piezoelectric six-dimensional force sensor in theoretical analysis. Based on the principle of actual work and deformation compatibility coherence, this paper deduces the parallel load sharing principle of the piezoelectric six-dimensional force sensor. The main effect factors which affect the load sharing ratio are obtained. The finite element model of the piezoelectric six-dimensional force sensor is established. In order to verify the load sharing principle of the sensor, a load sharing test device of piezoelectric force sensor is designed and fabricated. The load sharing experimental platform is set up. The experimental results are in accordance with the theoretical analysis and simulation results. The experiments show that the multi-dimensional and heavy force measurement can be realized by the parallel arrangement of the load sharing ring and the force sensitive element in the novel integrated piezoelectric six-dimensional force sensor. The ideal load sharing effect of the sensor can be achieved by appropriate size parameters. This paper has an important guide for the design of the force measuring device according to the load sharing mode. Copyright © 2017 ISA. Published by Elsevier Ltd. All rights reserved.

Equivalence principle and bound kinetic energy.

PubMed

Hohensee, Michael A; Müller, Holger; Wiringa, R B

2013-10-11

We consider the role of the internal kinetic energy of bound systems of matter in tests of the Einstein equivalence principle. Using the gravitational sector of the standard model extension, we show that stringent limits on equivalence principle violations in antimatter can be indirectly obtained from tests using bound systems of normal matter. We estimate the bound kinetic energy of nucleons in a range of light atomic species using Green's function Monte Carlo calculations, and for heavier species using a Woods-Saxon model. We survey the sensitivities of existing and planned experimental tests of the equivalence principle, and report new constraints at the level of between a few parts in 10(6) and parts in 10(8) on violations of the equivalence principle for matter and antimatter.

Development of an anti-HIV vaccine eliciting broadly neutralizing antibodies.

PubMed

Ahmed, Yousuf; Tian, Meijuan; Gao, Yong

2017-09-12

The extreme HIV diversity posts a great challenge on development of an effective anti-HIV vaccine. To solve this problem, it is crucial to discover an appropriate immunogens and strategies that are able to prevent the transmission of the diverse viruses that are circulating in the world. Even though there have been a number of broadly neutralizing anti-HIV antibodies (bNAbs) been discovered in recent years, induction of such antibodies to date has only been observed in HIV-1 infection. Here, in this mini review, we review the progress in development of HIV vaccine in eliciting broad immune response, especially production of bNAbs, discuss possible strategies, such as polyvalent sequential vaccination, that facilitates B cell maturation leading to bNAb response.

Le Chatelier's Principle, Temperature Effects, and Entropy.

ERIC Educational Resources Information Center

Campbell, J. Arthur

1985-01-01

One of the most useful methods of understanding chemical equilibria is provided by Le Chatelier's principle. The relationships between this principle, temperature, and entropy are discussed. Tables with thermodynamic data for some net reactions commonly used to illustrate the principle and for reactions involving gases are included. (JN)

International consensus principles for ethical wildlife control.

PubMed

Dubois, Sara; Fenwick, Nicole; Ryan, Erin A; Baker, Liv; Baker, Sandra E; Beausoleil, Ngaio J; Carter, Scott; Cartwright, Barbara; Costa, Federico; Draper, Chris; Griffin, John; Grogan, Adam; Howald, Gregg; Jones, Bidda; Littin, Kate E; Lombard, Amanda T; Mellor, David J; Ramp, Daniel; Schuppli, Catherine A; Fraser, David

2017-08-01

Human-wildlife conflicts are commonly addressed by excluding, relocating, or lethally controlling animals with the goal of preserving public health and safety, protecting property, or conserving other valued wildlife. However, declining wildlife populations, a lack of efficacy of control methods in achieving desired outcomes, and changes in how people value animals have triggered widespread acknowledgment of the need for ethical and evidence-based approaches to managing such conflicts. We explored international perspectives on and experiences with human-wildlife conflicts to develop principles for ethical wildlife control. A diverse panel of 20 experts convened at a 2-day workshop and developed the principles through a facilitated engagement process and discussion. They determined that efforts to control wildlife should begin wherever possible by altering the human practices that cause human-wildlife conflict and by developing a culture of coexistence; be justified by evidence that significant harms are being caused to people, property, livelihoods, ecosystems, and/or other animals; have measurable outcome-based objectives that are clear, achievable, monitored, and adaptive; predictably minimize animal welfare harms to the fewest number of animals; be informed by community values as well as scientific, technical, and practical information; be integrated into plans for systematic long-term management; and be based on the specifics of the situation rather than negative labels (pest, overabundant) applied to the target species. We recommend that these principles guide development of international, national, and local standards and control decisions and implementation. © 2017 The Authors. Conservation Biology published by Wiley Periodicals, Inc. on behalf of Society for Conservation Biology.

Indeterminacy and the principle of need.

PubMed

Herlitz, Anders

2017-02-01

The principle of need-the idea that resources should be allocated according to need-is often invoked in priority setting in the health care sector. In this article, I argue that a reasonable principle of need must be indeterminate, and examine three different ways that this can be dealt with: appendicizing the principle with further principles, imposing determinacy, or empowering decision makers. I argue that need must be conceptualized as a composite property composed of at least two factors: health shortfall and capacity to benefit. When one examines how the different factors relate to each other, one discovers that this is sometimes indeterminate. I illustrate this indeterminacy in this article by applying the small improvement argument. If the relation between the factors are always determinate, the comparative relation changes by a small adjustment. Yet, if two needs are dissimilar but of seemingly equal magnitude, the comparative relation does not change by a small adjustment of one of the factors. I then outline arguments in favor of each of the three strategies for dealing with indeterminacy, but also point out that all strategies have significant shortcomings. More research is needed concerning how to deal with this indeterminacy, and the most promising path seems to be to scrutinize the position of the principle of need among a plurality of relevant principles for priority setting in the health care sector.

Yesterday's Extraordinary Research Yields Today's Ordinary Principles

ERIC Educational Resources Information Center