Health-based audible noise guidelines account for infrasound and low-frequency noise produced by wind turbines.

PubMed

Berger, Robert G; Ashtiani, Payam; Ollson, Christopher A; Whitfield Aslund, Melissa; McCallum, Lindsay C; Leventhall, Geoff; Knopper, Loren D

2015-01-01

Setbacks for wind turbines have been established in many jurisdictions to address potential health concerns associated with audible noise. However, in recent years, it has been suggested that infrasound (IS) and low-frequency noise (LFN) could be responsible for the onset of adverse health effects self-reported by some individuals living in proximity to wind turbines, even when audible noise limits are met. The purpose of this paper was to investigate whether current audible noise-based guidelines for wind turbines account for the protection of human health, given the levels of IS and LFN typically produced by wind turbines. New field measurements of indoor IS and outdoor LFN at locations between 400 and 900 m from the nearest turbine, which were previously underrepresented in the scientific literature, are reported and put into context with existing published works. Our analysis showed that indoor IS levels were below auditory threshold levels while LFN levels at distances >500 m were similar to background LFN levels. A clear contribution to LFN due to wind turbine operation (i.e., measured with turbines on in comparison to with turbines off) was noted at a distance of 480 m. However, this corresponded to an increase in overall audible sound measures as reported in dB(A), supporting the hypothesis that controlling audible sound produced by normally operating wind turbines will also control for LFN. Overall, the available data from this and other studies suggest that health-based audible noise wind turbine siting guidelines provide an effective means to evaluate, monitor, and protect potential receptors from audible noise as well as IS and LFN.

Low-frequency noise in AlN/AlGaN/GaN metal-insulator-semiconductor devices: A comparison with Schottky devices

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

Le, Son Phuong; Nguyen, Tuan Quy; Shih, Hong-An

2014-08-07

We have systematically investigated low-frequency noise (LFN) in AlN/AlGaN/GaN metal-insulator-semiconductor (MIS) devices, where the AlN gate insulator layer was sputtering-deposited on the AlGaN surface, in comparison with LFN in AlGaN/GaN Schottky devices. By measuring LFN in ungated two-terminal devices and heterojunction field-effect transistors (HFETs), we extracted LFN characteristics in the intrinsic gated region of the HFETs. Although there is a bias regime of the Schottky-HFETs in which LFN is dominated by the gate leakage current, LFN in the MIS-HFETs is always dominated by only the channel current. Analyzing the channel-current-dominated LFN, we obtained Hooge parameters α for the gated regionmore » as a function of the sheet electron concentration n{sub s} under the gate. In a regime of small n{sub s}, both the MIS- and Schottky-HFETs exhibit α∝n{sub s}{sup −1}. On the other hand, in a middle n{sub s} regime of the MIS-HFETs, α decreases rapidly like n{sub s}{sup −ξ} with ξ ∼ 2-3, which is not observed for the Schottky-HFETs. In addition, we observe strong increase in α∝n{sub s}{sup 3} in a large n{sub s} regime for both the MIS- and Schottky-HFETs.« less

Lateral femoral notch depth is not associated with increased rotatory instability in ACL-injured knees: a quantitative pivot shift analysis.

PubMed

Kanakamedala, Ajay C; Burnham, Jeremy M; Pfeiffer, Thomas R; Herbst, Elmar; Kowalczuk, Marcin; Popchak, Adam; Irrgang, James; Fu, Freddie H; Musahl, Volker

2018-05-01

A deep lateral femoral notch (LFN) on lateral radiographs is indicative of ACL injury. Prior studies have suggested that a deep LFN may also be a sign of persistent rotatory instability and a concomitant lateral meniscus tear. Therefore, the purpose of this study was to evaluate the relationship between LFN depth and both quantitative measures of rotatory knee instability and the incidence of lateral meniscus tears. It was hypothesized that greater LFN depth would be correlated with increased rotatory instability, quantified by lateral compartment translation and tibial acceleration during a quantitative pivot shift test, and incidence of lateral meniscus tears. ACL-injured patients enrolled in a prospective ACL registry from 2014 to 2016 were analyzed. To limit confounders, patients were only included if they had primary ACL tears, no concurrent ligamentous or bony injuries requiring operative treatment, and no previous knee injuries or surgeries to either knee. Eighty-four patients were included in the final analysis. A standardized quantitative pivot shift test was performed pre-operatively under anesthesia in both knees, and rotatory instability, specifically lateral compartment translation and tibial acceleration, was quantified using tablet image analysis software and accelerometer sensors. Standard lateral radiographs and sagittal magnetic resonance images (MRI) of the injured knee were evaluated for LFN depth. There were no significant correlations between LFN depth on either imaging modality and ipsilateral lateral compartment translation or tibial acceleration during a quantitative pivot shift test or side-to-side differences in these measurements. Patients with lateral meniscus tears were found to have significantly greater LFN depths than those without on conventional radiograph and MRI (1.0 vs. 0.6 mm, p < 0.05; 1.2 vs. 0.8 mm, p < 0.05, respectively). There was no correlation between lateral femoral notch depth on conventional radiographs or MRI and quantitative measures of rotatory instability. Concomitant lateral meniscus injury was associated with significantly greater LFN depth. Based on these findings, LFN depth should not be used as an indicator of excessive rotatory instability, but may be an indicator of lateral meniscus injury in ACL-injured patients. Prognostic level IV.

Modeling and characterization of the low frequency noise behavior for amorphous InGaZnO thin film transistors in the subthreshold region

NASA Astrophysics Data System (ADS)

Cai, Minxi; Yao, Ruohe

2017-10-01

An analytical model of the low-frequency noise (LFN) for amorphous InGaZnO (a-IGZO) thin film transistors (TFTs) in the subthreshold region is developed. For a-IGZO TFTs, relations between the device noise and the subgap defects are characterized based on the dominant multiple trapping and release (MTR) mechanism. The LFN is considered to be contributed from trapping/detrapping of carriers both into the border traps and the subgap density of states (DOS). It is revealed that the LFN behavior of a-IGZO TFTs in the subthreshold region is significantly influenced by the distribution of tail states, where MTR process prevails. The 1/f α (with α < 1) spectrum of the drain current noise is also related to the characteristic temperature of the tail states. The new method is introduced to calculate the LFN of devices by extracting the LFN-related DOS parameters from the current-voltage characteristics.

Comprehensive analysis of low-frequency noise variability components in bulk and fully depleted silicon-on-insulator metal–oxide–semiconductor field-effect transistor

NASA Astrophysics Data System (ADS)

Maekawa, Keiichi; Makiyama, Hideki; Yamamoto, Yoshiki; Hasegawa, Takumi; Okanishi, Shinobu; Sonoda, Kenichiro; Shinkawata, Hiroki; Yamashita, Tomohiro; Kamohara, Shiro; Yamaguchi, Yasuo

2018-04-01

The low-frequency noise (LFN) variability in bulk and fully depleted silicon-on-insulator (FDSOI) metal–oxide–semiconductor field-effect transistor (MOSFET) with silicon on thin box (SOTB) technology was investigated. LFN typically shows a flicker noise component and a signal Lorentzian component by random telegraph noise (RTN). At a weak inversion state, the random dopant fluctuation (RDF) in a channel is strongly affected to not only RTN variability but also flicker noise variability in the bulk MOSFET compared with SOTB MOSFET because of local carrier number fluctuation in the channel. On the other hand, the typical level of LFN in SOTB MOSFET is slightly larger than that in the bulk MOSFET because of an additional interface on the buried oxide layer. However, considering the tailing characteristics of LFN variability, LFN in SOTB MOSFET can be assumed to be smaller than that in the bulk MOSFET, which enables the low-voltage operation of analog circuits.

Laboratory evaluation on a potential birth control diet for fruit fly sterile insect technique (SIT).

PubMed

Chang, Chiou Ling

2017-08-01

Sterile insect technique (SIT) is one of the most effective fruit fly control technologies. Irradiation has been used to sterilize male fruit flies before release to the field to compete with the wild males for females. Imagine an environmental and cost effective method using a rearing diet that can make insects sterile indefinitely, by feeding for 7days before release. This could replace costly irradiation process. A potential birth control diet was evaluated on fertility, mating, survival, and protein analysis for fruit fly species in Hawaii. Insects were continuously fed an agar diet with lufenuron (LFN) for 7d after emergence and then switched to a control diet to simulate the actual field condition. The influence on egg hatch was dose dependent. With dose of 2-4mg/g in the diet, egg hatch from LFN-fed was almost 100% suppressed for 24 experimental days if adults of Ceratitia capitate (Widemann), Bactrocera dorsalis (Hendel), and B. latifrons (Hendel) continued to feed on LFN diet. B. cucurbitae (Coquillett) was not affected by LFN. However, egg hatch from LFN fed B. latifrons and B. dorsalis were suppressed for at least 2weeks after switching to the control diet at 7d. Egg hatch did not recover >4% up to 24d. Proteome analysis revealed that ABD-4 protein was under expressed by 70-83% on LFN fed females and males of B. latifrons and B. dorsalis while Pbprp2 protein was significantly over expressed by 6-12 fold on LFN fed males only. These two proteins were not expressed in C. capitata and B. cucurbitae. Therefore, this report focused more on B. latifrons and B. dorsalis. This finding suggested a great potential for one alternative to sterilize fruit flies for SIT without irradiation. Published by Elsevier Inc.

Transfer characteristics and low-frequency noise in single- and multi-layer MoS{sub 2} field-effect transistors

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

Sharma, Deepak; Theiss Research, Inc., La Jolla, California 92037; Department of Electrical and Computer Engineering, George Mason University, Fairfax, Virginia 22030

Leveraging nanoscale field-effect transistors (FETs) in integrated circuits depends heavily on its transfer characteristics and low-frequency noise (LFN) properties. Here, we report the transfer characteristics and LFN in FETs fabricated with molybdenum disulfide (MoS{sub 2}) with different layer (L) counts. 4L to 6L devices showed highest I{sub ON}-I{sub OFF} ratio (≈10{sup 8}) whereas LFN was maximum for 1L device with normalized power spectral density (PSD) ≈1.5 × 10{sup −5 }Hz{sup −1}. For devices with L ≈ 6, PSD was minimum (≈2 × 10{sup −8 }Hz{sup −1}). Further, LFN for single and few layer devices satisfied carrier number fluctuation (CNF) model in both weak andmore » strong accumulation regimes while thicker devices followed Hooge's mobility fluctuation model in the weak accumulation regime and CNF model in strong accumulation regime, respectively. Transfer-characteristics and LFN experimental data are explained with the help of model incorporating Thomas-Fermi charge screening and inter-layer resistance coupling.« less

Health effects from low-frequency noise and infrasound in the general population: Is it time to listen? A systematic review of observational studies.

PubMed

Baliatsas, Christos; van Kamp, Irene; van Poll, Ric; Yzermans, Joris

2016-07-01

A systematic review of observational studies was conducted to assess the association between everyday life low-frequency noise (LFN) components, including infrasound and health effects in the general population. Literature databases Pubmed, Embase and PsycInfo and additional bibliographic sources such as reference sections of key publications and journal databases were searched for peer-reviewed studies published from 2000 to 2015. Seven studies met the inclusion criteria. Most of them examined subjective annoyance as primary outcome. The adequacy of provided information in the included papers and methodological quality of studies was also addressed. Moreover, studies were screened for meta-analysis eligibility. Some associations were observed between exposure to LFN and annoyance, sleep-related problems, concentration difficulties and headache in the adult population living in the vicinity of a range of LFN sources. However, evidence, especially in relation to chronic medical conditions, was very limited. The estimated pooled prevalence of high subjective annoyance attributed to LFN was about 10%. Epidemiological research on LFN and health effects is scarce and suffers from methodological shortcomings. Low frequency noise in the everyday environment constitutes an issue that requires more research attention, particularly for people living in the vicinity of relevant sources. Copyright © 2016 Elsevier B.V. All rights reserved.

Low-fat diet with omega-3 fatty acids increases plasma insulin-like growth factor concentration in healthy postmenopausal women.

PubMed

Young, Lindsay R; Kurzer, Mindy S; Thomas, William; Redmon, J Bruce; Raatz, Susan K

2013-07-01

The insulin-like growth factor pathway plays a central role in the normal and abnormal growth of tissues; however, nutritional determinants of insulin-like growth factor I (IGF-I) and its binding proteins in healthy individuals are not well defined. Three test diets-high-fat diet (40% energy as fat), low-fat diet (LF; 20% energy as fat), and a diet with low fat and high omega-3 fatty acid (LFn3; 23% energy as fat)--were tested in a randomized crossover designed controlled feeding trial in healthy postmenopausal women. Plasma IGF-I, IGF binding protein-3 (IGFBP-3), insulin, glucose, and ratio of IGF-I/IGFBP-3 concentrations were measured in response to diets. Insulin sensitivity was calculated using the homeostatic model assessment of insulin resistance We hypothesized that IGF-I, insulin, and glucose concentrations would decrease and IGFBP-3 concentration would increase in response to the low-fat diets. Eight weeks of the LFn3 diet increased circulating IGF-I (P < .001) and IGFBP-3 (P = .01) and the LF diet increased IGFBP-3 (P = .04), resulting in trends toward an increased IGF-I/IGFBP-3 ratio with the LFn3 diet and a decreased IGF-I/IGFBP-3 ratio with the LF diet (P = .13 for both comparisons). No statistically significant differences were detected between treatments at baseline or 8 weeks for IGF-1, IGFBP-3, or the ratio of IGF-1/IGFBP-3. Insulin, glucose, and the homeostatic model assessment of insulin resistance were not altered by the interventions. Low-fat diet with high n-3 fatty acids may increase circulating IGF-I concentrations without adversely affecting insulin sensitivity in healthy individuals. Published by Elsevier Inc.

Myocardial fibrosis in rats exposed to low frequency noise.

PubMed

Antunes, Eduardo; Oliveira, Pedro; Borrecho, Gonçalo; Oliveira, Maria João R; Brito, José; Aguas, Artur; Martins, Dos Santos José

2013-06-01

Low frequency noise (LFN) characterized by large pressure amplitude (> or =90 dB SPL) and low frequency bands (< or =500 Hz) can lead to structural and ultrastructural modifications in the extracellular matrix of several tissues, with an abnormal proliferation of collagen and development of fibrosis. It is not known whether LFN induces similar structural alterations in the ventricular myocardium of rats. The aim of this study was to evaluate and measure the myocardial fibrosis induced by LFN. Two groups of rats were considered: group A with 26 rats continuously exposed to LFN during a period of 3 months; group B with 20 control rats.The hearts were sectioned from the ventricular apex to the atria and the mid-ventricular fragment was selected. Chromotrope-aniline blue (CAB) staining was used for histological observation. The measurement of fibrosis was performed using the computer image analysis Image J software. Histological observation with CAB staining showed the presence of collagen deposition between the cardiomyocytes. Fibrosis increased 97.5%, 81.5% and 83.7%, respectively, in the left ventricle, interventricular septum and right ventricle, in exposed rats (P <0.001).The ratio fibrosis/muscle in left ventricle, interventricular septum and right ventricle was significantly higher in LFN exposed rats (P< 0.001). Our study demonstrates a significant myocardial fibrosis induced by low frequency noise in rats. Our results reinforce the need for further experimental and clinical investigations concerning the effects of low frequency noise on the heart.

Laparoscopic Surgical Treatment of Severe Obesity Combined with Gastroesophageal Reflux Disease: A Pilot Randomized Two-Arm Controlled Clinical Study

ERIC Educational Resources Information Center

Ospanov, Oral B.; Orekeshova, Akzhunis M.; Fursov, Roman A.; Yelemesov, Aset A.

2016-01-01

Obesity and gastroesophageal reflux disease (GERD) are serious medical, social, and economic problems of modern society. A pilot randomized two-arm controlled clinical study was conducted to compare laparoscopic plication of the greater gastric curvature combined with Nissen fundoplication (LFN+LGP) versus only Nissen fundoplication (LFN). The…

Infrasounds and biorhythms of the human brain

NASA Astrophysics Data System (ADS)

Panuszka, Ryszard; Damijan, Zbigniew; Kasprzak, Cezary; McGlothlin, James

2002-05-01

Low Frequency Noise (LFN) and infrasound has begun a new public health hazard. Evaluations of annoyance of (LFN) on human occupational health were based on standards where reactions of human auditory system and vibrations of parts of human body were small. Significant sensitivity has been observed on the central nervous system from infrasonic waves especially below 10 Hz. Observed follow-up effects in the brain gives incentive to study the relationship between parameters of waves and reactions obtained of biorhythms (EEG) and heart action (EKG). New results show the impact of LFN on the electrical potentials of the brain are dependent on the pressure waves on the human body. Electrical activity of circulatory system was also affected. Signals recorded in industrial workplaces were duplicated by loudspeakers and used to record data from a typical LFN spectra with 5 and 7 Hz in a laboratory chamber. External noise, electromagnetic fields, temperature, dust, and other elements were controlled. Results show not only a follow-up effect in the brain but also a result similar to arrhythmia in the heart. Relaxations effects were observed of people impacted by waves generated from natural sources such as streams and waterfalls.

Cost-effectiveness Analysis of Treatment Sequence Initiating With Etanercept Compared With Leflunomide in Rheumatoid Arthritis: Impact of Reduced Etanercept Cost With Patent Expiration in South Korea.

PubMed

Park, Sun-Kyeong; Park, Seung-Hoo; Lee, Min-Young; Park, Ji-Hyun; Jeong, Jae-Hong; Lee, Eui-Kyung

2016-11-01

In south Korea, the price of biologics has been decreasing owing to patent expiration and the availability of biosimilars. This study evaluated the cost-effectiveness of a treatment strategy initiated with etanercept (ETN) compared with leflunomide (LFN) after a 30% reduction in the medication cost of ETN in patients with active rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX-IR). A cohort-based Markov model was designed to evaluate the lifetime cost-effectiveness of treatment sequence initiated with ETN (A) compared with 2 sequences initiated with LFN: LFN-ETN sequence (B) and LFN sequence (C). Patients transited through the treatment sequences, which consisted of sequential biologics and palliative therapy, based on American College of Rheumatology (ACR) responses and the probability of discontinuation. A systematic literature review and a network meta-analysis were conducted to estimate ACR responses to ETN and LFN. Utility was estimated by mapping an equation for converting the Health Assessment Questionnaire-Disability Index score to utility weight. The costs comprised medications, outpatient visits, administration, dispensing, monitoring, palliative therapy, and treatment for adverse events. A subanalysis was conducted to identify the influence of the ETN price reduction compared with the unreduced price, and sensitivity analyses explored the uncertainty of model parameters and assumptions. The ETN sequence (A) was associated with higher costs and a gain in quality-adjusted life years (QALYs) compared with both sequences initiated with LFN (B, C) throughout the lifetime of patients with RA and MTX-IR. The incremental cost-effectiveness ratio (ICER) for strategy A versus B was ₩13,965,825 (US$1726) per QALY and that for strategy A versus C was ₩9,587,983 (US$8050) per QALY. The results indicated that strategy A was cost-effective based on the commonly cited ICER threshold of ₩20,000,000 (US$16,793) per QALY in South Korea. The robustness of the base-case analysis was confirmed using sensitivity analyses. When the unreduced medication cost of ETN was applied in a subanalysis, the ICER for strategy A versus B was ₩20,909,572 (US$17,556) per QALY and that for strategy A versus C was ₩22,334,713 (US$18,753) per QALY. This study indicated that a treatment strategy initiated with ETN was more cost-effective in patients with active RA and MTX-IR than 2 sequences initiated with LFN. The results also indicate that the reduced price of ETN affected the cost-effectiveness associated with its earlier use. Copyright © 2016 Elsevier HS Journals, Inc. All rights reserved.

Pregnancy-induced adaptations in the intrinsic structure of rat pelvic floor muscles.

PubMed

Alperin, Marianna; Lawley, Danielle M; Esparza, Mary C; Lieber, Richard L

2015-08-01

Maternal birth trauma to the pelvic floor muscles (PFMs) is a major risk factor for pelvic floor disorders. Modeling and imaging studies suggest that demands placed on PFMs during childbirth exceed their physiologic limits; however many parous women do not sustain PFM injury. Here we determine whether pregnancy induces adaptations in PFM architecture, the strongest predictor of muscle function, and/or intramuscular extracellular matrix (ECM), responsible for load bearing. To establish if parallel changes occur in muscles outside of the PFM, we also examined a hind limb muscle. Coccygeus, iliocaudalis, pubocaudalis, and tibialis anterior of 3-month-old Sprague-Dawley virgin, mid-pregnant, and late-pregnant; 6-month-old virgin; and 4- and 12-week postpartum rats (N = 10/group) were fixed in situ and harvested. Major architectural parameters determining muscle's excursion and force-generating capacity were quantified, namely, normalized fiber length (Lfn), physiologic cross-sectional area, and sarcomere length. Hydroxyproline content was used as a surrogate for intramuscular ECM quantity. Analyses were performed by 2-way analysis of variance with Tukey post hoc testing at a significance level of .05. Pregnancy induced a significant increase in Lfn in all PFMs by the end of gestation relative to virgin controls. Fibers were elongated by 37% in coccygeus (P < .0001), and by 21% in iliocaudalis and pubocaudalis (P < .0001). Importantly, no Lfn change was observed in the tibialis anterior. Physiologic cross-sectional area and sarcomere length were not affected by pregnancy. By 12 weeks' postpartum, Lfn of all PFMs returned to the prepregnancy values. Relative to virgin controls, ECM increased by 140% in coccygeus, 52% in iliocaudalis, and 75% in pubocaudalis in late-pregnant group, but remained unchanged across time in the tibialis anterior. Postpartum, ECM collagen content returned to prepregnancy levels in iliocaudalis and pubocaudalis, but continued to be significantly elevated in coccygeus (P < .0001). This study demonstrates that pregnancy induces unique adaptations in the structure of the PFMs, which adjust their architectural design by adding sarcomeres in series to increase fiber length as well as mounting a substantial synthesis of collagen in intramuscular ECM. Published by Elsevier Inc.

Light and heavy fractions of soil organic matter in response to climate warming and increased precipitation in a temperate steppe.

PubMed

Song, Bing; Niu, Shuli; Zhang, Zhe; Yang, Haijun; Li, Linghao; Wan, Shiqiang

2012-01-01

Soil is one of the most important carbon (C) and nitrogen (N) pools and plays a crucial role in ecosystem C and N cycling. Climate change profoundly affects soil C and N storage via changing C and N inputs and outputs. However, the influences of climate warming and changing precipitation regime on labile and recalcitrant fractions of soil organic C and N remain unclear. Here, we investigated soil labile and recalcitrant C and N under 6 years' treatments of experimental warming and increased precipitation in a temperate steppe in Northern China. We measured soil light fraction C (LFC) and N (LFN), microbial biomass C (MBC) and N (MBN), dissolved organic C (DOC) and heavy fraction C (HFC) and N (HFN). The results showed that increased precipitation significantly stimulated soil LFC and LFN by 16.1% and 18.5%, respectively, and increased LFC:HFC ratio and LFN:HFN ratio, suggesting that increased precipitation transferred more soil organic carbon into the quick-decayed carbon pool. Experimental warming reduced soil labile C (LFC, MBC, and DOC). In contrast, soil heavy fraction C and N, and total C and N were not significantly impacted by increased precipitation or warming. Soil labile C significantly correlated with gross ecosystem productivity, ecosystem respiration and soil respiration, but not with soil moisture and temperature, suggesting that biotic processes rather than abiotic factors determine variations in soil labile C. Our results indicate that certain soil carbon fraction is sensitive to climate change in the temperate steppe, which may in turn impact ecosystem carbon fluxes in response and feedback to climate change.

Effects of trap density on drain current LFN and its model development for E-mode GaN MOS-HEMT

NASA Astrophysics Data System (ADS)

Panda, D. K.; Lenka, T. R.

2017-12-01

In this paper the drain current low-frequency noise (LFN) of E-mode GaN MOS-HEMT is investigated for different gate insulators such as SiO2, Al2O3/Ga2O3/GdO3, HfO2/SiO2, La2O3/SiO2 and HfO2 with different trap densities by IFM based TCAD simulation. In order to analyze this an analytical model of drain current low frequency noise is developed. The model is developed by considering 2DEG carrier fluctuations, mobility fluctuations and the effects of 2DEG charge carrier fluctuations on the mobility. In the study of different gate insulators it is observed that carrier fluctuation is the dominant low frequency noise source and the non-uniform exponential distribution is critical to explain LFN behavior, so the analytical model is developed by considering uniform distribution of trap density. The model is validated with available experimental data from literature. The effect of total number of traps and gate length scaling on this low frequency noise due to different gate dielectrics is also investigated.

Implementing accountability for reasonableness--the case of pharmaceutical reimbursement in Sweden.

PubMed

Jansson, Sandra

2007-04-01

This paper aims to describe the priority-setting procedure for new original pharmaceuticals practiced by the Swedish Pharmaceutical Benefits Board (LFN), to analyse the outcome of the procedure in terms of decisions and the relative importance of ethical principles, and to examine the reactions of stakeholders. All the 'principally important' decisions made by the LFN during its first 33 months of operation were analysed. The study is theoretically anchored in the theory of fair and legitimate priority-setting procedures by Daniels and Sabin, and is based on public documents, media articles, and semi-structured interviews. Only nine cases resulted in a rejection of a subsidy by the LFN and 15 in a limited or conditional subsidy. Total rejections rather than limitations gave rise to actions by stakeholders. Primarily, the principle of cost-effectiveness was used when limiting/conditioning or totally rejecting a subsidy. This study suggests that implementing a priority-setting process that fulfils the conditions of accountability for reasonableness can result in a priority-setting process which is generally perceived as fair and legitimate by the major stakeholders and may increase social learning in terms of accepting the necessity of priority setting in health care. The principle of cost-effectiveness increased in importance when the demand for openness and transparency increased.

Origin of low-frequency noise in pentacene field-effect transistors

NASA Astrophysics Data System (ADS)

Xu, Yong; Minari, Takeo; Tsukagoshi, Kazuhito; Chroboczek, Jan; Balestra, Francis; Ghibaudo, Gerard

2011-07-01

Measurements of power spectral density (PSD) of low-frequency noise (LFN) in pentacene field-effect transistors reveal the preponderance of a 1/ f-type PSD behavior with the amplitude varying as the squared transistor gain and increasing as the inverse of the gate surface area. Such features impose an interpretation of LFN by carrier number fluctuations model involving capture/release of charges on traps uniformly distributed over the gate surface. The surface slow trap density extracted by the noise analysis is close to the surface states density deduced independently from static I(V) data, which confirms the validity of the proposed LFN interpretation. Further, we found that the trap densities in bottom-contact (BC) devices were higher than in their top-contact (TC) counterparts, in agreement with observations of a poorer crystal structure of BC devices, in the contact regions in particular. At the highest bias the noise originating from the contact resistance is also shown to be a dominant component in the PSD, and it is well explained by the noise originating from a gate-voltage dependent contact resistance. A gate area scaling was also performed, and the good scaling and the dispersion at the highest bias confirm the validity of the applied carrier number fluctuations model and the predominant contact noise at high current intensities.

Therapeutic Immunization In HIV Infected Ugandans Receiving Stable Antiretroviral Treatment: A Phase I Safety Study4

PubMed Central

Kityo, Cissy; Bousheri, Stephanie; Akao, Juliette; Ssali, Francis; Byaruhanga, Rose; Ssewanyana, Isaac; Muloma, Prossy; Myalo, Sula; Magala, Rose; Lu, Yichen; Mugyenyi, Peter; Cao, Huyen

2011-01-01

Therapeutic immunizations in HIV infection may boost immunity during antiretroviral treatment. We report on the first therapeutic vaccine trial in Uganda, Africa. This open label Phase I trial was designed to assess the safety, tolerability and immunogenicity of a therapeutic HIV-1 vaccine candidate. Thirty HIV positive volunteers receiving a stable regimen of antiretroviral therapy with CD4 counts > 400 were recruited for the safety evaluation of LFn-p24C, a detoxified anthrax-derived polypeptide fused to the subtype C HIV gag protein p24. The vaccine was well tolerated and HIV RNA levels remained undetectable following three immunizations. CD4 counts in vaccine recipients were significantly higher compared to the control individuals after 12 months. HIV-specific responses were associated with higher gain in CD4 counts following LFn-p24C immunizations. Volunteers were subsequently asked to undergo a 30-day period of observed treatment interruption. 8/24 (30%) individuals showed no evidence of viral rebound during treatment interruption. All demonstrated prompt suppression of viral load following resumption of ART. Our data demonstrates the safety of LFn-p24C and suggests that adjunct therapeutic immunization may benefit select individuals in further boosting an immune response. PMID:21211581

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

Choi, Hyun-Sik; Jeon, Sanghun, E-mail: jeonsh@korea.ac.kr; Department of Display and Semiconductor Physics, Korea University, 2511 Sejongro, Sejong 339-700

The influence of illumination on the electrical characteristics of amorphous indium–zinc oxide (a-IZO) thin-film transistors (TFTs) has been investigated. The electrical properties are found to depend significantly on the active thickness (T{sub IZO}) of the a-IZO TFT. The active thickness is seen to play a major role in the carrier transport mechanism. Based on the carrier fluctuation model, the low-frequency noise (LFN) characteristics of a-IZO devices of varying thicknesses were evaluated before as well as after illumination. Similar to the results of DC and capacitance–voltage (C–V) measurements, the LFN characteristics too show that the light-induced carrier transport becomes significantly enhancedmore » for relatively thick (T{sub IZO} ≥ 60 nm) a-IZO devices.« less

Effects of dihydroorotate dehydrogenase (DHODH) inhibitors on the growth of Theileria equi and Babesia caballi in vitro.

PubMed

Kamyingkird, Ketsarin; Cao, Shinuo; Tuvshintulga, Bumduuren; Salama, Akram; Mousa, Ahmed Abdelmoniem; Efstratiou, Artemis; Nishikawa, Yoshifumi; Yokoyama, Naoaki; Igarashi, Ikuo; Xuan, Xuenan

2017-05-01

Theileria equi and Babesia caballi are the causative agents of equine piroplasmosis (EP), which affects equine production in various parts of the world. However, a safe and effective drug is not currently available for treatment of EP. Dihydroorotate dehydrogenase (DHODH) is the fourth enzyme in the de novo pyrimidine synthesis pathway and has been known as a novel drug target for several apicomplexan protozoan parasites. In this study, we evaluated four DHODH inhibitors; atovaquone (ATV), leflunomide (LFN), brequinar (Breq), and 7-hydroxy-5-[1,2,4] triazolo [1,5,a] pyrimidine (TAZ) on the growth of T. equi and B. caballi in vitro and compared them to diminacene aceturate (Di) as the control drug. The growth of T. equi and B. caballi was significantly hindered by all inhibitors except TAZ. The half maximal inhibitory concentration (IC 50 ) of ATV, LFN, Breq and Di against T. equi was approximately 0.028, 109, 11 and 40 μM, respectively, whereas the IC 50 of ATV, LFN, Breq and Di against B. caballi was approximately 0.128, 193, 5.2 and 16.2 μM, respectively. Using bioinformatics and Western blot analysis, we showed that TeDHODH was similar to other Babesia parasite DHODHs, and confirmed that targeting DHODHs could be useful for the development of novel chemotherapeutics for treatment of EP. Copyright © 2017 Elsevier Inc. All rights reserved.

Low frequency noise study.

DOT National Transportation Integrated Search

2007-04-01

This report documents a study to investigate human response to the low-frequency : content of aviation noise, or low-frequency noise (LFN). The study comprised field : measurements and laboratory studies. The major findings were: : 1. Start-of-takeof...

Cardiovascular and autonomic responses to physiological stressors before and after six hours of water immersion.

PubMed

Florian, John P; Simmons, Erin E; Chon, Ki H; Faes, Luca; Shykoff, Barbara E

2013-11-01

The physiological responses to water immersion (WI) are known; however, the responses to stress following WI are poorly characterized. Ten healthy men were exposed to three physiological stressors before and after a 6-h resting WI (32-33°C): 1) a 2-min cold pressor test, 2) a static handgrip test to fatigue at 40% of maximum strength followed by postexercise muscle ischemia in the exercising forearm, and 3) a 15-min 70° head-up-tilt (HUT) test. Heart rate (HR), systolic and diastolic blood pressure (SBP and DBP), cardiac output (Q), limb blood flow (BF), stroke volume (SV), systemic and calf or forearm vascular resistance (SVR and CVR or FVR), baroreflex sensitivity (BRS), and HR variability (HRV) frequency-domain variables [low-frequency (LF), high-frequency (HF), and normalized (n)] were measured. Cold pressor test showed lower HR, SBP, SV, Q, calf BF, LFnHRV, and LF/HFHRV and higher CVR and HFnHRV after than before WI (P < 0.05). Handgrip test showed no effect of WI on maximum strength and endurance and lower HR, SBP, SV, Q, and calf BF and higher SVR and CVR after than before WI (P < 0.05). During postexercise muscle ischemia, HFnHRV increased from baseline after WI only, and LFnHRV was lower after than before WI (P < 0.05). HUT test showed lower SBP, DBP, SV, forearm BF, and BRS and higher HR, FVR, LF/HFHRV, and LFnHRV after than before WI (P < 0.05). The changes suggest differential activation/depression during cold pressor and handgrip (reduced sympathetic/elevated parasympathetic) and HUT (elevated sympathetic/reduced parasympathetic) following 6 h of WI.

Post-exercise heart-rate recovery correlates to resting heart-rate variability in healthy men.

PubMed

Molina, Guilherme Eckhardt; Fontana, Keila Elizabeth; Porto, Luiz Guilherme Grossi; Junqueira, Luiz Fernando

2016-12-01

The relationship between post-exercise heart-rate recovery (HRR) and resting cardiac autonomic modulation is an incompletely explored issue. To correlate HRR with resting supine and orthostatic autonomic status. HRR at the 1st, 3th, and 5th min following maximal treadmill exercise were correlated with 5-min time-domain (CV, pNN50 and rMSSD) and frequency-domain (TP, LF, HF, LFn, HFn, and LF/HF ratio) indices of heart-rate variability (HRV) in both supine and standing positions in 31 healthy physically active non-athletes men. Statistical analysis employed non-parametric tests with two-tailed p value set at 5 %. Absolute HRR and Δ %HRR at each post-exercise time did not correlated with HRV in supine position, as well as at 1st min in standing position. At the 3rd min and 5th min, these measures negatively correlated with pNN50, rMSSD, TP, and HF indices, and only in the 5th min, they showed negative correlation with HFn and positive correlation with LF, LFn, and LF/HF ratio in the standing position. Coefficient of HRR (CHRR) at the 1st min negatively correlated with pNN50 and rMSSD and at 3rd and 5th min showed positive correlation with LFn and LF/HF ratio in supine position. With HRV indices in standing position CHRR from the 1st to 5th min showed the same respective negative and positive correlations as the other measures. HRR from the 1st to 5th min post-exercise negatively correlated with parasympathetic modulation in resting orthostatic, but showed no correlation in supine position. At the 3rd and 5th min, a positive correlation with combined sympathetic-parasympathetic modulation in both positions was observed.

New opportunities for field research on the pathogenesis and treatment of Lassa fever.

PubMed

Khan, Sheik Humarr; Goba, Augustine; Chu, May; Roth, Cathy; Healing, Tim; Marx, Arthur; Fair, Joseph; Guttieri, Mary C; Ferro, Philip; Imes, Tiffany; Monagin, Corina; Garry, Robert F; Bausch, Daniel G

2008-04-01

Unlike many viral hemorrhagic fevers (VHFs), Lassa fever (LF) is not a rare disease that emerges only as sporadic cases or in outbreak form. Although surveillance is inadequate to determine the true incidence, up to 300,000 infections and 5000 deaths from LF are estimated to occur yearly. The highest incidence is in the "Mano River Union (MRU) countries" of Sierra Leone, Liberia, and Guinea. Although civil unrest in this region over the past two decades has impeded capacity building and research, new-found peace in recent years presents new opportunities. In 2004, the Mano River Union Lassa Fever Network (MRU LFN) was established to assist MRU countries in the development of national and regional surveillance, diagnosis, treatment, control, and prevention of LF. Here, we review the present literature on treatment and pathogenesis of LF and outline priorities for future research in the field made possible by the improved research capacity of the MRU LFN.

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

Le, Son Phuong; Ui, Toshimasa; Nguyen, Tuan Quy

Using aluminum titanium oxide (AlTiO, an alloy of Al{sub 2}O{sub 3} and TiO{sub 2}) as a high-k gate insulator, we fabricated and investigated AlTiO/AlGaN/GaN metal-insulator-semiconductor heterojunction field-effect transistors. From current low-frequency noise (LFN) characterization, we find Lorentzian spectra near the threshold voltage, in addition to 1/f spectra for the well-above-threshold regime. The Lorentzian spectra are attributed to electron trapping/detrapping with two specific time constants, ∼25 ms and ∼3 ms, which are independent of the gate length and the gate voltage, corresponding to two trap level depths of 0.5–0.7 eV with a 0.06 eV difference in the AlTiO insulator. In addition, gate leakage currents aremore » analyzed and attributed to the Poole-Frenkel mechanism due to traps in the AlTiO insulator, where the extracted trap level depth is consistent with the Lorentzian LFN.« less

Light and Heavy Fractions of Soil Organic Matter in Response to Climate Warming and Increased Precipitation in a Temperate Steppe

PubMed Central

Song, Bing; Niu, Shuli; Zhang, Zhe; Yang, Haijun; Li, Linghao; Wan, Shiqiang

2012-01-01

Soil is one of the most important carbon (C) and nitrogen (N) pools and plays a crucial role in ecosystem C and N cycling. Climate change profoundly affects soil C and N storage via changing C and N inputs and outputs. However, the influences of climate warming and changing precipitation regime on labile and recalcitrant fractions of soil organic C and N remain unclear. Here, we investigated soil labile and recalcitrant C and N under 6 years' treatments of experimental warming and increased precipitation in a temperate steppe in Northern China. We measured soil light fraction C (LFC) and N (LFN), microbial biomass C (MBC) and N (MBN), dissolved organic C (DOC) and heavy fraction C (HFC) and N (HFN). The results showed that increased precipitation significantly stimulated soil LFC and LFN by 16.1% and 18.5%, respectively, and increased LFC∶HFC ratio and LFN∶HFN ratio, suggesting that increased precipitation transferred more soil organic carbon into the quick-decayed carbon pool. Experimental warming reduced soil labile C (LFC, MBC, and DOC). In contrast, soil heavy fraction C and N, and total C and N were not significantly impacted by increased precipitation or warming. Soil labile C significantly correlated with gross ecosystem productivity, ecosystem respiration and soil respiration, but not with soil moisture and temperature, suggesting that biotic processes rather than abiotic factors determine variations in soil labile C. Our results indicate that certain soil carbon fraction is sensitive to climate change in the temperate steppe, which may in turn impact ecosystem carbon fluxes in response and feedback to climate change. PMID:22479373

Laboratory evaluation for a potential birth control diet for fruit fly sterilization insect technique (SIT)

USDA-ARS?s Scientific Manuscript database

A potential fruit fly steilizing diet was evaluated on fertility, mating, survival, and protein anaylsis for fruit fly species in Hawaii. Insects were continuously fed an agar diet with lufenuron(LFN) for an initial 7d after emergence and then switched to a control diet to simulate the actual field ...

Anthrax lethal factor inhibitors as potential countermeasure of the infection.

PubMed

Kumar, B V S Suneel; Malik, Siddharth; Grandhi, Pradeep; Dayam, Raveendra; Sarma, J A R P

2014-01-01

Anthrax Lethal Factor (LF) is a zinc-dependent metalloprotease, one of the virulence factor of anthrax infection. Three forms of the anthrax infection have been identified: cutaneous (through skin), gastrointestinal (through alimentary tract), and pulmonary (by inhalation of spores). Anthrax toxin is composed of protective antigen (PA), lethal factor (LF), and edema factor (EF). Protective antigen mediates the entry of Lethal Factor/Edema Factor into the cytosol of host cells. Lethal factor (LF) inactivates mitogen-activated protein kinase kinase inducing cell death, and EF is an adenylyl cyclase impairing host defenses. In the past few years, extensive studies are undertaken to design inhibitors targeting LF. The current review focuses on the small molecule inhibitors targeting LF activity and its structure activity relationships (SAR).

Electrical transport and low-frequency noise in chemical vapor deposited single-layer MoS2 devices.

PubMed

Sharma, Deepak; Amani, Matin; Motayed, Abhishek; Shah, Pankaj B; Birdwell, A Glen; Najmaei, Sina; Ajayan, Pulickel M; Lou, Jun; Dubey, Madan; Li, Qiliang; Davydov, Albert V

2014-04-18

We have studied temperature-dependent (77-300 K) electrical characteristics and low-frequency noise (LFN) in chemical vapor deposited (CVD) single-layer molybdenum disulfide (MoS2) based back-gated field-effect transistors (FETs). Electrical characterization and LFN measurements were conducted on MoS2 FETs with Al2O3 top-surface passivation. We also studied the effect of top-surface passivation etching on the electrical characteristics of the device. Significant decrease in channel current and transconductance was observed in these devices after the Al2O3 passivation etching. For passivated devices, the two-terminal resistance variation with temperature showed a good fit to the activation energy model, whereas for the etched devices the trend indicated a hopping transport mechanism. A significant increase in the normalized drain current noise power spectral density (PSD) was observed after the etching of the top passivation layer. The observed channel current noise was explained using a standard unified model incorporating carrier number fluctuation and correlated surface mobility fluctuation mechanisms. Detailed analysis of the gate-referred noise voltage PSD indicated the presence of different trapping states in passivated devices when compared to the etched devices. Etched devices showed weak temperature dependence of the channel current noise, whereas passivated devices exhibited near-linear temperature dependence.

Soluble factor(s) from bone marrow cells can rescue lethally irradiated mice by protecting endogenous hematopoietic stem cells.

PubMed

Zhao, Yi; Zhan, Yuxia; Burke, Kathleen A; Anderson, W French

2005-04-01

Ionizing radiation-induced myeloablation can be rescued via bone marrow transplantation (BMT) or administration of cytokines if given within 2 hours after radiation exposure. There is no evidence for the existence of soluble factors that can rescue an animal after a lethal dose of radiation when administered several hours postradiation. We established a system that could test the possibility for the existence of soluble factors that could be used more than 2 hours postirradiation to rescue animals. Animals with an implanted TheraCyte immunoisolation device (TID) received lethal-dose radiation and then normal bone marrow Lin- cells were loaded into the device (thereby preventing direct interaction between donor and recipient cells). Animal survival was evaluated and stem cell activity was tested with secondary bone marrow transplantation and flow cytometry analysis. Donor cell gene expression of five antiapoptotic cytokines was examined. Bone marrow Lin- cells rescued lethally irradiated animals via soluble factor(s). Bone marrow cells from the rescued animals can rescue and repopulate secondary lethally irradiated animals. Within the first 6 hours post-lethal-dose radiation, there is no significant change of gene expression of the known radioprotective factors TPO, SCF, IL-3, Flt-3 ligand, and SDF-1. Hematopoietic stem cells can be protected in lethally irradiated animals by soluble factors produced by bone marrow Lin- cells.

Spatial and Temporal Self-Calibration of a Hydroeconomic Model

NASA Astrophysics Data System (ADS)

Howitt, R. E.; Hansen, K. M.

2008-12-01

Hydroeconomic modeling of water systems where risk and reliability of water supply are of critical importance must address explicitly how to model water supply uncertainty. When large fluctuations in annual precipitation and significant variation in flows by location are present, a model which solves with perfect foresight of future water conditions may be inappropriate for some policy and research questions. We construct a simulation-optimization model with limited foresight of future water conditions using positive mathematical programming and self-calibration techniques. This limited foresight netflow (LFN) model signals the value of storing water for future use and reflects a more accurate economic value of water at key locations, given that future water conditions are unknown. Failure to explicitly model this uncertainty could lead to undervaluation of storage infrastructure and contractual mechanisms for managing water supply risk. A model based on sequentially updated information is more realistic, since water managers make annual storage decisions without knowledge of yet to be realized future water conditions. The LFN model runs historical hydrological conditions through the current configuration of the California water system to determine the economically efficient allocation of water under current economic conditions and infrastructure. The model utilizes current urban and agricultural demands, storage and conveyance infrastructure, and the state's hydrological history to indicate the scarcity value of water at key locations within the state. Further, the temporal calibration penalty functions vary by year type, reflecting agricultural water users' ability to alter cropping patterns in response to water conditions. The model employs techniques from positive mathematical programming (Howitt, 1995; Howitt, 1998; Cai and Wang, 2006) to generate penalty functions that are applied to deviations from observed data. The functions are applied to monthly flows across key nodes on the network and to annual carryover storage at ground and surface water storage facilities. To our knowledge, this is the first hydroeconomic model to perform spatial and temporal calibration simultaneously. The base for the LFN model is CALVIN, a hydroeconomic optimization model of the California water system developed at the University of California, Davis (Draper, et al. 2003). The LFN model, programmed in GAMS, is nonlinear, which permits incorporation of dynamic groundwater pumping costs that reflect head elevation. Hydropower production, also nonlinear in storage levels, could be added in the future. In this paper, we describe model implementation and performance over a sequence of water years drawn from the historical hydrologic record in California. Preliminary findings indicate that calibration occurs within acceptable limits and simulations replicate base case results well. Cai, X., and Wang, D. 2006. "Calibrating Holistic Water Resources-Economic Models." Journal of Water Resources Planning and Management November-December. Draper, A.J., M.W. Jenkins, K.W. Kirby, J.R. Lund, and R.E. Howitt. 2003. "Economic-Engineering Optimization for California Water Management." Journal of Water Resources Planning and Management 129(3):155-164. Howitt, R.E. 1995. "Positive Mathematical Programming." American Journal of Agricultural Economics 77:329-342. Howitt, R.E. 1998. "Self-Calibrating Network Flow Models." Working Paper, Department of Agricultural and Resource Economics, University of California, Davis. October 1998. class="ab'>

76 FR 53480 - Prospective Grant of Exclusive License: Conjugate Vaccines Against B. anthracis

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-26

.... anthracis Protective Antigen (PA), Lethal Factor (LF) and Edema Factor (EF)'', U.S. Patent Application... catalytic proteins known as ``lethal factor'' (LF) and ``edema factor'' (EF). Although production of an...

Factors Associated with Increased Risk for Lethal Violence in Intimate Partner Relationships among Ethnically Diverse Black Women

PubMed Central

Sabri, Bushra; Stockman, Jamila K.; Campbell, Jacquelyn C.; O’Brien, Sharon; Campbell, Doris; Callwood, Gloria B.; Bertrand, Desiree; Sutton, Lorna W.; Hart-Hyndman, Greta

2014-01-01

The purpose of this study was to identify factors associated with increased risk for lethal violence among ethnically diverse Black women in Baltimore, Maryland (MD) and the US Virgin Islands (USVI). Women with abuse experiences (n=456) were recruited from primary care, prenatal or family planning clinics in Baltimore, MD and St. Thomas and St. Croix, USVI. Logistic regression was used to examine factors associated with the risk for lethal violence among abused women. Factors independently related to increased risk of lethal violence included fear of abusive partners, PTSD symptoms, and use of legal resources. These factors must be considered in assessing safety needs of Black women in abusive relationships. PMID:25429191

Employment growth through labor flow networks.

PubMed

Guerrero, Omar A; Axtell, Robert L

2013-01-01

It is conventional in labor economics to treat all workers who are seeking new jobs as belonging to a labor pool, and all firms that have job vacancies as an employer pool, and then match workers to jobs. Here we develop a new approach to study labor and firm dynamics. By combining the emerging science of networks with newly available employment micro-data, comprehensive at the level of whole countries, we are able to broadly characterize the process through which workers move between firms. Specifically, for each firm in an economy as a node in a graph, we draw edges between firms if a worker has migrated between them, possibly with a spell of unemployment in between. An economy's overall graph of firm-worker interactions is an object we call the labor flow network (LFN). This is the first study that characterizes a LFN for an entire economy. We explore the properties of this network, including its topology, its community structure, and its relationship to economic variables. It is shown that LFNs can be useful in identifying firms with high growth potential. We relate LFNs to other notions of high performance firms. Specifically, it is shown that fewer than 10% of firms account for nearly 90% of all employment growth. We conclude with a model in which empirically-salient LFNs emerge from the interaction of heterogeneous adaptive agents in a decentralized labor market.

Employment Growth through Labor Flow Networks

PubMed Central

Guerrero, Omar A.; Axtell, Robert L.

2013-01-01

It is conventional in labor economics to treat all workers who are seeking new jobs as belonging to a labor pool, and all firms that have job vacancies as an employer pool, and then match workers to jobs. Here we develop a new approach to study labor and firm dynamics. By combining the emerging science of networks with newly available employment micro-data, comprehensive at the level of whole countries, we are able to broadly characterize the process through which workers move between firms. Specifically, for each firm in an economy as a node in a graph, we draw edges between firms if a worker has migrated between them, possibly with a spell of unemployment in between. An economy's overall graph of firm-worker interactions is an object we call the labor flow network (LFN). This is the first study that characterizes a LFN for an entire economy. We explore the properties of this network, including its topology, its community structure, and its relationship to economic variables. It is shown that LFNs can be useful in identifying firms with high growth potential. We relate LFNs to other notions of high performance firms. Specifically, it is shown that fewer than 10% of firms account for nearly 90% of all employment growth. We conclude with a model in which empirically-salient LFNs emerge from the interaction of heterogeneous adaptive agents in a decentralized labor market. PMID:23658682

The novel functional nucleic acid iRed effectively regulates target genes following cytoplasmic delivery by faint electric treatment

NASA Astrophysics Data System (ADS)

Hasan, Mahadi; Tarashima, Noriko; Fujikawa, Koki; Ohgita, Takashi; Hama, Susumu; Tanaka, Tamotsu; Saito, Hiroyuki; Minakawa, Noriaki; Kogure, Kentaro

2016-01-01

An intelligent shRNA expression device (iRed) contains the minimum essential components needed for shRNA production in cells, and could be a novel tool to regulate target genes. However, general delivery carriers consisting of cationic polymers/lipids could impede function of a newly generated shRNA via electrostatic interaction in the cytoplasm. Recently, we found that faint electric treatment (fET) of cells enhanced delivery of siRNA and functional nucleic acids into the cytoplasm in the absence of delivery carriers. Here, we examined fET of cells stably expressing luciferase in the presence of iRed encoding anti-luciferase shRNA. Transfection of lipofectamine 2000 (LFN)/iRed lipoplexes showed an RNAi effect, but fET-mediated iRed transfection did not, likely because of the endosomal localization of iRed after delivery. However, fET in the presence of lysosomotropic agent chloroquine significantly improved the RNAi effect of iRed/fET to levels that were higher than those for the LFN/iRed lipoplexes. Furthermore, the amount of lipid droplets in adipocytes significantly decreased following fET with iRed against resistin in the presence of chloroquine. Thus, iRed could be a useful tool to regulate target genes following fET-mediated cytoplasmic delivery with endosomal escape devices.

A Software Planning and Development Methodology with Resource Allocation Capability

DTIC Science & Technology

1986-01-01

vll ACKNOWLEDGEMENTS There are many people who must be acknowledged for the support they provided during my graduate program at Texas A&M Dr. Lee ...acquisition, research/development, and operations/ maintenance sources. The concept of a resource mm >^"^*»T’i»"<Wt"> i PH D« mm^ ivi i t-il^’lfn" i^ I...James, Unpublished ICAM Industry Days address. New Orleans, Louisiana, May 1982. IllllHUIIIIVf 127 46. Ledbetter , William N., et al., "Education

Environmental Assessment for the Military Housing Privatization Initiative (MHPI) Tinker Air Force Base, Oklahoma

DTIC Science & Technology

2007-10-01

determine how MNA is impacting the rate of CAH destruction, and 3) evaluate the success of the pilot testing . The recommended locations, frequencies...Wells N ...... Trichloroethylene (ICE) c~•’-: lfN Concentration In ppb A 1.,(.,.111*-hl D .... TAFB Boundary - Sppb OtWI-Ht-11!1 ... NO = Not...Additionally, ACM tested positive from glue in the flooring of the units (U.S. Air Force, 2003; U.S. Air Force, 2007b). Tinker AFB maintains a computerized

Lifestyle and dietary factors in the prevention of lethal prostate cancer

PubMed Central

Wilson, Kathryn M; Giovannucci, Edward L; Mucci, Lorelei A

2012-01-01

The prevention of lethal prostate cancer is a critical public health challenge that would improve health and reduce suffering from this disease. In this review, we discuss the evidence surrounding specific lifestyle and dietary factors in the prevention of lethal prostate cancer. We present a summary of evidence for the following selected behavioral risk factors: obesity and weight change, physical activity, smoking, antioxidant intake, vitamin D and calcium, and coffee intake. PMID:22504869

Species Origin of Genomic Factors in Nicotiana nudicaulis Watson Controlling Hybrid Lethality in Interspecific Hybrids between N. nudicaulis Watson and N. tabacum L

PubMed Central

Liu, Hongshuo; Marubashi, Wataru

2014-01-01

Hybrid lethality is expressed at 28°C in the cross Nicotiana nudicaulis×N. tabacum. The S subgenome of N. tabacum has been identified as controlling this hybrid lethality. To clarify the responsible genomic factor(s) of N. nudicaulis, we crossed N. trigonophylla (paternal progenitor of N. nudicaulis) with N. tabacum, because hybrids between N. sylvestris (maternal progenitor of N. nudicaulis) and N. tabacum are viable when grown in a greenhouse. In the cross N. trigonophylla×N. tabacum, approximately 50% of hybrids were vitrified, 20% were viable, and 20% were nonviable at 28°C. To reveal which subgenome of N. tabacum was responsible for these phenotypes, we crossed N. trigonophylla with two progenitors of N. tabacum, N. sylvestris (SS) and N. tomentosiformis (TT). In the cross N. sylvestris×N. trigonophylla, we confirmed that over half of hybrids of N. sylvestris×N. trigonophylla were vitrified, and none of the hybrids of N. trigonophylla×N. tomentosiformis were. The results imply that the S subgenome, encoding a gene or genes inducing hybrid lethality in the cross between N. nudicaulis and N. tabacum, has one or more genomic factors that induce vitrification. Furthermore, in vitrified hybrids of N. trigonophylla×N. tabacum and N. sylvestris×N. trigonophylla, we found that nuclear fragmentation, which progresses during expression of hybrid lethality, was accompanied by vitrification. This observation suggests that vitrification has a relationship to hybrid lethality. Based on these results, we speculate that when N. nudicaulis was formed approximately 5 million years ago, several causative genomic factors determining phenotypes of hybrid seedlings were inherited from N. trigonophylla. Subsequently, genome downsizing and various recombination-based processes took place. Some of the causative genomic factors were lost and some became genomic factor(s) controlling hybrid lethality in extant N. nudicaulis. PMID:24806486

[WHO programs "Acute Myocardial Infarction Register", MONICA: thirty years (1977-2006) of epidemiological studies of myocardial infarction in a high-risk population].

PubMed

Gafarov, V V; Gafarova, A V

2011-01-01

To reveal 30 year (1977-2006) trends of myocardial infarction (MI) morbidity, lethality and mortality in population of the West Siberia megapolis (Novosibirsk). WHO programs "Acute Myocardial Infarction Register (AMIR) and MONICA covered 3 districts of Novosibirsk. MI morbidity in 25-64 year old population of Novosibirsk (high-risk population) in Russia is one of the highest in the world. MI morbidity was stable for 30 years excluding in 1988, 1994 and 1998 when it rose and in 2002-2004, 2006 when it lowered. Changes in mortality and lethality resemble changes in morbidity trend excluding 1977-1978 (fall) and 2002-2005 (rise). Prehospital mortality and lethality were much higher than those in hospital. Mortality and lethality in 1988, 1994, 1998 and 2002-2005 increased due to prehospital lethality and mortality, while it decreased in 1977-1978 due to hospital one. Reduction of mortality and lethality in stable MI morbidity shows improvement of medical care for MI patients, increased lethality and mortality in MI morbidity decline reflect deterioration of such care. Changes in behavioral and somatic factors of cardiovascular risk in population of Novosibirsk for 30 years were not observed while psychosocial risk factors gain a significant importance. By indirect indications, MI morbidity, mortality and lethality mark growing social stress in the population. MI mortality is 2-3 times higher than that of alcohol and is a basic factor of mortality increase in the population of Russia. MI morbidity, mortality and lethality are markers of social stress in population.

Effectiveness of Non-Lethal Capabilities in a Maritime Environment

DTIC Science & Technology

2006-09-01

demonstrates both the space filling properties for quantitative factors of the NOLH and the lack of correlation between the factors. 27 Figure 12 ...11 b. Optical Dazzler ........................................................................ 12 c...Warning Munitions................................................................. 12 2. Lethal Capabilities

Blue light treatment of Pseudomonas aeruginosa: Strong bactericidal activity, synergism with antibiotics and inactivation of virulence factors.

PubMed

Fila, Grzegorz; Kawiak, Anna; Grinholc, Mariusz Stanislaw

2017-08-18

Pseudomonas aeruginosa is among the most common pathogens responsible for both acute and chronic infections of high incidence and severity. Additionally, P. aeruginosa resistance to conventional antimicrobials has increased rapidly over the past decade. Therefore, it is crucial to explore new therapeutic options, particularly options that specifically target the pathogenic mechanisms of this microbe. The ability of a pathogenic bacterium to cause disease is dependent upon the production of agents termed 'virulence factors', and approaches to mitigate these agents have gained increasing attention as new antibacterial strategies. Although blue light irradiation is a promising alternative approach, only limited and preliminary studies have described its effect on virulence factors. The current study aimed to investigate the effects of lethal and sub-lethal doses of blue light treatment (BLT) on P. aeruginosa virulence factors. We analyzed the inhibitory effects of blue light irradiation on the production/activity of several virulence factors. Lethal BLT inhibited the activity of pyocyanin, staphylolysin, pseudolysin and other proteases, but sub-lethal BLT did not affect the production/expression of proteases, phospholipases, and flagella- or type IV pili-associated motility. Moreover, a eukaryotic cytotoxicity test confirmed the decreased toxicity of blue light-treated extracellular P. aeruginosa fractions. Finally, the increased antimicrobial susceptibility of P. aeruginosa treated with sequential doses of sub-lethal BLT was demonstrated with a checkerboard test. Thus, this work provides evidence-based proof of the susceptibility of drug-resistant P. aeruginosa to BLT-mediated killing, accompanied by virulence factor reduction, and describes the synergy between antibiotics and sub-lethal BLT.

Effects of space flight factors on Drosophila.

PubMed

Dubinin, N P; Glembotsky, Y L; Vaulina, E N; Grozdova, T Y; Kamshilova, E M; Ivaschenko, N I; Kholikova, I A; Nechitailo, G S; Mashinsky, A L; Iordanishvili, E K

1973-01-01

Drosophila melanogaster flies of strain D-32 were exposed aboard the Soyuz 10 spaceship. An insert with a nutritional medium and insects was placed in a small on-board thermostat (Biotherm II) providing a constant temperature (24 degrees C +/- 1 degree) for Drosophila development. The frequency of dominant lethals was determined in the females. Dominant, autosomal and sex-linked recessive lethals were estimated in hatching virgin males and females; the time of hatching was rigorously fixed. Sex-linked recessive lethals were related to certain stages of gametogenesis. The 1-5 oocyte stage showed an increased sensitivity to space-flight factors as regards the frequency of both dominant and recessive lethals.

Psychosocial influences on prisoner suicide: a case-control study of near-lethal self-harm in women prisoners.

PubMed

Marzano, Lisa; Hawton, Keith; Rivlin, Adrienne; Fazel, Seena

2011-03-01

We examined the psychosocial influences on female prisoner suicide by carrying out a study of near-lethal self-harm. We interviewed 60 women prisoners who had recently engaged in near-lethal self-harm (cases) and 60 others who had never carried out near-lethal acts in prison (controls) from all closed female prison establishments in England and Wales, using mixed quantitative and qualitative methods. We gathered information on socio-demographic and criminological variables, life events and childhood trauma, exposure to suicidal behaviour, contributory and precipitating factors for near-lethal self-harm, social support and psychological characteristics. While socio-demographic factors were only modestly associated with near-lethal self-harm, being on remand, in single cell accommodation, and reporting negative experiences of imprisonment were strong correlates. Recent life events and past trauma, including different forms of childhood abuse, were also significantly associated with near-lethal self-harm, as were a family history of suicide and high scores on measures of depression, aggression, impulsivity and hostility, and low levels of self-esteem and social support. Our findings underline the importance of both individual and prison-related factors for suicide in custody, and hence the need for a comprehensive approach to suicide prevention in women's prisons. Given the multiple needs of female prisoners at-risk of self-harm and suicide, complex psychosocial interventions are likely to be required, including interventions for abused and bereaved women, and initiatives to improve staff-prisoner relationships and reduce bullying. The findings of this research may provide insights into factors leading to suicidal behaviour in other forensic and institutional settings, such as detention centres and psychiatric hospitals, and may assist in developing suicide prevention policies for prisoners and other at-risk populations. Copyright © 2011 Elsevier Ltd. All rights reserved.

Prevention of Suicidal Behavior in Prisons

PubMed Central

2016-01-01

Abstract. Background: Worldwide, prisoners are at high risk of suicide. Research on near-lethal suicide attempts can provide important insights into risk and protective factors, and inform suicide prevention initiatives in prison. Aims: To synthesize findings of research on near-lethal attempts in prisons, and consider their implications for suicide prevention policies and practice, in the context of other research in custody and other settings. Method: We searched two bibliographic indexes for studies in any language on near-lethal and severe self-harm in prisoners, supplemented by targeted searches over the period 2000–2014. We extracted information on risk factors descriptively. Data were not meta-analyzed owing to heterogeneity of samples and methods. Results: We identified eight studies reporting associations between prisoner near-lethal attempts and specific factors. The latter included historical, prison-related, and clinical factors, including psychiatric morbidity and comorbidity, trauma, social isolation, and bullying. These factors were also identified as important in prisoners' own accounts of what may have contributed to their attempts (presented in four studies). Conclusion: Factors associated with prisoners' severe suicide attempts include a range of potentially modifiable clinical, psychosocial, and environmental factors. We make recommendations to address these factors in order to improve detection, management, and prevention of suicide risk in prisoners. PMID:27278569

Myxoma virus M130R is a novel virulence factor required for lethal myxomatosis in rabbits.

PubMed

Barrett, John W; Werden, Steven J; Wang, Fuan; McKillop, William M; Jimenez, June; Villeneuve, Danielle; McFadden, Grant; Dekaban, Gregory A

2009-09-01

Myxoma virus (MV) is a highly lethal, rabbit-specific poxvirus that induces a disease called myxomatosis in European rabbits. In an effort to understand the function of predicted immunomodulatory genes we have deleted various viral genes from MV and tested the ability of these knockout viruses to induce lethal myxomatosis. MV encodes a unique 15 kD cytoplasmic protein (M130R) that is expressed late (12h post infection) during infection. M130R is a non-essential gene for MV replication in rabbit, monkey or human cell lines. Construction of a targeted gene knockout virus (vMyx130KO) and infection of susceptible rabbits demonstrate that the M130R knockout virus is attenuated and that loss of M130R expression allows the rabbit host immune system to effectively respond to and control the lethal effects of MV. M130R expression is a bona fide poxviral virulence factor necessary for full and lethal development of myxomatosis.

Vestibular short-latency evoked potential abolished by low-frequency noise exposure in rats.

PubMed

Stewart, Courtney E; Kanicki, Ariane C; Altschuler, Richard A; King, W M

2018-02-01

The vestibular system plays a critical role in detection of head movements and is essential for normal postural control. Because of their anatomical proximity to the cochlea, the otolith organs are selectively exposed to sound pressure and are at risk for noise overstimulation. Clinical reports suggest a link between noise exposure and balance problems, but the structural and physiological basis for this linkage is not well understood. The goal of this study was to determine the effects of low-frequency noise (LFN) on the otolith organs by correlating changes in vestibular short-latency evoked potentials (VsEPs) with changes in saccular afferent endings following noise exposure. LFN exposure transiently abolished the VsEP and reduced the number of stained calyces within the sacculus. Although some recovery of the VsEP waveform could be observed within 3 days after noise, at 3 wk recovery was only partial in most animals, consistent with a reduced number of afferents with calyceal endings. These data show that a single intense noise exposure is capable of causing a vestibular deficit that appears to mirror the synaptic deficit associated with hidden hearing loss after noise-induced cochlear injury. NEW & NOTEWORTHY This is the first study to explore the effects of low-frequency high-intensity noise on vestibular short-latency evoked potential (VsEP) responses, which shows a linkage between attenuated noise-induced VsEPs and pathological changes to otolith organ afferents. This finding suggests a potential limitation of the VsEP for evaluation of vestibular dysfunction, since the VsEP measurement may assess the activity of a specific class rather than all afferents.

Ectopic expression of Cripto-1 in transgenic mouse embryos causes hemorrhages, fatal cardiac defects and embryonic lethality

PubMed Central

Lin, Xiaolin; Zhao, Wentao; Jia, Junshuang; Lin, Taoyan; Xiao, Gaofang; Wang, Shengchun; Lin, Xia; Liu, Yu; Chen, Li; Qin, Yujuan; Li, Jing; Zhang, Tingting; Hao, Weichao; Chen, Bangzhu; Xie, Raoying; Cheng, Yushuang; Xu, Kang; Yao, Kaitai; Huang, Wenhua; Xiao, Dong; Sun, Yan

2016-01-01

Targeted disruption of Cripto-1 in mice caused embryonic lethality at E7.5, whereas we unexpectedly found that ectopic Cripto-1 expression in mouse embryos also led to embryonic lethality, which prompted us to characterize the causes and mechanisms underlying embryonic death due to ectopic Cripto-1 expression. RCLG/EIIa-Cre embryos displayed complex phenotypes between embryonic day 14.5 (E14.5) and E17.5, including fatal hemorrhages (E14.5-E15.5), embryo resorption (E14.5-E17.5), pale body surface (E14.5-E16.5) and no abnormal appearance (E14.5-E16.5). Macroscopic and histological examination revealed that ectopic expression of Cripto-1 transgene in RCLG/EIIa-Cre embryos resulted in lethal cardiac defects, as evidenced by cardiac malformations, myocardial thinning, failed assembly of striated myofibrils and lack of heartbeat. In addition, Cripto-1 transgene activation beginning after E8.5 also caused the aforementioned lethal cardiac defects in mouse embryos. Furthermore, ectopic Cripto-1 expression in embryonic hearts reduced the expression of cardiac transcription factors, which is at least partially responsible for the aforementioned lethal cardiac defects. Our results suggest that hemorrhages and cardiac abnormalities are two important lethal factors in Cripto-1 transgenic mice. Taken together, these findings are the first to demonstrate that sustained Cripto-1 transgene expression after E11.5 causes fatal hemorrhages and lethal cardiac defects, leading to embryonic death at E14.5-17.5. PMID:27687577

The maternally expressed WRKY transcription factor TTG2 controls lethality in interploidy crosses of Arabidopsis.

PubMed

Dilkes, Brian P; Spielman, Melissa; Weizbauer, Renate; Watson, Brian; Burkart-Waco, Diana; Scott, Rod J; Comai, Luca

2008-12-09

The molecular mechanisms underlying lethality of F1 hybrids between diverged parents are one target of speciation research. Crosses between diploid and tetraploid individuals of the same genotype can result in F1 lethality, and this dosage-sensitive incompatibility plays a role in polyploid speciation. We have identified variation in F1 lethality in interploidy crosses of Arabidopsis thaliana and determined the genetic architecture of the maternally expressed variation via QTL mapping. A single large-effect QTL, DR. STRANGELOVE 1 (DSL1), was identified as well as two QTL with epistatic relationships to DSL1. DSL1 affects the rate of postzygotic lethality via expression in the maternal sporophyte. Fine mapping placed DSL1 in an interval encoding the maternal effect transcription factor TTG2. Maternal parents carrying loss-of-function mutations in TTG2 suppressed the F1 lethality caused by paternal excess interploidy crosses. The frequency of cellularization in the endosperm was similarly affected by both natural variation and ttg2 loss-of-function mutants. The simple genetic basis of the natural variation and effects of single-gene mutations suggests that F1 lethality in polyploids could evolve rapidly. Furthermore, the role of the sporophytically active TTG2 gene in interploidy crosses indicates that the developmental programming of the mother regulates the viability of interploidy hybrid offspring.

Examining the impact of psychiatric diagnosis and comorbidity on the medical lethality of adolescent suicide attempts.

PubMed

McManama O'Brien, Kimberly H; Berzin, Stephanie C

2012-08-01

Specific psychiatric diagnoses and comorbidity patterns were examined to determine if they were related to the medical lethality of suicide attempts among adolescents presenting to an urban general hospital (N=375). Bivariate analysis showed that attempters with substance abuse disorders had higher levels of lethality than attempters without substance abuse. Regression results indicated having depression comorbid with any other diagnosis was not associated with medical lethality. However, having a substance abuse disorder was associated with higher suicide attempt lethality, highlighting the importance of substance abuse as a risk factor for lethal suicide attempts in adolescents. This finding stimulates critical thinking around the understanding of suicidal behavior in youth and the development and implementation of treatment strategies for suicidal adolescents with substance abuse disorders. © 2012 The American Association of Suicidology.

Does ethnicity matter in risk and protective factors for suicide attempts and suicide lethality?

PubMed Central

Choo, Carol C.; Harris, Keith M.; Chew, Peter K. H.; Ho, Roger C.

2017-01-01

This study explored ethnic differences in risk and protective factors for suicide attempts, for the major ethnic groups in Singapore, and ethnic differences in prediction of lethality. Three years of medical records related to suicide attempters (N = 666) who were admitted to the emergency department of a large teaching hospital in Singapore were subjected to analysis. Of the sample, 69.2% were female, 30.8% male; 63.8% Chinese, 15.8% Indian, and 15.0% Malay. Indians were over-represented in this sample, as compared with the ethnic distribution in the general population. Ages ranged from 10 to 85 years old (M = 29.7, SD = 16.1). Ethnic differences were found in risk and protective factors, and perceived lethality of suicide attempts. All available variables were subjected to regression analyses for Chinese, Indian and Malay attempters to arrive at parsimonious models for prediction of perceived lethality. The findings were discussed in regards to implications in assessment of suicide risk and primary prevention for the multiethnic society in Singapore. PMID:28426687

EVALUATING THE PREDICTIVE VALIDITY OF SUICIDAL INTENT AND MEDICAL LETHALITY IN YOUTH

PubMed Central

Sapyta, Jeffrey; Goldston, David B.; Erkanli, Alaattin; Daniel, Stephanie S.; Heilbron, Nicole; Mayfield, Andrew; Treadway, S. Lyn

2012-01-01

Objectives To examine whether suicidal intent and medical lethality of past suicide attempts are predictive of future attempts, the association between intent and lethality, and the consistency of these characteristics across repeated attempts among youth. Method Suicide attempts in a 15-year prospective study of 180 formerly psychiatrically hospitalized adolescents (Mage at hospitalization = 14.83; 51% female; 80% Caucasian) were characterized using the Subjective Intent Rating Scale and Lethality of Attempt Rating Scale. Anderson-Gill recurrent events survival models and generalized estimating equations were used to assess predictive validity. Generalized linear models were used to examine stability of characteristics across attempts. Results Neither intent nor lethality from the most recent attempt predicted future attempts. The highest level of intent and most severe lethality of attempts during the follow-up predicted subsequent attempts, but the degree to which highest intent and most severe lethality contributed to prediction after considering methods of suicide attempts, past number of attempts, or psychiatric diagnoses was mixed. Across successive attempts, there was little consistency in reported characteristics. Intent and lethality were related to each other only for attempts occurring in early adulthood. Conclusions Highest intent and lethality were better predictors of future attempts than intent and lethality of the most recent attempt. However, these characteristics should only be considered as predictors within the context of other factors. For youth, clinicians should not infer true intent from the lethality of attempts, nor assume that characteristics of future suicide attempts will be similar to previous attempts. PMID:22250854

Lethality of First Contact Dysentery Epidemics on Pacific Islands

PubMed Central

Shanks, G. Dennis

2016-01-01

Infectious diseases depopulated many isolated Pacific islands when they were first exposed to global pathogen circulation from the 18th century. Although the mortality was great, the lack of medical observers makes determination of what happened during these historical epidemics largely speculative. Bacillary dysentery caused by Shigella is the most likely infection causing some of the most lethal island epidemics. The fragmentary historical record is reviewed to gain insight into the possible causes of the extreme lethality that was observed during first-contact epidemics in the Pacific. Immune aspects of the early dysentery epidemics and postmeasles infection resulting in subacute inflammatory enteric disease suggest that epidemiologic isolation was the major lethality risk factor on Pacific islands in the 19th century. Other possible risk factors include human leukocyte antigen homogeneity from a founder effect and pathogen-induced derangement of immune tolerance to gut flora. If this analysis is correct, then Pacific islands are currently at no greater risk of emerging disease epidemics than other developing countries despite their dark history. PMID:27185765

Deadly Lessons: Understanding Lethal School Violence.

ERIC Educational Resources Information Center

Moore, Mark H., Ed.; Petrie, Carol V., Ed.; Braga, Anthony A., Ed.; McLaughlin, Brenda L., Ed.

This collection of papers is the outcome of the National Academies' effort to glean information from six different case studies of student-perpetrated school shootings. Part 1, "Case Studies of Lethal School Violence," includes: "The Copycat Factor: Mental Illness, Guns, and the Shooting Incident at Heritage High School, Rockdale…

[Screening of full human anthrax lethal factor neutralizing antibody in transgenic mice].

PubMed

Wang, Xiaolin; Chi, Xiangyang; Liu, Ju; Liu, Weicen; Liu, Shuling; Qiu, Shunfang; Wen, Zhonghua; Fan, Pengfei; Liu, Kun; Song, Xiaohong; Fu, Ling; Zhang, Jun; Yu, Changming

2016-11-25

Anthrax is a highly lethal infectious disease caused by the spore-forming bacterium Bacillus anthracis. The major virulence factor of B. anthracis consists of protective antigen (PA), lethal factor (LF) and edema factor (EF). PA binds with LF to form lethal toxin (LT), and PA binds with EF to form edema toxin (ET). Antibiotics is hard to work in advanced anthrax infections, because injuries and deaths of the infected are mainly caused by lethal toxin (LT). Thus, the therapeutic neutralizing antibody is the most effective treatment of anthrax. Currently most of the anthrax toxin antibodies are monoclonal antibodies (MAbs) for PA and US FDA has approved ABTHRAX humanized PA monoclonal antibody for the treatment of inhalational anthrax. Once B. anthracis was artificially reconstructed or PA had mutations within recognized neutralization epitopes, anti-PA MAbs would no longer be effective. Therefore, anti-LF MAbs is an important supplement for anthrax treatment. Most of the anti-LF antibodies are murine or chimeric antibodies. By contrast, fully human MAbs can avoid the high immunogenicity of murine antibodies. First, we used LF to immunize the transgenic mice and used fluorescent cell sorting to get antigen-specific memory B cells from transgenic mice spleen lymphocytes. By single cell PCR method, we quickly found two strains of anti-LF MAbs with binding activity, 1D7 and 2B9. Transiently transfected Expi 293F cells to obtain MAbs protein after purification. Both 1D7 and 2B9 efficiently neutralized LT in vitro, and had good synergistic effect when mixed with anti-PA MAbs. In summary, combining the advantages of transgenic mice, fluorescent cell sorting and single-cell PCR methods, this study shows new ideas and methods for the rapid screening of fully human monoclonal antibodies.

Transcription factor activating protein 4 is synthetically lethal and a master regulator of MYCN-amplified neuroblastoma. | Office of Cancer Genomics

Cancer.gov

Despite the identification of MYCN amplification as an adverse prognostic marker in neuroblastoma, MYCN inhibitors have yet to be developed. Here, by integrating evidence from a whole-genome shRNA library screen and the computational inference of master regulator proteins, we identify transcription factor activating protein 4 (TFAP4) as a critical effector of MYCN amplification in neuroblastoma, providing a novel synthetic lethal target.

Suicide Lethality: A Concept Analysis.

PubMed

DeBastiani, Summer; De Santis, Joseph P

2018-02-01

Suicide is a significant health problem internationally. Those who complete suicide may have different behaviors and risk factors than those who attempt a non-fatal suicide. The purpose of this article is to analyze the concept of suicide lethality and propose a clear definition of the concept through the identification of antecedents, attributes, and consequences. A literature search for articles published in the English language between 1970 and 2016 was conducted using MEDLINE, the Cochrane Library, Pubmed, Psychlit, Ovid, PsycINFO, and Proquest. The bibliographies of all included studies were also reviewed to identify additional relevant citations. A concept analysis was conducted on the literature findings using six stages of Walker and Avant's method. The concept analysis differentiated between suicide, lethality, suicidal behavior, and suicide lethality. Presence of a suicide plan or a written suicide note was not found to be associated with the majority of completed suicides included in the definition of suicide lethality. There are a few scales that measure the lethality of a suicide attempt, but none that attempt to measure the concept of suicide lethality as described in this analysis. Clarifying the concept of suicide lethality encourages awareness of the possibility of different suicidal behaviors associated with different suicide outcomes and will inform the development of future nursing interventions. A clearer definition of the concept of suicide lethality will guide clinical practice, research, and policy development aimed at suicide prevention.

Low-frequency noise in multilayer MoS2 field-effect transistors: the effect of high-k passivation.

PubMed

Na, Junhong; Joo, Min-Kyu; Shin, Minju; Huh, Junghwan; Kim, Jae-Sung; Piao, Mingxing; Jin, Jun-Eon; Jang, Ho-Kyun; Choi, Hyung Jong; Shim, Joon Hyung; Kim, Gyu-Tae

2014-01-07

Diagnosing of the interface quality and the interactions between insulators and semiconductors is significant to achieve the high performance of nanodevices. Herein, low-frequency noise (LFN) in mechanically exfoliated multilayer molybdenum disulfide (MoS2) (~11.3 nm-thick) field-effect transistors with back-gate control was characterized with and without an Al2O3 high-k passivation layer. The carrier number fluctuation (CNF) model associated with trapping/detrapping the charge carriers at the interface nicely described the noise behavior in the strong accumulation regime both with and without the Al2O3 passivation layer. The interface trap density at the MoS2-SiO2 interface was extracted from the LFN analysis, and estimated to be Nit ~ 10(10) eV(-1) cm(-2) without and with the passivation layer. This suggested that the accumulation channel induced by the back-gate was not significantly influenced by the passivation layer. The Hooge mobility fluctuation (HMF) model implying the bulk conduction was found to describe the drain current fluctuations in the subthreshold regime, which is rarely observed in other nanodevices, attributed to those extremely thin channel sizes. In the case of the thick-MoS2 (~40 nm-thick) without the passivation, the HMF model was clearly observed all over the operation regime, ensuring the existence of the bulk conduction in multilayer MoS2. With the Al2O3 passivation layer, the change in the noise behavior was explained from the point of formation of the additional top channel in the MoS2 because of the fixed charges in the Al2O3. The interface trap density from the additional CNF model was Nit = 1.8 × 10(12) eV(-1) cm(-2) at the MoS2-Al2O3 interface.

Determinants of the lethality of climate-related disasters in the Caribbean Community (CARICOM): a cross-country analysis

PubMed Central

Andrewin, Aisha N.; Rodriguez-Llanes, Jose M.; Guha-Sapir, Debarati

2015-01-01

Floods and storms are climate-related hazards posing high mortality risk to Caribbean Community (CARICOM) nations. However risk factors for their lethality remain untested. We conducted an ecological study investigating risk factors for flood and storm lethality in CARICOM nations for the period 1980–2012. Lethality - deaths versus no deaths per disaster event- was the outcome. We examined biophysical and social vulnerability proxies and a decadal effect as predictors. We developed our regression model via multivariate analysis using a generalized logistic regression model with quasi-binomial distribution; removal of multi-collinear variables and backward elimination. Robustness was checked through subset analysis. We found significant positive associations between lethality, percentage of total land dedicated to agriculture (odds ratio [OR] 1.032; 95% CI: 1.013–1.053) and percentage urban population (OR 1.029, 95% CI 1.003–1.057). Deaths were more likely in the 2000–2012 period versus 1980–1989 (OR 3.708, 95% CI 1.615–8.737). Robustness checks revealed similar coefficients and directions of association. Population health in CARICOM nations is being increasingly impacted by climate-related disasters connected to increasing urbanization and land use patterns. Our findings support the evidence base for setting sustainable development goals (SDG). PMID:26153115

Sub-lethal oxidative stress induces lysosome biogenesis via a lysosomal membrane permeabilization-cathepsin-caspase 3-transcription factor EB-dependent pathway.

PubMed

Leow, San Min; Chua, Shu Xian Serene; Venkatachalam, Gireedhar; Shen, Liang; Luo, Le; Clement, Marie-Veronique

2017-03-07

Here we provide evidence to link sub-lethal oxidative stress to lysosome biogenesis. Exposure of cells to sub-lethal concentrations of exogenously added hydrogen peroxide resulted in cytosol to nuclear translocation of the Transcription Factor EB (TFEB), the master controller of lysosome biogenesis and function. Nuclear translocation of TFEB was dependent upon the activation of a cathepsin-caspase 3 signaling pathway, downstream of lysosomal membrane permeabilization and accompanied by a significant increase in lysosome numbers as well as induction of TFEB-dependent lysosome-associated genes expression such as Ctsl, Lamp2 and its spliced variant Lamp2a, Neu1and Ctsb and Sqstm1 and Atg9b. The effects of sub-lethal oxidative stress on lysosomal gene expression and biogenesis were rescued upon gene silencing of caspase 3 and TFEB. Notably, caspase 3 activation was not associated with phenotypic hallmarks of apoptosis, evidenced by the absence of caspase 3 substrate cleavage, such as PARP, Lamin A/C or gelsolin. Taken together, these data demonstrate for the first time an unexpected and non-canonical role of a cathepsin-caspase 3 axis in the nuclear translocation of TFEB leading to lysosome biogenesis under conditions of sub-lethal oxidative stress.

Protective effects of granulocyte colony-stimulating factor on endotoxin shock in mice with retrovirus-induced immunodeficiency syndrome.

PubMed

Toki, S; Hiromatsu, K; Aoki, Y; Makino, M; Yoshikai, Y

1997-10-01

Mice with retrovirus-induced murine acquired immunodeficiency syndrome (MAIDS) were hypersensitive to lipopolysaccharide (LPS)-induced lethal shock accompanied by marked elevations of systematic interleukin 1beta (IL-beta) and interferon gamma (IFN-gamma) after LPS challenge. Pretreatment with 10 microg of recombinant human granulocyte colony-stimulating factor (rhG-CSF) protected MAIDS mice from hypersensitivity to LPS-induced lethal shock and this protection was concomitant with suppression of IFN-gamma production. Copyright 1997 Academic Press Limited.

Interleukin-10 protects neonatal mice from lethal group B streptococcal infection.

PubMed Central

Cusumano, V; Genovese, F; Mancuso, G; Carbone, M; Fera, M T; Teti, G

1996-01-01

We investigated the role of interleukin-10 (IL-10) in a neonatal mouse model of lethal group B streptococci (GBS) sepsis. Plasma IL-10 levels significantly increased at 24 and 48 h after GBS inoculation. Neutralization of IL-10 with specific antibodies had no effect on lethality. Administration of recombinant IL-10 at 20 or 4 h before challenge, but not at later times, resulted in decreased tumor necrosis factor alpha levels and improved survival. IL-10 could be potentially useful for the treatment of GBS sepsis. PMID:8698523

Lethality of First Contact Dysentery Epidemics on Pacific Islands.

PubMed

Shanks, G Dennis

2016-08-03

Infectious diseases depopulated many isolated Pacific islands when they were first exposed to global pathogen circulation from the 18th century. Although the mortality was great, the lack of medical observers makes determination of what happened during these historical epidemics largely speculative. Bacillary dysentery caused by Shigella is the most likely infection causing some of the most lethal island epidemics. The fragmentary historical record is reviewed to gain insight into the possible causes of the extreme lethality that was observed during first-contact epidemics in the Pacific. Immune aspects of the early dysentery epidemics and postmeasles infection resulting in subacute inflammatory enteric disease suggest that epidemiologic isolation was the major lethality risk factor on Pacific islands in the 19th century. Other possible risk factors include human leukocyte antigen homogeneity from a founder effect and pathogen-induced derangement of immune tolerance to gut flora. If this analysis is correct, then Pacific islands are currently at no greater risk of emerging disease epidemics than other developing countries despite their dark history. © The American Society of Tropical Medicine and Hygiene.

[Analysis of risk factors of fatal outcome in pregnant and puerperant patients with severe H1N1 influenza].

PubMed

Zabolotskikh, I B; Penzhoian, G A; Musaeva, T S; Goncharenko, S I

2010-01-01

As well as previous epidemics and pandemias of influenza, the 2009 H1N1 influenza pandemia increases the risk of severe illness in pregnant. Data were reported for 28 pregnant and 2 postpartum women who have been hospitalized in ICUs of Krasnodar Region with H1N1 influenza diagnosis. The laboratory tests for H1N1 were negative in 53.3% of suspected cases of H1N1 influenza (16 of 30). The major lethal risk factor in pregnant with H1N1 influenza is a development of septic shock with low PaO2\\FiO2 ratio (less than 140) and high Murray's Acute Lung Injury Score (higher than 2.5). High Apache II, Apache III, SAPS 2, SAPS 3 and SOFA scores are the additional lethal risk factors. Lethal outcomes were more frequent in the end of the second trimester of pregnancy.

A Study of Communication Processor Systems

DTIC Science & Technology

1979-12-01

STUDYSCOFONLA (A . TIS R I8TIO S" - EEG R AN T-i R $a t 17. DITR UTO STTEeN in h b’*l.elldi 1Ok 0 ~45ft i9~a R,1OI)7 -C S. APeMr’wl NOTES Uh a DC gt~ & C...MM Fig. 3.3 Pluribus syste m II 24 -4~ I tm ap B u s- ----I FP K K Cmi Cornrnjer MeodUlO Fig. 3.4 Carnegie "iellLfn CmI* 25 0I M r K K P M K KP M K...144 bits incurs a mean transmission delay (o ) of 0.29 milli- seconds. The maximum transmission delays TDF and TDC can be obtained as 15 milliseconds

Seasonal variation in abiotic factors and ferulic acid toxicity in snail-attractant pellets against the intermediate host snail Lymnaea acuminata.

PubMed

Agrahari, P; Singh, D K

2013-11-01

Laboratory evaluation was made to access the seasonal variations in abiotic environmental factors temperature, pH, dissolved oxygen, carbon dioxide, electrical conductivity and ferulic acid toxicity in snail-attractant pellets (SAP) against the intermediate host snail Lymnaea acuminata in each month of the years 2010 and 2011. On the basis of a 24-h toxicity assay, it was noted that lethal concentration values of 4.03, 3.73% and 4.45% in SAP containing starch and 4.16, 4.23% and 4.29% in SAP containing proline during the months of May, June and September, respectively, were most effective in killing the snails, while SAP containing starch/proline + ferulic acid was least effective in the month of January/February (24-h lethal concentration value was 7.67%/7.63% in SAP). There was a significant positive correlation between lethal concentration value of ferulic acid containing SAP and levels of dissolved O2 /pH of water in corresponding months. On the contrary, a negative correlation was observed between lethal concentration value and dissolved CO2 /temperature of test water in the same months. To ascertain that such a relationship between toxicity and abiotic factors is not co-incidental, the nervous tissue of treated (40% and 80% of 24-h lethal concentration value) and control group of snails was assayed for the activity of acetylcholinesterase (AChE) in each of the 12 months of the same year. There was a maximum inhibition of 58.43% of AChE, in snails exposed to 80% of the 24-h lethal concentration value of ferulic acid + starch in the month of May. This work shows conclusively that the best time to control snail population with SAP containing ferulic acid is during the months of May, June and September. © 2012 Blackwell Verlag GmbH.

Certhrax Toxin, an Anthrax-related ADP-ribosyltransferase from Bacillus cereus*

PubMed Central

Visschedyk, Danielle; Rochon, Amanda; Tempel, Wolfram; Dimov, Svetoslav; Park, Hee-Won; Merrill, A. Rod

2012-01-01

We identified Certhrax, the first anthrax-like mART toxin from the pathogenic G9241 strain of Bacillus cereus. Certhrax shares 31% sequence identity with anthrax lethal factor from Bacillus anthracis; however, we have shown that the toxicity of Certhrax resides in the mART domain, whereas anthrax uses a metalloprotease mechanism. Like anthrax lethal factor, Certhrax was found to require protective antigen for host cell entry. This two-domain enzyme was shown to be 60-fold more toxic to mammalian cells than anthrax lethal factor. Certhrax localizes to distinct regions within mouse RAW264.7 cells by 10 min postinfection and is extranuclear in its cellular location. Substitution of catalytic residues shows that the mART function is responsible for the toxicity, and it binds NAD+ with high affinity (KD = 52.3 ± 12.2 μm). We report the 2.2 Å Certhrax structure, highlighting its structural similarities and differences with anthrax lethal factor. We also determined the crystal structures of two good inhibitors (P6 (KD = 1.7 ± 0.2 μm, Ki = 1.8 ± 0.4 μm) and PJ34 (KD = 5.8 ± 2.6 μm, Ki = 9.6 ± 0.3 μm)) in complex with Certhrax. As with other toxins in this family, the phosphate-nicotinamide loop moves toward the NAD+ binding site with bound inhibitor. These results indicate that Certhrax may be important in the pathogenesis of B. cereus. PMID:22992735

Psychosocial Characteristics and Social Networks of Suicidal Prisoners: Towards a Model of Suicidal Behaviour in Detention

PubMed Central

Rivlin, Adrienne; Hawton, Keith; Marzano, Lisa; Fazel, Seena

2013-01-01

Prisoners are at increased risk of suicide. Investigation of both individual and environmental risk factors may assist in developing suicide prevention policies for prisoners and other high-risk populations. We conducted a matched case-control interview study with 60 male prisoners who had made near-lethal suicide attempts in prison (cases) and 60 male prisoners who had not (controls). We compared levels of depression, hopelessness, self-esteem, impulsivity, aggression, hostility, childhood abuse, life events (including events occurring in prison), social support, and social networks in univariate and multivariate models. A range of psychosocial factors was associated with near-lethal self-harm in prisoners. Compared with controls, cases reported higher levels of depression, hopelessness, impulsivity, and aggression, and lower levels of self-esteem and social support (all p values <0.001). Adverse life events and criminal history factors were also associated with near-lethal self-harm, especially having a prior prison spell and having been bullied in prison, both of which remained significant in multivariate analyses. The findings support a model of suicidal behaviour in prisoners that incorporates imported vulnerability factors, clinical factors, and prison experiences, and underscores their interaction. Strategies to reduce self-harm and suicide in prisoners should include attention to such factors. PMID:23922671

Rescue of the mouse DDK syndrome by parent-of-origin-dependent modifiers.

PubMed

Ideraabdullah, Folami Y; Kim, Kuikwon; Pomp, Daniel; Moran, Jennifer L; Beier, David; de Villena, Fernando Pardo-Manuel

2007-02-01

When females of the DDK inbred mouse strain are mated to males of other strains, 90-100% of the resulting embryos die during early embryonic development. This DDK syndrome lethality results from incompatibility between an ooplasmic DDK factor and a non-DDK paternal gene, which map to closely linked loci on chromosome 11. It has been proposed that the expression of the gene that encodes the ooplasmic factor is subject to allelic exclusion in oocytes. Previous studies have demonstrated the existence of recessive modifiers that increase lethality in the C57BL/6 and BALB/c strains. These modifiers are thought to skew the choice of allele undergoing allelic exclusion in the oocytes of heterozygous females. In the present study, we demonstrate the presence of modifiers in three Mus musculus domesticus wild-derived strains, PERA, PERC, and RBA. These modifiers completely rescued DDK syndrome lethality. We mapped the major locus that is responsible for rescue in PERA and PERC crosses to proximal chromosome 13 and named this locus Rmod1 (Rescue Modifier of the DDK Syndrome 1). Our experiments demonstrate that PERA or PERC alleles at Rmod1 rescue lethality independently of allelic exclusion. In addition, rescue of the lethal phenotype depends on the parental origin of the Rmod1 alleles; transmission through the dam leads to rescue, while transmission through the sire has no effect.

Impact of acute alcohol consumption on lethality of suicide methods.

PubMed

Park, C Hyung Keun; Yoo, Seong Ho; Lee, Jaewon; Cho, Sung Joon; Shin, Min-Sup; Kim, Eun Young; Kim, Se Hyun; Ham, Keunsoo; Ahn, Yong Min

2017-05-01

The influence of acute alcohol consumption on the factors related to suicide remains understudied. Thus, the present study investigated the relationship between blood alcohol content (BAC) and the lethality of suicide methods. Autopsy data on 315 South Korean suicide completers with a positive BAC were collected from a nationwide pool between May 2015 and November 2015, and the methods were dichotomised as suicide methods of low lethality (SMLL; drug/chemical overdose and sharp objects, n=67) and suicide methods of high lethality (SMHL; everything else, n=243). BAC at the time of autopsy and various suicide-related factors of these two groups were compared with logistic regression analyses. Compared to suicide completers with a BAC in the lowest range of 0.011-0.049%, suicide completers with a BAC in the range of 0.150-0.199% were more likely to use SMHL (odds ratio [OR]: 3.644, 95% confidence interval [CI]: 1.221-10.874). Additionally, the adoption of SMHL was significantly associated with the absence of a psychiatric illness (OR: 0.433, 95% CI: 0.222-0.843) and a younger age; the OR for high BAC among subjects in their 40s was 0.266 (95% CI: 0.083-0.856); in their 50s, 0.183 (95% CI: 0.055-0.615); and in their 60s, 0.057 (95% CI: 0.015-0.216). The relationship between BAC and suicide method lethality was represented by a bell-shaped pattern in which suicide methods of high lethality were more likely to be used by suicide completers with mid-range BAC levels. The increased impulsivity and impairments in particular executive functions, including planning and organization, associated with acute alcohol use may influence the selection of a particular suicide method based on its lethality. Copyright © 2017 Elsevier Inc. All rights reserved.

Inhibition of anthrax lethal factor by ssDNA aptamers.

PubMed

Lahousse, Mieke; Park, Hae-Chul; Lee, Sang-Choon; Ha, Na-Reum; Jung, In-Pil; Schlesinger, Sara R; Shackelford, Kaylin; Yoon, Moon-Young; Kim, Sung-Kun

2018-05-15

Anthrax is caused by Bacillus anthracis, a bacterium that is able to secrete the toxins protective antigen, edema factor and lethal factor. Due to the high level of secretion from the bacteria and its severe virulence, lethal factor (LF) has been sought as a biomarker for detecting bacterial infection and as an effective target to neutralize toxicity. In this study, we found three aptamers, and binding affinity was determined by fluorescently labeled aptamers. One of the aptamers exhibited high affinity, with a K d value of 11.0 ± 2.7 nM, along with low cross reactivity relative to bovine serum albumin and protective antigen. The therapeutic functionality of the aptamer was examined by assessing the inhibition of LF protease activity against a mitogen-activated protein kinase kinase. The aptamer appears to be an effective inhibitor of LF with an IC 50 value of 15 ± 1.5 μM and approximately 85% cell viability, suggesting that this aptamer provides a potential clue for not only development of a sensitive diagnostic device of B. anthracis infection but also the design of novel inhibitors of LF. Copyright © 2018 Elsevier Inc. All rights reserved.

Social Network Analysis of Crowds

DTIC Science & Technology

2009-08-06

crowd responses to non-lethal weapons d tan sys ems – Prior, existing social relationships – Real time social interactions – Formal/informal...Crowd Behavior Testbed Layout Video Cameras on Trusses Importance of Social Factors • Response to non-lethal weapons fire depends on social ... relationships among crowd members – Pre-existing Personal Relationships – Ongoing Real Time Social Interactions – Formal/Informal Hierarchies • Therefore

Purification and biophysical characterization of the core protease domain of anthrax lethal factor

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

Gkazonis, Petros V.; Dalkas, Georgios A.; Chasapis, Christos T.

2010-06-04

Anthrax lethal toxin (LeTx) stands for the major virulence factor of the anthrax disease. It comprises a 90 kDa highly specific metalloprotease, the anthrax lethal factor (LF). LF possesses a catalytic Zn{sup 2+} binding site and is highly specific against MAPK kinases, thus representing the most potent native biomolecule to alter and inactivate MKK [MAPK (mitogen-activated protein kinase) kinases] signalling pathways. Given the importance of the interaction between LF and substrate for the development of anti-anthrax agents as well as the potential treatment of nascent tumours, the analysis of the structure and dynamic properties of the LF catalytic site aremore » essential to elucidate its enzymatic properties. Here we report the recombinant expression and purification of a C-terminal part of LF (LF{sub 672-776}) that harbours the enzyme's core protease domain. The biophysical characterization and backbone assignments ({sup 1}H, {sup 13}C, {sup 15}N) of the polypeptide revealed a stable, well folded structure even in the absence of Zn{sup 2+}, suitable for high resolution structural analysis by NMR.« less

Toxic Effect of Staphylococcal Lysins for Goldfish1

PubMed Central

Kaplan, Milton T.; Appleman, Milo D.

1963-01-01

Goldfish died within 24 hr after intraperitoneal injections of 0.2 ml of Seitz filtrates of hemolytic Staphylococcus aureus cultures grown on Dolman and Wilson medium under increased CO2 pressure for 72 to 96 hr. Two lethal toxins differing in heat sensitivity, antigenicity, and degree of toxicity were demonstrated. Studies of the relationship between the lethal factors and the hemolysins in the filtrates suggested that α- and β-lysin were responsible for the lethal effects. Filtrates of nonhemolytic staphylococcal cultures were innocuous. Goldfish were suitable animals for detecting toxicity in staphylococcal culture filtrates and for quantitative studies of the toxins. The results were highly reproducible. PMID:14030754

Role of decoy molecules in neuronal ischemic preconditioning

PubMed Central

Panneerselvam, Mathivadhani; Patel, Piyush M.; Roth, David M.; Kidd, Michael W.; Chin-Lee, Blake; Head, Brian P.; Niesman, Ingrid R.; Inoue, Satoki; Patel, Hemal H.; Davis, Daniel P.

2011-01-01

Decoy receptors bind with TNF related apoptosis inducing ligands (TRAIL) but do not contain the cytoplasmic domains necessary to transduce apoptotic signals. We hypothesized that decoy receptors may confer neuronal protection against lethal ischemia after ischemic preconditioning (IPC). Mixed cortical neurons were exposed to IPC one day prior to TRAIL treatment or lethal ischemia. IPC increased decoy receptor but reduced death receptor expression compared to lethal ischemia. IPC-induced increase in decoy receptor expression was reduced by prior treatment with CAPE, a nuclear factor-kappa B inhibitor (NFκB). Expression of decoy molecules, dependent on NFκB, may mediate neuronal survival induced by IPC. PMID:21315738

Ligand-induced expansion of the S1' site in the anthrax toxin lethal factor

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

Maize, Kimberly M.; Kurbanov, Elbek K.; Johnson, Rodney L.

2016-07-05

The Bacillus anthracis lethal factor (LF) is one component of a tripartite exotoxin partly responsible for persistent anthrax cytotoxicity after initial bacterial infection. Inhibitors of the zinc metalloproteinase have been investigated as potential therapeutic agents, but LF is a challenging target because inhibitors lack sufficient selectivity or possess poor pharmaceutical properties. These structural studies reveal an alternate conformation of the enzyme, induced upon binding of specific inhibitors, that opens a previously unobserved deep pocket termed S1'* which might afford new opportunities to design selective inhibitors that target this subsite.

Chronic toxicity of copper to five benthic invertebrates in laboratory-formulated sediment: sensitivity comparison and preliminary risk assessment.

PubMed

Roman, Yblin E; De Schamphelaere, Karel A C; Nguyen, Lien T H; Janssen, Colin R

2007-11-15

Five benthic organisms commonly used for sediment toxicity testing were chronically (28 to 35 days) exposed to copper in standard laboratory-formulated sediment (following Organization for Economic Cooperation and Development guidelines) and lethal and sub-lethal toxicities were evaluated. Sub-lethal endpoints considered were reproduction and biomass production for Lumbriculus variegatus, growth and reproduction for Tubifex tubifex, growth and emergence for Chironomus riparius, and growth for Gammarus pulex and Hyalella azteca. Expressed on whole-sediment basis the observed lethal sensitivity ranking (from most to least sensitive) was: G. pulex>L. variegatus>H. azteca=C. riparius=T. tubifex, with median chronic lethal concentrations (LC50) between 151 and 327 mg/kg dry wt. The sub-lethal sensitivity ranking (from most to least sensitive, with the most sensitive endpoint between parentheses): C. riparius (emergence)>T. tubifex (reproduction)=L. variegatus (reproduction)>G. pulex (growth)>H. azteca (growth), with median effective concentrations (EC50) between 59.2 and 194 mg/kg dry wt. No observed effect concentrations (NOEC) or 10% effective concentrations (EC10) for the five benthic invertebrates were used to perform a preliminary risk assessment for copper in freshwater sediment by means of (a) the "assessment factor approach" or (b) the statistical extrapolation approach (species sensitivity distribution). Depending on the data (NOEC or EC10) and the methodology used, we calculated a Predicted No Effect Concentration (PNEC) for sediment between 3.3 and 47.1 mg Cu/dry wt. This range is similar to the range of natural (geochemical) background concentrations of copper in sediments in Europe, i.e. 90% of sediments have a concentration between 5 and 49 mg Cu/kg dry wt. A detailed analysis of the outcome of this preliminary exercise highlighted that multiple issues need to be explored for achieving a scientifically more sound risk assessment and for the development of robust sediment quality criteria for copper, including (i) the use of the assessment factor approach vs. the statistical extrapolation approach, (ii) the importance of bioavailability modifying factors (e.g., organic carbon, acid volatile sulfide), and (iii) the influence of prevailing geochemical (bioavailable) background concentrations on the copper sensitivity of local benthic biota.

Leukemia inhibitory factor protects against experimental lethal Escherichia coli septic shock in mice.

PubMed Central

Waring, P M; Waring, L J; Billington, T; Metcalf, D

1995-01-01

Leukemia inhibitory factor (LIF) has recently been associated with septic shock in humans. In this study we sought to determine, in mice, the role of LIF in septic shock. During sublethal endotoxemia, serum LIF levels, as determined by radio-receptor competition assay, peaked at 2 h and were low (3 ng/ml), whereas in lethal Escherichia coli septic shock serum LIF levels rose progressively (> 30 ng/ml) in the premorbid phase coincident with the development of tissue injury. Single i.v. injections of high doses (up to 50 micrograms per mouse) of recombinant murine LIF had no obvious acute detrimental effects, whereas continued i.p. administration (30 micrograms per mouse per day) for 3-4 days induced a fatal catabolic state without evidence of preceding hemodynamic collapse or shock. Simultaneous or subsequent administration of high doses of LIF had no effect on mortality from sublethal and lethal E. coli septic shock, whereas prior administration conferred significant protection against lethality (P << 0.001 by log-rank test), an effect that was dose and interval dependent. This protective effect resembled endotoxin tolerance and was characterized by suppression of E. coli-induced serum tumor necrosis factor concentration (P < 0.05), reduction in the number of viable bacteria (P < 0.05), and prevention of sepsis-induced tissue injury. These observations suggest that systemic LIF production is part of the host response to both endotoxin and sepsis-induced tissue injury. Images Fig. 2 Fig. 5 PMID:7877978

Lethal exposure: An integrated approach to pathogen transmission via environmental reservoirs.

PubMed

Turner, Wendy C; Kausrud, Kyrre L; Beyer, Wolfgang; Easterday, W Ryan; Barandongo, Zoë R; Blaschke, Elisabeth; Cloete, Claudine C; Lazak, Judith; Van Ert, Matthew N; Ganz, Holly H; Turnbull, Peter C B; Stenseth, Nils Chr; Getz, Wayne M

2016-06-06

To mitigate the effects of zoonotic diseases on human and animal populations, it is critical to understand what factors alter transmission dynamics. Here we assess the risk of exposure to lethal concentrations of the anthrax bacterium, Bacillus anthracis, for grazing animals in a natural system over time through different transmission mechanisms. We follow pathogen concentrations at anthrax carcass sites and waterholes for five years and estimate infection risk as a function of grass, soil or water intake, age of carcass sites, and the exposure required for a lethal infection. Grazing, not drinking, seems the dominant transmission route, and transmission is more probable from grazing at carcass sites 1-2 years of age. Unlike most studies of virulent pathogens that are conducted under controlled conditions for extrapolation to real situations, we evaluate exposure risk under field conditions to estimate the probability of a lethal dose, showing that not all reservoirs with detectable pathogens are significant transmission pathways.

Satellite teleradiology test bed for digital mammography

NASA Astrophysics Data System (ADS)

Barnett, Bruce G.; Dudding, Kathryn E.; Abdel-Malek, Aiman A.; Mitchell, Robert J.

1996-05-01

Teleradiology offers significant improvement in efficiency and patient compliance over current practices in traditional film/screen-based diagnosis. The increasing number of women who need to be screened for breast cancer, including those in remote rural regions, make the advantages of teleradiology especially attractive for digital mammography. At the same time, the size and resolution of digital mammograms are among the most challenging to support in a cost effective teleradiology system. This paper will describe a teleradiology architecture developed for use with digital mammography by GE Corporate Research and Development in collaboration with Massachusetts General Hospital under National Cancer Institute (NCI/NIH) grant number R01 CA60246-01. The testbed architecture is based on the Digital Imaging and Communications in Medicine (DICOM) standard, created by the American College of Radiology and National Electrical Manufacturers Association. The testbed uses several Sun workstations running SunOS, which emulate a rural examination facility connected to a central diagnostic facility, and uses a TCP-based DICOM application to transfer images over a satellite link. Network performance depends on the product of the bandwidth times the round- trip time. A satellite link has a round trip of 513 milliseconds, making the bandwidth-delay a significant problem. This type of high bandwidth, high delay network is called a Long Fat Network, or LFN. The goal of this project was to quantify the performance of the satellite link, and evaluate the effectiveness of TCP over an LFN. Four workstations have Sun's HSI/S (High Speed Interface) option. Two are connected by a cable, and two are connected through a satellite link. Both interfaces have the same T1 bandwidth (1.544 Megabits per second). The only difference was the round trip time. Even with large window buffers, the time to transfer a file over the satellite link was significantly longer, due to the bandwidth-delay. To compensate for this, TCP extensions for LFNs such as the Window Scaling Option (described in RFC1323) were necessary to optimize the use of the link. A high level analysis of throughput, with and without these TCP extensions, will be discussed. Recommendations will be made as to the critical areas for future work.

Lethal effects of Clostridium perfringens epsilon toxin are potentiated by alpha and perfringolysin-O toxins in a mouse model.

PubMed

Fernandez-Miyakawa, Mariano E; Jost, B Helen; Billington, Stephen J; Uzal, Francisco A

2008-03-18

Epsilon toxin (ETX) is the most important virulence factor of Clostridium perfringens type D. Two other important toxins, alpha toxin (CPA) and perfringolysin-O (PFO), are encoded and potentially produced by most C. perfringens type D isolates. The biological effects of these toxins are dissimilar although they are all lethal. Since the possible interaction of these toxins during infection is unknown, the effects of CPA and PFO on the lethal activity of ETX were studied in a mouse model. Mice were injected intravenously or intragastrically with CPA or PFO with or without ETX. Sublethal doses of CPA or PFO did not affect the lethality of ETX when either was injected together with the latter intravenously. However, sublethal or lethal doses of CPA or PFO resulted in reduction of the survival time of mice injected simultaneously with ETX when compared with the intravenous effect of ETX injected alone. When PFO was inoculated intragastrically with ETX, a reduction of the survival time was observed. CPA did not alter the survival time when inoculated intragastrically with ETX. The results of the present study suggest that both CPA and PFO have the potential to enhance the ETX lethal effects during enterotoxemia in natural hosts such as sheep and goats.

When a Wife Says "No": Wife Sexual Refusal as a Factor in Husband-Wife Homicides in Ghana.

PubMed

Adinkrah, Mensah

2017-11-01

In Ghana, wife sexual refusal is a key factor in uxoricides or husband-to-wife murders. Despite this, there is a dearth of systematic research that examines sexual strife as a precipitant of domestic violence and spousal murder. The present article addresses the current lack of research by systematically examining 25 cases of homicides and attempted homicides where wives were lethally and nonlethally assaulted by their husbands following the former's refusal to engage in husband-initiated sexual intercourse. A content analysis was conducted of all print and electronic media news items where a wife's refusal of sexual intercourse with a husband triggered lethal or aggravated violence. The results showed that the victims were aged 23 to 55 years old and were generally of low socioeconomic status. The assailants were aged 28 to 60 years old. Assailants used machetes, knives, and personal weapons to perpetrate the crimes, and extreme violence was a frequent feature of both lethal and nonlethal acts.

Assisted suicide of a selfish gene.

PubMed

Thomson, M S; Beeman, R W

1999-01-01

Medea (M) factors and the hybrid incompatibility factor (H) are involved in two incompatibility systems in flour beetles that were previously thought to be independent. M factors are a novel class of selfish genes that act by maternal lethality to nonself. The H factor causes the death of hybrids with a paternally derived H gene and previously uncharacterized maternal cofactors. We now find that M factors exhibit their selfish behavior only in the absence of the H factor. Furthermore, we show that the previously uncharacterized maternal cofactors required for H-associated hybrid inviability are identical to M factors. We propose that incompatibility between H strains and M strains is due to suppression by the H factor of the self-rescuing activity of the lethal M genes. This interaction has the effect of converting M elements from selfish into self-destructive or "suicidal" genes. M factors are globally widespread, but are conspicuously absent from India, the only country where the H factor is known to occur. Such a mechanism could prevent the spread of selfish M elements by establishing an absolute barrier to hybridization in the boundary between M and non-M zones.

Lethal and nonlethal violence against an intimate female partner: comparing male murderers to nonlethal abusers.

PubMed

Dobash, R Emerson; Dobash, Russell P; Cavanagh, Kate; Medina-Ariza, Juanjo

2007-04-01

Men's lethal and nonlethal violence against an intimate female partner are compared. Various risk factors are examined to compare men's lethal and nonlethal violence against an intimate woman partner. Relative to abusers, men who kill are generally more conventional with respect to childhood backgrounds, education, employment, and criminal careers, are more likely to be possessive and jealous, and are more likely to be separated from their partner at the time of the event. Men who kill are more likely to have used violence against a previous partner, to have sexually assaulted and strangled the victim, and to have used a weapon or instrument. However, they were less likely to have been drunk at the time of the event and/or to have previously used violence against the woman they killed. Overall, the findings do not support the notion of a simple progression from nonlethal to lethal violence and raise some dilemmas for the growing area of risk assessment.

Lethal exposure: An integrated approach to pathogen transmission via environmental reservoirs

PubMed Central

Turner, Wendy C.; Kausrud, Kyrre L.; Beyer, Wolfgang; Easterday, W. Ryan; Barandongo, Zoë R.; Blaschke, Elisabeth; Cloete, Claudine C.; Lazak, Judith; Van Ert, Matthew N.; Ganz, Holly H.; Turnbull, Peter C. B.; Stenseth, Nils Chr.; Getz, Wayne M.

2016-01-01

To mitigate the effects of zoonotic diseases on human and animal populations, it is critical to understand what factors alter transmission dynamics. Here we assess the risk of exposure to lethal concentrations of the anthrax bacterium, Bacillus anthracis, for grazing animals in a natural system over time through different transmission mechanisms. We follow pathogen concentrations at anthrax carcass sites and waterholes for five years and estimate infection risk as a function of grass, soil or water intake, age of carcass sites, and the exposure required for a lethal infection. Grazing, not drinking, seems the dominant transmission route, and transmission is more probable from grazing at carcass sites 1–2 years of age. Unlike most studies of virulent pathogens that are conducted under controlled conditions for extrapolation to real situations, we evaluate exposure risk under field conditions to estimate the probability of a lethal dose, showing that not all reservoirs with detectable pathogens are significant transmission pathways. PMID:27265371

A Systems Biology Approach to Link Nuclear Factor Kappa B Activation with Lethal Prostate Cancer

DTIC Science & Technology

2014-05-01

developed as a routine clinical assay. 12 Task 1B: Perform protein profiling of circulating blood proteins and determine whether a protein...or set of proteins indicative of NFκB activation are associated with lethal prostate cancer. Circulating proteins will be assessed in two cohorts of...throughput functional genomic data. Nucleic acids research 2009;37:D885-90. 3. Parkinson H, Kapushesky M, Kolesnikov N, et al. ArrayExpress update--from

Characterization of Synthetic-Lethal Mutants Reveals a Role for the Saccharomyces Cerevisiae Guanine-Nucleotide Exchange Factor Cdc24p in Vacuole Function and Na(+) Tolerance

PubMed Central

White, W. H.; Johnson, D. I.

1997-01-01

Cdc24p is the guanine-nucleotide exchange factor for the Cdc42p GTPase, which controls cell polarity in Saccharomyces cerevisiae. To identify new genes that may affect cell polarity, we characterized six UV-induced csl (CDC24 synthetic-lethal) mutants that exhibited synthetic-lethality with cdc24-4(ts) at 23°. Five mutants were not complemented by plasmid-borne CDC42, RSR1, BUD5, BEM1, BEM2, BEM3 or CLA4 genes, which are known to play a role in cell polarity. The csl3 mutant displayed phenotypes similar to those observed with calcium-sensitive, Pet(-) vma mutants defective in vacuole function. CSL5 was allelic to VMA5, the vacuolar H(+)-ATPase subunit C, and one third of csl5 cdc24-4(ts) cells were elongated or had misshapen buds. A cdc24-4(ts) Δvma5::LEU2 double mutant did not exhibit synthetic lethality, suggesting that the csl5/vma5 cdc24-4(ts) synthetic-lethality was not simply due to altered vacuole function. The cdc24-4(ts) mutant, like Δvma5::LEU2 and csl3 mutants, was sensitive to high levels of Ca(2+) as well as Na(+) in the growth media, which did not appear to be a result of a fragile cell wall because the phenotypes were not remedied by 1 M sorbitol. Our results indicated that Cdc24p was required in one V-ATPase mutant and another mutant affecting vacuole morphology, and also implicated Cdc24p in Na(+) tolerance. PMID:9286667

The Major Acute-Phase Protein, Serum Amyloid P Component, in Mice Is Not Involved in Endogenous Resistance against Tumor Necrosis Factor Alpha-Induced Lethal Hepatitis, Shock, and Skin Necrosis

PubMed Central

Van Molle, Wim; Hochepied, Tino; Brouckaert, Peter; Libert, Claude

2000-01-01

The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) induces lethal hepatitis when injected into d-(+)-galactosamine-sensitized mice on the one hand or systemic inflammatory response syndrome (SIRS) in normal mice on the other hand. We studied whether serum amyloid P component (SAP), the major acute-phase protein in mice, plays a protective role in both lethal models. For this purpose, we used SAP0/0 mice generated by gene targeting. We studied the lethal response of SAP0/0 or SAP+/+ mice to both lethal triggers but found no differences in the sensitivity of both types of mice. We also investigated whether SAP is involved in establishing two types of endogenous protection: one using a single injection of interleukin-1β (IL-1β) for desensitization and clearly involving a liver protein, the other by tolerizing mice for 5 days using small doses of human TNF-α. Although after IL-1β or after tolerization the SAP levels in the serum had risen fourfold in the control mice and not in the SAP0/0 mice, the same extents of desensitization and tolerization were achieved. Finally, we observed that the induction of hemorrhagic necrosis in the skin of mice by two consecutive local injections with TNF-α was not altered in SAP0/0 mice. We conclude that the presence or absence of SAP has no influence on the sensitivity of mice to TNF-α-induced hepatitis, SIRS, and hemorrhagic necrosis or on the endogenous protective mechanisms of desensitization or tolerization. PMID:10948120

Exposure to low UVA doses increases KatA and KatB catalase activities, and confers cross-protection against subsequent oxidative injuries in Pseudomonas aeruginosa.

PubMed

Pezzoni, Magdalena; Tribelli, Paula M; Pizarro, Ramón A; López, Nancy I; Costa, Cristina S

2016-05-01

Solar UVA radiation is one of the main environmental stress factors for Pseudomonas aeruginosa. Exposure to high UVA doses produces lethal effects by the action of the reactive oxygen species (ROS) it generates. P. aeruginosa has several enzymes, including KatA and KatB catalases, which provide detoxification of ROS. We have previously demonstrated that KatA is essential in defending P. aeruginosa against high UVA doses. In order to analyse the mechanisms involved in the adaptation of this micro-organism to UVA, we investigated the effect of exposure to low UVA doses on KatA and KatB activities, and the physiological consequences. Exposure to UVA induced total catalase activity; assays with non-denaturing polyacrylamide gels showed that both KatA and KatB activities were increased by radiation. This regulation occurred at the transcriptional level and depended, at least partly, on the increase in H2O2 levels. We demonstrated that exposure to low UVA produced a protective effect against subsequent lethal doses of UVA, sodium hypochlorite and H2O2. Protection against lethal UVA depends on katA, whilst protection against sodium hypochlorite depends on katB, demonstrating that different mechanisms are involved in the defence against these oxidative agents, although both genes can be involved in the global cellular response. Conversely, protection against lethal doses of H2O2 could depend on induction of both genes and/or (an)other defensive factor(s). A better understanding of the adaptive response of P. aeruginosa to UVA is relevant from an ecological standpoint and for improving disinfection strategies that employ UVA or solar irradiation.

A Diverse Set of Single-domain Antibodies (VHHs) against the Anthrax Toxin Lethal and Edema Factors Provides a Basis for Construction of a Bispecific Agent That Protects against Anthrax Infection.

PubMed

Vrentas, Catherine E; Moayeri, Mahtab; Keefer, Andrea B; Greaney, Allison J; Tremblay, Jacqueline; O'Mard, Danielle; Leppla, Stephen H; Shoemaker, Charles B

2016-10-07

Infection with Bacillus anthracis, the causative agent of anthrax, can lead to persistence of lethal secreted toxins in the bloodstream, even after antibiotic treatment. VHH single-domain antibodies have been demonstrated to neutralize diverse bacterial toxins both in vitro and in vivo, with protein properties such as small size and high stability that make them attractive therapeutic candidates. Recently, we reported on VHHs with in vivo activity against the protective antigen component of the anthrax toxins. Here, we characterized a new set of 15 VHHs against the anthrax toxins that act by binding to the edema factor (EF) and/or lethal factor (LF) components. Six of these VHHs are cross-reactive against both EF and LF and recognize the N-terminal domain (LF N , EF N ) of their target(s) with subnanomolar affinity. The cross-reactive VHHs block binding of EF/LF to the protective antigen C-terminal binding interface, preventing toxin entry into the cell. Another VHH appears to recognize the LF C-terminal domain and exhibits a kinetic effect on substrate cleavage by LF. A subset of the VHHs neutralized against EF and/or LF in murine macrophage assays, and the neutralizing VHHs that were tested improved survival of mice in a spore model of anthrax infection. Finally, a bispecific VNA (VHH-based neutralizing agent) consisting of two linked toxin-neutralizing VHHs, JMN-D10 and JMO-G1, was fully protective against lethal anthrax spore infection in mice as a single dose. This set of VHHs should facilitate development of new therapeutic VNAs and/or diagnostic agents for anthrax. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

The Decline of the Military Ethos and Profession of Arms: An Argument Against Autonomous Lethal Engagements

DTIC Science & Technology

2012-10-01

very limited to support near-term, clear-cut, small-scale tactical objectives avoiding mass applications which could compromise long term strategic...principles of double effect and double intent factor into the calculus of the use of force as well.26 The professional community is divided on the...lethal force and those who prosecute it and a lack of empathy for those who it is waged upon.54 Finally, Hartle writes that one purpose of professional

A Systems Biology Approach to Link Nuclear Factor Kappa B Activation with Lethal Prostate Cancer

DTIC Science & Technology

2013-05-01

developed as a routine clinical assay. Task 1B: Perform protein profiling of circulating blood proteins and determine whether a protein or set of...proteins indicative of NFκB activation are associated with lethal prostate cancer. Circulating proteins will be assessed in two cohorts of 312...functional genomic data. Nucleic Acids Res 2009;37:D885-90. 3. Parkinson H, Kapushesky M, Kolesnikov N, et al. ArrayExpress update--from an archive of

Preparation and characterization of cobalt-substituted anthrax lethal factor

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

Saebel, Crystal E.; Carbone, Ryan; Dabous, John R.

2011-12-09

Highlights: Black-Right-Pointing-Pointer Cobalt-substituted anthrax lethal factor (CoLF) is highly active. Black-Right-Pointing-Pointer CoLF can be prepared by bio-assimilation and direct exchange. Black-Right-Pointing-Pointer Lethal factor binds cobalt tightly. Black-Right-Pointing-Pointer The electronic spectrum of CoLF reveals penta-coordination. Black-Right-Pointing-Pointer Interaction of CoLF with thioglycolic acid follows a 2-step mechanism. -- Abstract: Anthrax lethal factor (LF) is a zinc-dependent endopeptidase involved in the cleavage of mitogen-activated protein kinase kinases near their N-termini. The current report concerns the preparation of cobalt-substituted LF (CoLF) and its characterization by electronic spectroscopy. Two strategies to produce CoLF were explored, including (i) a bio-assimilation approach involving the cultivation of LF-expressingmore » Bacillus megaterium cells in the presence of CoCl{sub 2}, and (ii) direct exchange by treatment of zinc-LF with CoCl{sub 2}. Independent of the method employed, the protein was found to contain one Co{sup 2+} per LF molecule, and was shown to be twice as active as its native zinc counterpart. The electronic spectrum of CoLF suggests the Co{sup 2+} ion to be five-coordinate, an observation similar to that reported for other Co{sup 2+}-substituted gluzincins, but distinct from that documented for the crystal structure of native LF. Furthermore, spectroscopic studies following the exposure of CoLF to thioglycolic acid (TGA) revealed a sequential mechanism of metal removal from LF, which likely involves the formation of an enzyme: Co{sup 2+}:TGA ternary complex prior to demetallation of the active site. CoLF reported herein constitutes the first spectroscopic probe of LF's active site, which may be utilized in future studies to gain further insight into the enzyme's mechanism and inhibitor interactions.« less

Targeted Disruption of Mouse Yin Yang 1 Transcription Factor Results in Peri-Implantation Lethality

PubMed Central

Donohoe, Mary E.; Zhang, Xiaolin; McGinnis, Lynda; Biggers, John; Li, En; Shi, Yang

1999-01-01

Yin Yang 1 (YY1) is a zinc finger-containing transcription factor and a target of viral oncoproteins. To determine the biological role of YY1 in mammalian development, we generated mice deficient for YY1 by gene targeting. Homozygosity for the mutated YY1 allele results in embryonic lethality in the mouse. YY1 mutants undergo implantation and induce uterine decidualization but rapidly degenerate around the time of implantation. A subset of YY1 heterozygote embryos are developmentally retarded and exhibit neurulation defects, suggesting that YY1 may have additional roles during later stages of mouse embryogenesis. Our studies demonstrate an essential function for YY1 in the development of the mouse embryo. PMID:10490658

Killed but metabolically active Bacillus anthracis vaccines induce broad and protective immunity against anthrax.

PubMed

Skoble, Justin; Beaber, John W; Gao, Yi; Lovchik, Julie A; Sower, Laurie E; Liu, Weiqun; Luckett, William; Peterson, Johnny W; Calendar, Richard; Portnoy, Daniel A; Lyons, C Rick; Dubensky, Thomas W

2009-04-01

Bacillus anthracis is the causative agent of anthrax. We have developed a novel whole-bacterial-cell anthrax vaccine utilizing B. anthracis that is killed but metabolically active (KBMA). Vaccine strains that are asporogenic and nucleotide excision repair deficient were engineered by deleting the spoIIE and uvrAB genes, rendering B. anthracis extremely sensitive to photochemical inactivation with S-59 psoralen and UV light. We also introduced point mutations into the lef and cya genes, which allowed inactive but immunogenic toxins to be produced. Photochemically inactivated vaccine strains maintained a high degree of metabolic activity and secreted protective antigen (PA), lethal factor, and edema factor. KBMA B. anthracis vaccines were avirulent in mice and induced less injection site inflammation than recombinant PA adsorbed to aluminum hydroxide gel. KBMA B. anthracis-vaccinated animals produced antibodies against numerous anthrax antigens, including high levels of anti-PA and toxin-neutralizing antibodies. Vaccination with KBMA B. anthracis fully protected mice against challenge with lethal doses of toxinogenic unencapsulated Sterne 7702 spores and rabbits against challenge with lethal pneumonic doses of fully virulent Ames strain spores. Guinea pigs vaccinated with KBMA B. anthracis were partially protected against lethal Ames spore challenge, which was comparable to vaccination with the licensed vaccine anthrax vaccine adsorbed. These data demonstrate that KBMA anthrax vaccines are well tolerated and elicit potent protective immune responses. The use of KBMA vaccines may be broadly applicable to bacterial pathogens, especially those for which the correlates of protective immunity are unknown.

The putative RNA helicase Dbp6p functionally interacts with Rpl3p, Nop8p and the novel trans-acting Factor Rsa3p during biogenesis of 60S ribosomal subunits in Saccharomyces cerevisiae.

PubMed Central

de la Cruz, Jesús; Lacombe, Thierry; Deloche, Olivier; Linder, Patrick; Kressler, Dieter

2004-01-01

Ribosome biogenesis requires at least 18 putative ATP-dependent RNA helicases in Saccharomyces cerevisiae. To explore the functional environment of one of these putative RNA helicases, Dbp6p, we have performed a synthetic lethal screen with dbp6 alleles. We have previously characterized the nonessential Rsa1p, whose null allele is synthetically lethal with dbp6 alleles. Here, we report on the characterization of the four remaining synthetic lethal mutants, which reveals that Dbp6p also functionally interacts with Rpl3p, Nop8p, and the so-far-uncharacterized Rsa3p (ribosome assembly 3). The nonessential Rsa3p is a predominantly nucleolar protein required for optimal biogenesis of 60S ribosomal subunits. Both Dbp6p and Rsa3p are associated with complexes that most likely correspond to early pre-60S ribosomal particles. Moreover, Rsa3p is co-immunoprecipitated with protA-tagged Dbp6p under low salt conditions. In addition, we have established a synthetic interaction network among factors involved in different aspects of 60S-ribosomal-subunit biogenesis. This extensive genetic analysis reveals that the rsa3 null mutant displays some specificity by being synthetically lethal with dbp6 alleles and by showing some synthetic enhancement with the nop8-101 and the rsa1 null allele. PMID:15126390

The Klebsiella pneumoniae O Antigen Contributes to Bacteremia and Lethality during Murine Pneumonia

PubMed Central

Shankar-Sinha, Sunita; Valencia, Gabriel A.; Janes, Brian K.; Rosenberg, Jessica K.; Whitfield, Chris; Bender, Robert A.; Standiford, Ted J.; Younger, John G.

2004-01-01

Bacterial surface carbohydrates are important pathogenic factors in gram-negative pneumonia infections. Among these factors, O antigen has been reported to protect pathogens against complement-mediated killing. To examine further the role of O antigen, we insertionally inactivated the gene encoding a galactosyltransferase necessary for serotype O1 O-antigen synthesis (wbbO) from Klebsiella pneumoniae 43816. Analysis of the mutant lipopolysaccharide by sodium dodecyl sulfate-polyacrylamide gel electrophoresis confirmed the absence of O antigen. In vitro, there were no detectable differences between wild-type K. pneumoniae and the O-antigen-deficient mutant in regard to avid binding by murine complement C3 or resistance to serum- or whole-blood-mediated killing. Nevertheless, the 72-h 50% lethal dose of the wild-type strain was 30-fold greater than that of the mutant (2 × 103 versus 6 × 104 CFU) after intratracheal injection in ICR strain mice. Despite being less lethal, the mutant organism exhibited comparable intrapulmonary proliferation at 24 h compared to the level of the wild type. Whole-lung chemokine expression (CCL3 and CXCL2) and bronchoalveolar inflammatory cell content were also similar between the two infections. However, whereas the wild-type organism produced bacteremia within 24 h of infection in every instance, bacteremia was not seen in mutant-infected mice. These results suggest that during murine pneumonia caused by K. pneumoniae, O antigen contributes to lethality by increasing the propensity for bacteremia and not by significantly changing the early course of intrapulmonary infection. PMID:14977947

Lethal factor antibodies contribute to lethal toxin neutralization in recipients of anthrax vaccine precipitated.

PubMed

Dumas, Eric K; Garman, Lori; Cuthbertson, Hannah; Charlton, Sue; Hallis, Bassam; Engler, Renata J M; Choudhari, Shyamal; Picking, William D; James, Judith A; Farris, A Darise

2017-06-08

A major difference between two currently licensed anthrax vaccines is presence (United Kingdom Anthrax Vaccine Precipitated, AVP) or absence (United States Anthrax Vaccine Adsorbed, AVA) of quantifiable amounts of the Lethal Toxin (LT) component Lethal Factor (LF). The primary immunogen in both vaccine formulations is Protective Antigen (PA), and LT-neutralizing antibodies directed to PA are an accepted correlate of vaccine efficacy; however, vaccination studies in animal models have demonstrated that LF antibodies can be protective. In this report we compared humoral immune responses in cohorts of AVP (n=39) and AVA recipients (n=78) matched 1:2 for number of vaccinations and time post-vaccination, and evaluated whether the LF response contributes to LT neutralization in human recipients of AVP. PA response rates (≥95%) and PA IgG concentrations were similar in both groups; however, AVP recipients exhibited higher LT neutralization ED 50 values (AVP: 1464.0±214.7, AVA: 544.9±83.2, p<0.0001) and had higher rates of LF IgG positivity (95%) compared to matched AVA vaccinees (1%). Multiple regression analysis revealed that LF IgG makes an independent and additive contribution to the LT neutralization response in the AVP group. Affinity purified LF antibodies from two independent AVP recipients neutralized LT and bound to LF Domain 1, confirming contribution of LF antibodies to LT neutralization. This study documents the benefit of including an LF component to PA-based anthrax vaccines. Copyright © 2017 Elsevier Ltd. All rights reserved.

The origin of Behçet's disease geoepidemiology: possible role of a dual microbial-driven genetic selection.

PubMed

Piga, Matteo; Mathieu, Alessandro

2014-01-01

It is recognised that the genetic profiles that give rise to chronic inflammatory diseases, under the influence of environmental agents, might have been implicated in the host defence mechanism against lethal infections in the past. Behçet's disease (BD) is an immune-mediated inflammatory disease, expressed as vasculitis, triggered by environmental factors in genetically susceptible individuals. We carried out a review of published data to draw up an evolutionary adaptation model, as Author's perspective, for genetic susceptibility factors and inflammatory immune response involved in BD pathogenesis. Two lethal infectious agents, Plasmodium Falciparum and Yersinia Pestis, are proposed as the putative driving forces that favoured the fixing of the major genetic susceptibility factors to BD, thus determining its geoepidemiology. Further studies are needed to confirm the validity of this evolutionary model which includes and integrates the key insights of previous hypotheses.

Anthrax Pathogenesis.

PubMed

Moayeri, Mahtab; Leppla, Stephen H; Vrentas, Catherine; Pomerantsev, Andrei P; Liu, Shihui

2015-01-01

Anthrax is caused by the spore-forming, gram-positive bacterium Bacillus anthracis. The bacterium's major virulence factors are (a) the anthrax toxins and (b) an antiphagocytic polyglutamic capsule. These are encoded by two large plasmids, the former by pXO1 and the latter by pXO2. The expression of both is controlled by the bicarbonate-responsive transcriptional regulator, AtxA. The anthrax toxins are three polypeptides-protective antigen (PA), lethal factor (LF), and edema factor (EF)-that come together in binary combinations to form lethal toxin and edema toxin. PA binds to cellular receptors to translocate LF (a protease) and EF (an adenylate cyclase) into cells. The toxins alter cell signaling pathways in the host to interfere with innate immune responses in early stages of infection and to induce vascular collapse at late stages. This review focuses on the role of anthrax toxins in pathogenesis. Other virulence determinants, as well as vaccines and therapeutics, are briefly discussed.

Stability assessment of structures under earthquake hazard through GRID technology

NASA Astrophysics Data System (ADS)

Prieto Castrillo, F.; Boton Fernandez, M.

2009-04-01

This work presents a GRID framework to estimate the vulnerability of structures under earthquake hazard. The tool has been designed to cover the needs of a typical earthquake engineering stability analysis; preparation of input data (pre-processing), response computation and stability analysis (post-processing). In order to validate the application over GRID, a simplified model of structure under artificially generated earthquake records has been implemented. To achieve this goal, the proposed scheme exploits the GRID technology and its main advantages (parallel intensive computing, huge storage capacity and collaboration analysis among institutions) through intensive interaction among the GRID elements (Computing Element, Storage Element, LHC File Catalogue, federated database etc.) The dynamical model is described by a set of ordinary differential equations (ODE's) and by a set of parameters. Both elements, along with the integration engine, are encapsulated into Java classes. With this high level design, subsequent improvements/changes of the model can be addressed with little effort. In the procedure, an earthquake record database is prepared and stored (pre-processing) in the GRID Storage Element (SE). The Metadata of these records is also stored in the GRID federated database. This Metadata contains both relevant information about the earthquake (as it is usual in a seismic repository) and also the Logical File Name (LFN) of the record for its later retrieval. Then, from the available set of accelerograms in the SE, the user can specify a range of earthquake parameters to carry out a dynamic analysis. This way, a GRID job is created for each selected accelerogram in the database. At the GRID Computing Element (CE), displacements are then obtained by numerical integration of the ODE's over time. The resulting response for that configuration is stored in the GRID Storage Element (SE) and the maximum structure displacement is computed. Then, the corresponding Metadata containing the response LFN, earthquake magnitude and maximum structure displacement is also stored. Finally, the displacements are post-processed through a statistically-based algorithm from the available Metadata to obtain the probability of collapse of the structure for different earthquake magnitudes. From this study, it is possible to build a vulnerability report for the structure type and seismic data. The proposed methodology can be combined with the on-going initiatives to build a European earthquake record database. In this context, Grid enables collaboration analysis over shared seismic data and results among different institutions.

Role of the protective antigen octamer in the molecular mechanism of anthrax lethal toxin stabilization in plasma

PubMed Central

Kintzer, Alexander F.; Sterling, Harry J.; Tang, Iok I.; Abdul-Gader, Ali; Miles, Andrew J.; Wallace, B. A.; Williams, Evan R.; Krantz, Bryan A.

2010-01-01

Anthrax is caused by strains of Bacillus anthracis that produce two key virulence factors, anthrax toxin (Atx) and a poly-γ-D-glutamic acid capsule. Atx is comprised of three-proteins: protective antigen (PA) and two enzymes, lethal factor (LF) and edema factor (EF). To disrupt cell function, these components must assemble into holotoxin complexes, which contain either a ring-shaped homooctameric or homoheptameric PA oligomer bound to multiple copies of either LF and/or EF, producing lethal toxin (LT), edema toxin, or mixtures thereof. Once a host cell endocytoses these complexes, PA converts into a membrane-inserted channel that translocates LF and EF into the cytosol. LT may assemble on host cell surfaces or extracellularly in plasma. We show that under physiological conditions in bovine plasma that LT complexes containing heptameric PA aggregate and inactivate more readily than LT complexes containing octameric PA. LT complexes containing octameric PA possess enhanced stability, channel forming activity, and macrophage cytotoxicity relative to those containing heptameric PA. Under physiological conditions, multiple biophysical probes reveal that heptameric PA can prematurely adopt the channel conformation, but octameric PA complexes remain in their soluble prechannel configuration allowing them to resist aggregation and inactivation. We conclude that PA may form an octameric oligomeric state as a means to produce a more stable and active LT complex that may circulate freely in the blood. PMID:20433851

Low susceptibility of NC/Nga mice to tumor necrosis factor-alpha-mediated lethality and hepatocellular damage with D-galactosamine sensitization.

PubMed

Koide, Naoki; Morikawa, Akiko; Naiki, Yoshikazu; Tumurkhuu, Gantsetseg; Yoshida, Tomoaki; Ikeda, Hiroshi; Yokochi, Takashi

2009-02-01

The susceptibility of NC/Nga mice to tumor necrosis factor (TNF)-alpha was examined by using sensitization with d-galactosamine (d-GalN). Administration of TNF-alpha and d-GalN killed none of the NC/Nga mice, whereas it killed all of the BALB/c mice. Treatment with TNF-alpha and d-GalN caused few hepatic lesions in NC/Nga mice but massive hepatocellular apoptosis in BALB/c mice. Unlike BALB/c mice, there was no elevation in caspase 3 and 8 activities in the livers of NC/Nga mice receiving TNF-alpha and d-GalN. On the other hand, administration of anti-Fas antibody definitely killed both NC/Nga and BALB/c mice via activation of caspases 3 and 8. Treatment with TNF-alpha and d-GalN led to translocation of nuclear factor (NF)-kappaB in NC/Nga and BALB/c mice. However, NF-kappaB translocation was sustained in NC/Nga mice, although it disappeared in BALB/c mice 7 h after the treatment. NF-kappaB inhibitors activated caspases 3 and 8, and enhanced TNF-alpha-mediated lethality in NC/Nga. Taken together, the low susceptibility of NC/Nga mice to TNF-alpha-mediated lethality was suggested to be responsible for the sustained NF-kappaB activation.

The population genetics of human disease: The case of recessive, lethal mutations

PubMed Central

Gao, Ziyue; Baker, Zachary; Diesel, José Francisco; Simons, Yuval B.; Haque, Imran S.; Pickrell, Joseph; Przeworski, Molly

2017-01-01

Do the frequencies of disease mutations in human populations reflect a simple balance between mutation and purifying selection? What other factors shape the prevalence of disease mutations? To begin to answer these questions, we focused on one of the simplest cases: recessive mutations that alone cause lethal diseases or complete sterility. To this end, we generated a hand-curated set of 417 Mendelian mutations in 32 genes reported to cause a recessive, lethal Mendelian disease. We then considered analytic models of mutation-selection balance in infinite and finite populations of constant sizes and simulations of purifying selection in a more realistic demographic setting, and tested how well these models fit allele frequencies estimated from 33,370 individuals of European ancestry. In doing so, we distinguished between CpG transitions, which occur at a substantially elevated rate, and three other mutation types. Intriguingly, the observed frequency for CpG transitions is slightly higher than expectation but close, whereas the frequencies observed for the three other mutation types are an order of magnitude higher than expected, with a bigger deviation from expectation seen for less mutable types. This discrepancy is even larger when subtle fitness effects in heterozygotes or lethal compound heterozygotes are taken into account. In principle, higher than expected frequencies of disease mutations could be due to widespread errors in reporting causal variants, compensation by other mutations, or balancing selection. It is unclear why these factors would have a greater impact on disease mutations that occur at lower rates, however. We argue instead that the unexpectedly high frequency of disease mutations and the relationship to the mutation rate likely reflect an ascertainment bias: of all the mutations that cause recessive lethal diseases, those that by chance have reached higher frequencies are more likely to have been identified and thus to have been included in this study. Beyond the specific application, this study highlights the parameters likely to be important in shaping the frequencies of Mendelian disease alleles. PMID:28957316

Myc requires RhoA/SRF to reprogram glutamine metabolism.

PubMed

Haikala, Heidi M; Marques, Elsa; Turunen, Mikko; Klefström, Juha

2018-05-04

RhoA regulates actin cytoskeleton but recent evidence suggest a role for this conserved Rho GTPase also in other cellular processes, including transcriptional control of cell proliferation and survival. Interestingy, loss of RhoA is synthetic lethal with oncogenic Myc, a master transcription factor that turns on anabolic metabolism to promote cell growth in many cancers. We show evidence indicating that the synthetic lethal interaction between RhoA loss and Myc arises from deficiency in glutamine utilization, resulting from impaired co-regulation of glutaminase expression and anaplerosis by Myc and RhoA - serum response factor (SRF) pathway. The results suggest metabolic coordination between Myc and RhoA/SRF in sustaining cancer cell viability and indicate RhoA/SRF as a potential vulnerability in cancer cells for therapeutic targeting.

Mapping the epitopes of a neutralizing antibody fragment directed against the lethal factor of Bacillus anthracis and cross-reacting with the homologous edema factor.

PubMed

Thullier, Philippe; Avril, Arnaud; Mathieu, Jacques; Behrens, Christian K; Pellequer, Jean-Luc; Pelat, Thibaut

2013-01-01

The lethal toxin (LT) of Bacillus anthracis, composed of the protective antigen (PA) and the lethal factor (LF), plays an essential role in anthrax pathogenesis. PA also interacts with the edema factor (EF, 20% identity with LF) to form the edema toxin (ET), which has a lesser role in anthrax pathogenesis. The first recombinant antibody fragment directed against LF was scFv 2LF; it neutralizes LT by blocking the interaction between PA and LF. Here, we report that scFv 2LF cross-reacts with EF and cross-neutralizes ET, and we present an in silico method taking advantage of this cross-reactivity to map the epitope of scFv 2LF on both LF and EF. This method identified five epitope candidates on LF, constituted of a total of 32 residues, which were tested experimentally by mutating the residues to alanine. This combined approach precisely identified the epitope of scFv 2LF on LF as five residues (H229, R230, Q234, L235 and Y236), of which three were missed by the consensus epitope candidate identified by pre-existing in silico methods. The homolog of this epitope on EF (H253, R254, E258, L259 and Y260) was experimentally confirmed to constitute the epitope of scFv 2LF on EF. Other inhibitors, including synthetic molecules, could be used to target these epitopes for therapeutic purposes. The in silico method presented here may be of more general interest.

Reanalysis of parabiosis of obesity mutants in the age of leptin.

PubMed

Zeng, Wenwen; Lu, Yi-Hsueh; Lee, Jonah; Friedman, Jeffrey M

2015-07-21

In this study we set out to explain the differing effects of parabiosis with genetically diabetic (db) mice versus administration of recombinant leptin. Parabiosis of db mutant, which overexpress leptin, to wildtype (WT) or genetically obese (ob) mice has been reported to cause death by starvation, whereas leptin infusions do not produce lethality at any dose or mode of delivery tested. Leptin is not posttranslationally modified other than a single disulphide bond, raising the possibility that it might require additional factor(s) to exert the maximal appetite-suppressing effect. We reconfirmed the lethal effect of parabiosis of db mutant on WT mice and further showed that this lethality could not be rescued by administration of ghrelin or growth hormone. We then initiated a biochemical fractionation of a high-molecular-weight leptin complex from human plasma and identified clusterin as a major component of this leptin-containing complex. However, in contrast to previous reports, we failed to observe a leptin-potentiating effect of either exogenous or endogenous clusterin, and parabiosis of db clusterin(-/-) double-mutant to WT mice still caused lethality. Intriguingly, in parabiotic pairs of two WT mice, leptin infusion into one of the mice led to an enhanced starvation response during calorie restriction as evidenced by increased plasma ghrelin and growth-hormone levels. Moreover, leptin treatment resulted in death of the parabiotic pairs. These data suggest that the appetite suppression in WT mice after parabiosis to db mutants is the result of induced hyperleptinemia combined with the stress or other aspect(s) of the parabiosis procedure.

Reanalysis of parabiosis of obesity mutants in the age of leptin

PubMed Central

Zeng, Wenwen; Lu, Yi-Hsueh; Lee, Jonah; Friedman, Jeffrey M.

2015-01-01

In this study we set out to explain the differing effects of parabiosis with genetically diabetic (db) mice versus administration of recombinant leptin. Parabiosis of db mutant, which overexpress leptin, to wildtype (WT) or genetically obese (ob) mice has been reported to cause death by starvation, whereas leptin infusions do not produce lethality at any dose or mode of delivery tested. Leptin is not posttranslationally modified other than a single disulphide bond, raising the possibility that it might require additional factor(s) to exert the maximal appetite-suppressing effect. We reconfirmed the lethal effect of parabiosis of db mutant on WT mice and further showed that this lethality could not be rescued by administration of ghrelin or growth hormone. We then initiated a biochemical fractionation of a high-molecular-weight leptin complex from human plasma and identified clusterin as a major component of this leptin-containing complex. However, in contrast to previous reports, we failed to observe a leptin-potentiating effect of either exogenous or endogenous clusterin, and parabiosis of db clusterin−/− double-mutant to WT mice still caused lethality. Intriguingly, in parabiotic pairs of two WT mice, leptin infusion into one of the mice led to an enhanced starvation response during calorie restriction as evidenced by increased plasma ghrelin and growth-hormone levels. Moreover, leptin treatment resulted in death of the parabiotic pairs. These data suggest that the appetite suppression in WT mice after parabiosis to db mutants is the result of induced hyperleptinemia combined with the stress or other aspect(s) of the parabiosis procedure. PMID:26150485

Smyd1 Facilitates Heart Development by Antagonizing Oxidative and ER Stress Responses

PubMed Central

Park, Chong Yon; Harriss, June; Pierce, Stephanie A.; Dekker, Joseph D.; Valenzuela, Nicolas; Srivastava, Deepak; Schwartz, Robert J.; Stewart, M. David; Tucker, Haley O.

2015-01-01

Smyd1/Bop is an evolutionary conserved histone methyltransferase previously shown by conventional knockout to be critical for embryonic heart development. To further explore the mechanism(s) in a cell autonomous context, we conditionally ablated Smyd1 in the first and second heart fields of mice using a knock-in (KI) Nkx2.5-cre driver. Robust deletion of floxed-Smyd1 in cardiomyocytes and the outflow tract (OFT) resulted in embryonic lethality at E9.5, truncation of the OFT and right ventricle, and additional defects consistent with impaired expansion and proliferation of the second heart field (SHF). Using a transgenic (Tg) Nkx2.5-cre driver previously shown to not delete in the SHF and OFT, early embryonic lethality was bypassed and both ventricular chambers were formed; however, reduced cardiomyocyte proliferation and other heart defects resulted in later embryonic death at E11.5-12.5. Proliferative impairment prior to both early and mid-gestational lethality was accompanied by dysregulation of transcripts critical for endoplasmic reticulum (ER) stress. Mid-gestational death was also associated with impairment of oxidative stress defense—a phenotype highly similar to the previously characterized knockout of the Smyd1-interacting transcription factor, skNAC. We describe a potential feedback mechanism in which the stress response factor Tribbles3/TRB3, when directly methylated by Smyd1, acts as a co-repressor of Smyd1-mediated transcription. Our findings suggest that Smyd1 is required for maintaining cardiomyocyte proliferation at minimally two different embryonic heart developmental stages, and its loss leads to linked stress responses that signal ensuing lethality. PMID:25803368

Mutations in the histone fold domain of the TAF12 gene show synthetic lethality with the TAF1 gene lacking the TAF N-terminal domain (TAND) by different mechanisms from those in the SPT15 gene encoding the TATA box-binding protein (TBP)

PubMed Central

Kobayashi, Akiko; Miyake, Tsuyoshi; Kawaichi, Masashi; Kokubo, Tetsuro

2003-01-01

The general transcription factor TFIID, composed of the TATA box-binding protein (TBP) and 14 TBP-associated factors (TAFs), is important for both basal and regulated transcription by RNA polymerase II. Although it is well known that the TAF N-terminal domain (TAND) at the amino-terminus of the TAF1 protein binds to TBP and thereby inhibits TBP function in vitro, the physiological role of this domain remains obscure. In our previous study, we screened for mutations that cause lethality when co-expressed with the TAF1 gene lacking TAND (taf1-ΔTAND) and identified two ΔTAND synthetic lethal (nsl) mutations as those in the SPT15 gene encoding TBP. In this study we isolated another nsl mutation in the same screen and identified it to be a mutation in the histone fold domain (HFD) of the TAF12 gene. Several other HFD mutations of this gene also exhibit nsl phenotypes, and all of them are more or less impaired in transcriptional activation in vivo. Interestingly, a set of genes affected in the taf1-ΔTAND mutant is similarly affected in the taf12 HFD mutants but not in the nsl mutants of TBP. Therefore, we discovered that the nsl mutations of these two genes cause lethality in the taf1-ΔTAND mutant by different mechanisms. PMID:12582246

Evaluating a 4-marker signature of aggressive prostate cancer using time-dependent AUC.

PubMed

Gerke, Travis A; Martin, Neil E; Ding, Zhihu; Nuttall, Elizabeth J; Stack, Edward C; Giovannucci, Edward; Lis, Rosina T; Stampfer, Meir J; Kantoff, Phillip W; Parmigiani, Giovanni; Loda, Massimo; Mucci, Lorelei A

2015-12-01

We previously identified a protein tumor signature of PTEN, SMAD4, SPP1, and CCND1 that, together with clinical features, was associated with lethal outcomes among prostate cancer patients. In the current study, we sought to validate the molecular model using time-dependent measures of AUC and predictive values for discriminating lethal from non-lethal prostate cancer. Using data from the initial study, we fit survival models for men with prostate cancer who were participants in the Physicians' Health Study (PHS; n = 276). Based on these models, we generated prognostic risk scores in an independent population, the Health Professionals Follow-up Study (HPFS; n = 347) to evaluate external validity. In each cohort, men were followed prospectively from cancer diagnosis through 2011 for development of distant metastasis or cancer mortality. We measured protein tumor expression of PTEN, SMAD4, SPP1, and CCND1 on tissue microarrays. During a median of 11.9 and 14.3 years follow-up in the PHS and HPFS cohorts, 24 and 32 men (9%) developed lethal disease. When used as a prognostic factor in a new population, addition of the four markers to clinical variables did not improve discriminatory accuracy through 15 years of follow-up. Although the four markers have been identified as key biological mediators in metastatic progression, they do not provide independent, long-term prognostic information beyond clinical factors when measured at diagnosis. This finding may underscore the broad heterogeneity in aggressive prostate tumors and highlight the challenges that may result from overfitting in discovery-based research. © 2015 Wiley Periodicals, Inc.

[An investigation on self-harm episodes and their relationship with suicidal psychology and behaviors in 2713 college students].

PubMed

Su, Pu-Yu; Hao, Jia-Hu; Huang, Zhao-Hui; Tao, Fang-Biao

2010-11-01

To investigate the episodes and influencing factors on self-harm and to explore the relationship between self-harm episodes and suicidal psychology and behaviors in college students. Four universities were selected using cluster sampling method in Anqing city and Chaohu city. Totally, 2713 college students completed this survey. Data were analyzed by Pearson Chi-square and logistic regression. In the last six months, rates of highly lethal self-harm, less lethal self-harm with visible tissue damage, self-injury without visible tissue damage, self-harmful behaviors with latency damage, other self-harmful behaviors with menticide were 1.9%, 5.5%, 15.3%, 21.2% and 17.0% respectively. The total rate of self-harm was 31.3%. 73.1% of the students with self harmful experiences had the above mentioned behaviors more than 3 times in the last six months. The top 3 reasons for taking self-harm actions were: having learning problems (43.1%), failed love affairs (25.0%) and having conflicts with others (23.9%). There were different influencing factors among different kinds of self-harm episodes. Depression was the risk factor of self-harm. The higher score of having high self-esteem was the protective factor of all kinds of self-harm actions except highly lethal ones. Higher score of difficulties in identifying feelings was one of the risk factors. The rates of suicidal psychology and behaviors in students with self-harm were significantly higher than those in students without those behaviors. Result from linear χ(2) test indicated that the graveness of tissue damage of self-harm was higher along with the rates of suicidal psychology and behaviors (P < 0.01). Among 2713 college students, about 1/3 adolescents having experienced self-harm in the last 6 months, many with repeated ones. Depression and difficulties in identifying feelings were the two risk factors while self-esteem was the protective factor related to most of the self-harm cases.

Prevention of suicidal behavior

PubMed Central

Hegerl, Ulrich

2016-01-01

More than 800 000 people die every year from suicide, and about 20 times more attempt suicide. In most countries, suicide risk is highest in older males, and risk of attempted suicide is highest in younger females. The higher lethal level of suicidal acts in males is explained by the preference for more lethal methods, as well as other factors. In the vast majority of cases, suicidal behavior occurs in the context of psychiatric disorders, depression being the most important one. Improving the treatment of depression, restricting access to lethal means, and avoiding the Werther effect (imitation suicide) are central aspects of suicide prevention programs. In several European regions, the four-level intervention concept of the European Alliance Against Depression (www.EAAD.net), simultaneously targeting depression and suicidal behavior, has been found to have preventive effects on suicidal behavior. It has already been implemented in more than 100 regions in Europe. PMID:27489458

Interactive lethal and mutagenic effects of ultraviolet light and bleomycin in yeast: synergism or antagonism?

PubMed

Lillo, O L; Severgnini, A A; Nunes, E M

1997-11-01

The mutagenic interactions of ultraviolet light and bleomycin in haploid populations of Saccharomyces cerevisiae were analyzed. Survival and mutation frequency as a function of different bleomycin concentrations after one conditioning dose of UV radiation were determined. Furthermore, corresponding interaction functions and sensitization factors were calculated. A synergistic interaction between UV light and bleomycin was shown for both lethal and mutagenic events when the cells were in nutrient broth during the treatments. Conversely, the interaction between UV light and bleomycin was antagonistic when the cells were in deionized water during the treatment. The magnitude of lethal and mutagenic interactions depends on dose, and thus presumably on the number of lesions. The observed interactions between UV light and bleomycin suggest that the mechanism that is most likely involved is the induction of repair systems with different error probabilities during the delay of cell division.

alpha-Galactosylceramide (AGL-517) treatment protects mice from lethal irradiation.

PubMed

Inoue, H; Koezuka, Y; Nishi, N; Osawa, M; Motoki, K; Kobayashi, E; Kabaya, K; Obuchi, M; Fukushima, H; Mori, K J

1997-08-01

AGL-517 (AGL) has an alpha-galactosylceramide structure and is a derivative of agelasphin-9b, which in turn is isolated from Agelas mauritianus and has immunomodulating activity. When administered before irradiation, AGL has been found to increase survival rates in lethally irradiated mice. In this study, we found that a single injection of AGL administered within 2 hours of lethal irradiation resulted in the long-term survival of mice without bone marrow transplantation. Peripheral blood hematology showed that AGL administration accelerated the recovery of hematopoietic parameters, including reticulocytes and red and white blood cells. Recovery of platelets was moderate. In addition, AGL significantly increased the number of endogenous colony forming units-spleen (E-CFU-S). AGL itself displayed no colony-stimulating activity, but AGL-stimulated spleen cell-conditioned medium (AGL-SCM) promoted the proliferation and differentiation of bone marrow mononuclear cells from normal mice and Lin marrow cells from 5-fluorouracil (5-FU)-treated mice. Using suitable assay systems, we analyzed cytokines in AGL-SCM and found significant increases in stem cell factor (SCF), interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-6 levels compared with control SCM. Additionally, using immunoenzymetric assays, we assessed serum levels of these factors in AGL-treated mice after lethal irradiation. The serum concentrations of IL-3, GM-CSF, and IL-6 were substantially elevated, the maximum levels being reached within 2 hours of injection. Despite inducing the in vitro increase in SCF, AGL did not elevate serum SCF levels. However, certain levels of SCF (approximately 5 ng/mL) were detected in mouse serum regardless of irradiation or AGL treatment. When irradiated mice were given a cytokine cocktail composed of recombinant murine (rm) IL-3, rmGM-CSF, and recombinant human (rh) IL-6 three times a day for 6 days (1 microg of each factor per mouse per day) starting 2 hours after irradiation, 60% of the mice achieved 50-day survival. The radioprotective effect of AGL can be attributed, in part, to the cooperative effect of the cytokines induced by AGL in vivo. These findings suggest that AGL may be a useful in treating radiation-induced hematopoietic damage.

Cardiac Med1 deletion promotes early lethality, cardiac remodeling, and transcriptional reprogramming

PubMed Central

Spitler, Kathryn M.; Ponce, Jessica M.; Oudit, Gavin Y.; Hall, Duane D.

2017-01-01

The mediator complex, a multisubunit nuclear complex, plays an integral role in regulating gene expression by acting as a bridge between transcription factors and RNA polymerase II. Genetic deletion of mediator subunit 1 (Med1) results in embryonic lethality, due in large part to impaired cardiac development. We first established that Med1 is dynamically expressed in cardiac development and disease, with marked upregulation of Med1 in both human and murine failing hearts. To determine if Med1 deficiency protects against cardiac stress, we generated two cardiac-specific Med1 knockout mouse models in which Med1 is conditionally deleted (Med1cKO mice) or inducibly deleted in adult mice (Med1cKO-MCM mice). In both models, cardiac deletion of Med1 resulted in early lethality accompanied by pronounced changes in cardiac function, including left ventricular dilation, decreased ejection fraction, and pathological structural remodeling. We next defined how Med1 deficiency alters the cardiac transcriptional profile using RNA-sequencing analysis. Med1cKO mice demonstrated significant dysregulation of genes related to cardiac metabolism, in particular genes that are coordinated by the transcription factors Pgc1α, Pparα, and Errα. Consistent with the roles of these transcription factors in regulation of mitochondrial genes, we observed significant alterations in mitochondrial size, mitochondrial gene expression, complex activity, and electron transport chain expression under Med1 deficiency. Taken together, these data identify Med1 as an important regulator of vital cardiac gene expression and maintenance of normal heart function. NEW & NOTEWORTHY Disruption of transcriptional gene expression is a hallmark of dilated cardiomyopathy; however, its etiology is not well understood. Cardiac-specific deletion of the transcriptional coactivator mediator subunit 1 (Med1) results in dilated cardiomyopathy, decreased cardiac function, and lethality. Med1 deletion disrupted cardiac mitochondrial and metabolic gene expression patterns. PMID:28159809

Pathways to Late-Life Suicidal Behavior: Cluster Analysis and Predictive Validation of Suicidal Behavior in a Sample of Older Adults With Major Depression.

PubMed

Szanto, Katalin; Galfalvy, Hanga; Vanyukov, Polina M; Keilp, John G; Dombrovski, Alexandre Y

Clinical heterogeneity is a key challenge to understanding suicidal risk, as different pathways to suicidal behavior are likely to exist. We aimed to identify such pathways by uncovering latent classes of late-life depression cases and relating them to prior and future suicidal behavior. Data were collected from June 2010 to September 2015. In this longitudinal study we examined distinct associations of clinical and cognitive/decision-making factors with suicidal behavior in 194 older (50+ years) nondemented, depressed patients; 57 nonpsychiatric healthy controls provided benchmark data. The DSM-IV was used to establish diagnostic criteria. We identified multivariate patterns of risk factors, defining clusters based on personality traits, perceived social support, cognitive performance, and decision-making in an analysis blinded to participants' history of suicidal behavior. We validated these clusters using past and prospective suicidal ideation and behavior. Of 5 clusters identified, 3 were associated with high risk for suicidal behavior: (1) cognitive deficits, dysfunctional personality, low social support, high willingness to delay future rewards, and overrepresentation of high-lethality attempters; (2) high-personality pathology (ie, low self-esteem), minimal or no cognitive deficits, and overrepresentation of low-lethality attempters and ideators; (3) cognitive deficits, inability to delay future rewards, and similar distribution of high- and low-lethality attempters. There were significant between-cluster differences in number (P < .001) and lethality (P = .002) of past suicide attempts and in the likelihood of future suicide attempts (P = .010, 30 attempts by 22 patients, 2 fatal) and emergency psychiatric hospitalizations to prevent suicide (P = .005, 31 participants). Three pathways to suicidal behavior in older patients were found, marked by (1) very high levels of cognitive and dispositional risk factors suggesting a dementia prodrome, (2) dysfunctional personality traits, and (3) impulsive decision-making and cognitive deficits. © Copyright 2018 Physicians Postgraduate Press, Inc.

Modeling response of species to microcontaminants: comparative ecotoxicology by (sub)lethal body burdens as a function of species size and partition ratio of chemicals.

PubMed

Hendriks, A J

1995-11-01

A model was designed and calibrated with accumulation data to calculate the internal concentrations of microcontaminants in organisms as a function of a few constants and variables. The main factors are the exposure time, the external exposure concentration, the partition ratio of the compound, and the size of the taxon concerned. The model was applied to calculate the lethal and sublethal body burdens of several priority compounds and some major taxa. Estimations were generally confirmed at the order of magnitude level by measured residues and applied doses if available. According to the estimations, most priority compounds chosen were critical for most taxa above internal concentrations of 0.1 mmol.kg-1 wet wt. Trichloromethane, 1,2,4-trichlorobenzene, and hexachlorobenzene were lethal above this level only, whereas other organic microcontaminants affected at least some taxa at lower body burdens. The log(Kow) of the organic compounds ranged from 2.0 to 7.0. Keeping in mind that bioconcentration and -magnification ratios for metals may be quite variable, the lowest critical residues estimated were just below the value of 0.1 mmol.kg-1 wet wt. Here, external concentrations encountered in natural habitats seem to be a promising tool for predictive comparative ecotoxicology. The critical body burdens for plants and invertebrates may have been overestimated due to uncertainty about the parameters. Among the different taxa, however, the fish families chosen (Salmonidae and Cyprinidae) seem to be most sensitive to most compounds. Internal response concentrations of the herbicide atrazine were the lowest in micro- and macrophytes, whereas parathion affected invertebrates at low levels. The database that provided the external response concentrations was also consulted to estimate so-called extrapolation or safety factors. On average, long-term no effect concentrations in water are estimated to be about 10-30 times below short-term median lethal levels. In general, short-term versus long-term, lethal versus sublethal, and median versus no response concentration ratios each contributed factors of about 2-3 to this overall ratio. The model for internal concentrations indicated that the ratio between the short-term and the long-term LC50 will be high for large species and high octanol-water partition ratios.

Complement component 5 promotes lethal thrombosis

PubMed Central

Mizuno, Tomohiro; Yoshioka, Kengo; Mizuno, Masashi; Shimizu, Mie; Nagano, Fumihiko; Okuda, Tomoyuki; Tsuboi, Naotake; Maruyama, Shoichi; Nagamatsu, Tadashi; Imai, Masaki

2017-01-01

Extracellular histones promote platelet aggregation and thrombosis; this is followed by induction of coagulation disorder, which results in exhaustion of coagulation factors. Complement component 5 (C5) is known to be associated with platelet aggregation and coagulation system activation. To date, the pathological mechanism underlying liver injury has remained unclear. Here, we investigated whether C5 promotes liver injury associated with histone-induced lethal thrombosis. C5-sufficient and C5-deficient mice received single tail vein injections of purified, unfractionated histones obtained from calf thymus (45–75 μg/g). Subsequently, the mice were monitored for survival for up to 72 h. Based on the survival data, the 45 μg/g dose was used for analysis of blood cell count, liver function, blood coagulation ability, and promotion of platelet aggregation and platelet/leukocyte aggregate (PLA) production by extracellular histones. C5-deficient mice were protected from lethal thrombosis and had milder thrombocytopenia, consumptive coagulopathy, and liver injury with embolism and lower PLA production than C5-sufficient mice. These results indicate that C5 is associated with coagulation disorders, PLA production, and embolism-induced liver injury. In conclusion, C5 promotes liver injury associated with histone-induced lethal thrombosis. PMID:28205538

Synthetic Lethal Therapy for KRAS Mutant Non-small-cell Lung Carcinoma with Nanoparticle-mediated CDK4 siRNA Delivery

PubMed Central

Mao, Cheng-Qiong; Xiong, Meng-Hua; Liu, Yang; Shen, Song; Du, Xiao-Jiao; Yang, Xian-Zhu; Dou, Shuang; Zhang, Pei-Zhuo; Wang, Jun

2014-01-01

The KRAS mutation is present in ~20% of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in non-small-cell lung carcinomas (NSCLCs) and confers resistance to standard anticancer treatment drugs, including epidermal growth factor receptor tyrosine kinase inhibitors. In this study, we exploited a new therapeutic strategy based on the synthetic lethal interaction between cyclin-dependent kinase 4 (CDK4) downregulation and the KRAS mutation to deliver micellar nanoparticles (MNPs) containing small interfering RNA targeting CDK4 (MNPsiCDK4) for treatment in NSCLCs harboring the oncogenic KRAS mutation. Following MNPsiCDK4 administration, CDK4 expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLCs. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4 significantly inhibited tumor growth in an A549 NSCLC xenograft murine model, with depressed expression of CDK4 and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4 delivery in KRAS mutant NSCLCs via a synthetic lethal interaction between KRAS and CDK4. PMID:24496383

[High anion gap metabolic acidosis (pyroglutamic acidosis) induced by chronic acetaminophen use].

PubMed

Tchougang Nono, J; Mistretta, V; Noirot, I; Canivet, J L; Damas, P

2018-01-01

Acetaminophen is the most consumable analgesic in the world in the form of medical prescription or self-medication. It is one of the active ingredients most often involved in voluntary poisoning. Lethal dose of acetaminophen classically induces acute hepatic failure on hepatic necrosis. Chronic intake of sub-lethal doses (i.e. near recommended therapeutic doses) of acetaminophen in the presence of certain risk factors may be responsible for another much less recognized pathological manifestation: severe metabolic acidosis with an increased anion gap due to the accumulation of 5-oxoproline or pyroglutamic acid.

Shortened Lifespan and Lethal Hemorrhage in a Hemophilia A Mouse Model.

PubMed

Staber, Janice M; Pollpeter, Molly J

2016-01-01

Hemophilia A animal models have helped advance our understanding of factor VIII deficiency. Previously, factor VIII deficient mouse models were reported to have a normal life span without spontaneous bleeds. However, the bleeding frequency and survival in these animals has not been thoroughly evaluated. To investigate the survival and lethal bleeding frequency in two strains of E-16 hemophilia A mice. We prospectively studied factor VIII deficient hemizygous affected males (n = 83) and homozygous affected females (n = 55) for survival and bleeding frequency. Animals were evaluated for presence and location of bleeds as potential cause of death. Hemophilia A mice had a median survival of 254 days, which is significantly shortened compared to wild type controls (p < 0.0001). In addition, the hemophilia A mice experienced hemorrhage in several tissues. This previously-underappreciated shortened survival in the hemophilia A murine model provides new outcomes for investigation of therapeutics and also reflects the shortened lifespan of patients if left untreated.

Combined Administration of Recombinant Human Megakaryocyte Growth and Development Factor and Granulocyte Colony-Stimulating Factor Enhances Multilineage Hematopoietic Reconstitution in Nonhuman Primates after Radiation-Induced Marrow Aplasia

DTIC Science & Technology

1996-05-01

dose would yield an equivalent or better biological activity. Neupogen ® ( Filgrastim ), r-metHuG-CSF, was produced in E. coli as a...recombinant human granulocyte colony-stimulating factor on hematopoiesis of normal dogs and on hematopoi- etic recovery after otherwise lethal total body

Are High-Lethality Suicide Attempters With Bipolar Disorder a Distinct Phenotype?

PubMed Central

Oquendo, Maria A.; Carballo, Juan Jose; Rajouria, Namita; Currier, Dianne; Tin, Adrienne; Merville, Jessica; Galfalvy, Hanga C.; Sher, Leo; Grunebaum, Michael F.; Burke, Ainsley K.; Mann, J. John

2013-01-01

Because Bipolar Disorder (BD) individuals making highly lethal suicide attempts have greater injury burden and risk for suicide, early identification is critical. BD patients were classified as high- or low-lethality attempters. High-lethality attempts required inpatient medical treatment. Mixed effects logistic regression models and permutation analyses examined correlations between lethality, number, and order of attempts. High-lethality attempters reported greater suicidal intent and more previous attempts. Multiple attempters showed no pattern of incremental lethality increase with subsequent attempts, but individuals with early high-lethality attempts more often made high-lethality attempts later. A subset of high-lethality attempters make only high-lethality attempts. However, presence of previous low-lethality attempts does not indicate that risk for more lethal, possibly successful, attempts is reduced. PMID:19590998

What Are Reasons for the Large Gender Differences in the Lethality of Suicidal Acts? An Epidemiological Analysis in Four European Countries

PubMed Central

Heinrichs, Katherina; Székely, András; Tóth, Mónika Ditta; Coyne, James; Quintão, Sónia; Arensman, Ella; Coffey, Claire; Maxwell, Margaret; Värnik, Airi; van Audenhove, Chantal; McDaid, David; Sarchiapone, Marco; Schmidtke, Armin; Genz, Axel; Gusmão, Ricardo; Hegerl, Ulrich

2015-01-01

Background In Europe, men have lower rates of attempted suicide compared to women and at the same time a higher rate of completed suicides, indicating major gender differences in lethality of suicidal behaviour. The aim of this study was to analyse the extent to which these gender differences in lethality can be explained by factors such as choice of more lethal methods or lethality differences within the same suicide method or age. In addition, we explored gender differences in the intentionality of suicide attempts. Methods and Findings Methods. Design: Epidemiological study using a combination of self-report and official data. Setting: Mental health care services in four European countries: Germany, Hungary, Ireland, and Portugal. Data basis: Completed suicides derived from official statistics for each country (767 acts, 74.4% male) and assessed suicide attempts excluding habitual intentional self-harm (8,175 acts, 43.2% male). Main Outcome Measures and Data Analysis. We collected data on suicidal acts in eight regions of four European countries participating in the EU-funded “OSPI-Europe”-project (www.ospi-europe.com). We calculated method-specific lethality using the number of completed suicides per method * 100 / (number of completed suicides per method + number of attempted suicides per method). We tested gender differences in the distribution of suicidal acts for significance by using the χ2-test for two-by-two tables. We assessed the effect sizes with phi coefficients (φ). We identified predictors of lethality with a binary logistic regression analysis. Poisson regression analysis examined the contribution of choice of methods and method-specific lethality to gender differences in the lethality of suicidal acts. Findings Main Results Suicidal acts (fatal and non-fatal) were 3.4 times more lethal in men than in women (lethality 13.91% (regarding 4106 suicidal acts) versus 4.05% (regarding 4836 suicidal acts)), the difference being significant for the methods hanging, jumping, moving objects, sharp objects and poisoning by substances other than drugs. Median age at time of suicidal behaviour (35–44 years) did not differ between males and females. The overall gender difference in lethality of suicidal behaviour was explained by males choosing more lethal suicide methods (odds ratio (OR) = 2.03; 95% CI = 1.65 to 2.50; p < 0.000001) and additionally, but to a lesser degree, by a higher lethality of suicidal acts for males even within the same method (OR = 1.64; 95% CI = 1.32 to 2.02; p = 0.000005). Results of a regression analysis revealed neither age nor country differences were significant predictors for gender differences in the lethality of suicidal acts. The proportion of serious suicide attempts among all non-fatal suicidal acts with known intentionality (NFSAi) was significantly higher in men (57.1%; 1,207 of 2,115 NFSAi) than in women (48.6%; 1,508 of 3,100 NFSAi) (χ2 = 35.74; p < 0.000001). Main limitations of the study Due to restrictive data security regulations to ensure anonymity in Ireland, specific ages could not be provided because of the relatively low absolute numbers of suicide in the Irish intervention and control region. Therefore, analyses of the interaction between gender and age could only be conducted for three of the four countries. Attempted suicides were assessed for patients presenting to emergency departments or treated in hospitals. An unknown rate of attempted suicides remained undetected. This may have caused an overestimation of the lethality of certain methods. Moreover, the detection of attempted suicides and the registration of completed suicides might have differed across the four countries. Some suicides might be hidden and misclassified as undetermined deaths. Conclusions Men more often used highly lethal methods in suicidal behaviour, but there was also a higher method-specific lethality which together explained the large gender differences in the lethality of suicidal acts. Gender differences in the lethality of suicidal acts were fairly consistent across all four European countries examined. Males and females did not differ in age at time of suicidal behaviour. Suicide attempts by males were rated as being more serious independent of the method used, with the exceptions of attempted hanging, suggesting gender differences in intentionality associated with suicidal behaviour. These findings contribute to understanding of the spectrum of reasons for gender differences in the lethality of suicidal behaviour and should inform the development of gender specific strategies for suicide prevention. PMID:26147965

Human prevalence of the spotted fever group (SFG) rickettsiae in endemic zones of Northwestern Colombia.

PubMed

Londoño, Andrés F; Acevedo-Gutiérrez, Leidy Y; Marín, Diana; Contreras, Verónica; Díaz, Francisco J; Valbuena, Gustavo; Labruna, Marcelo B; Hidalgo, Marylin; Arboleda, Margarita; Mattar, Salim; Solari, Sergio; Rodas, Juan D

2017-06-01

In February 2006, an outbreak of human rickettsiosis occurred in the municipality of Necoclí Colombia, with 35% of lethality. This episode was, followed by two more, one in the municipality of Los Cordobas in 2007 with a 54% of lethality and the other one in the municipality of Turbo in 2008 with 27% of lethality. The aim of this study was to perform serological tests in healthy persons to determine the seroprevalence of antibodies against spotted fever group (SFG) rickettsiae and develop a survey to study some infection risk-related factors. A cross-sectional study was performed in 2011 and 2012. A blood sample and survey of associated factors was performed in healthy persons. A prevalence of 32%-41% was found in healthy people. From the multivariate analysis, we found that people living more than 16 years in these sites had a 79% higher risk of being seropositive and a 46% higher risk when they reported having birds in their houses if the variable of having a horse was included in the model. In conclusion, this study shows endemicity of at least one spotted fever group Rickettsia in the study zone. Copyright © 2017 Elsevier GmbH. All rights reserved.

Cardiovascular effects of equinatoxin III from the sea anemone Actinia equina (L.).

PubMed

Suput, D; Frangez, R; Bunc, M

2001-09-01

Equinatoxin III is the most hemolytic, and the least lethal of the three basic proteins isolated from the sea anemone Actinia equina (L.). Its LD50 in mice is 83 microg/kg. Preliminary results on Wistar rats have suggested cardiorespiratory arrest as a putative cause of death, but the mechanism of its action has not yet been studied. So far only equinatoxin II has been investigated more thoroughly. As equinatoxin II is less lythic, but more toxic, than equinatoxin III (its LD50 in mice=35 microg/kg), it may be assumed that haemolysis with a consequent rise in plasma potassium level is not the major factor in the lethality of equinatoxins. To assess the relative contribution of hyperkalemia in the lethality of the toxin in rat, the effects of equinatoxin III were compared to the effects of hyperkalemia caused by the injection of KCl giving the same final concentration of K+ in the plasma as that observed after an i.v. injection of 3LD50 of equinatoxin III. As coronary vasoconstriction may be an important mechanism of the cardiotoxic action of equinatoxins, the effect of EqT III on isolated porcine coronary arteries was studied by measurements of smooth muscle tension in the presence of 1-100 nM equinatoxin III. The results revealed that animals survive the elevated K+ plasma concentration caused by an i.v. application of KCl. This suggests that equinatoxin III induced haemolysis is not the major mechanism of equinatoxin III lethality. However, equinatoxin III increases the potassium induced contractions of coronary smooth muscle for 289+/-29%, suggesting that coronary vasoconstriction may be an important factor in the cardiotoxic effects of equinatoxin III.

Access to means of suicide, occupation and the risk of suicide: a national study over 12 years of coronial data.

PubMed

Milner, A; Witt, K; Maheen, H; LaMontagne, A D

2017-04-04

Availability of lethal means is a significant risk factor for suicide. This study investigated whether occupations with greater access to lethal means had higher suicide rates than those without access, and further, whether this relationship differed for females versus males. A retrospective mortality study was conducted across the Australian population over the period 2001 to 2012. Data from the Australian Bureau of Statistics, which collects Census information on occupation for the Australian population, and the National Coroners Information System, which records information on suicide deaths, were combined. Employed suicide records were coded by occupation and work-related access to lethal means. Descriptive analysis and negative binomial regression were used to assess the relationship between access to means and suicide. Persons in occupations with access to firearms, medicines or drugs, and carbon monoxide more frequently used these methods to end their lives than those without access to means. Females employed in occupations with access to means had suicide rates that were 3.02 times greater (95% CI 2.60 to 3.50, p < 0.001) than those employed in occupations without access. Males in occupations with access had suicide rates that were 1.24 times greater than those without access (95% CI 1.16 to 1.33, p < 0.001). Work-related access to means is a risk factor for suicide in the employed population, but is associated with a greater risk for females than males. The findings of this study suggest the importance of controlling access to lethal methods in occupations where these are readily available.

Standard sub-thermoneutral caging temperature influences radiosensitivity of hematopoietic stem and progenitor cells.

PubMed

Povinelli, Benjamin J; Kokolus, Kathleen M; Eng, Jason W-L; Dougher, Christopher W; Curtin, Leslie; Capitano, Maegan L; Sailsbury-Ruf, Christi T; Repasky, Elizabeth A; Nemeth, Michael J

2015-01-01

The production of new blood cells relies on a hierarchical network of hematopoietic stem and progenitor cells (HSPCs). To maintain lifelong hematopoiesis, HSPCs must be protected from ionizing radiation or other cytotoxic agents. For many years, murine models have been a valuable source of information regarding factors that either enhance or reduce the survival of HSPCs after exposure of marrow to ionizing radiation. In a recent series of studies, however, it has become clear that housing-related factors such as the cool room temperature required for laboratory mice can exert a surprising influence on the outcome of experiments. Here we report that the mild, but chronic cold-stress endured by mice housed under these conditions exerts a protective effect on HSPCs after both non-lethal and lethal doses of total body irradiation (TBI). Alleviation of this cold-stress by housing mice at a thermoneutral temperature (30°C) resulted in significantly greater baseline radiosensitivity to a lethal dose of TBI with more HSPCs from mice housed at thermoneutral temperature undergoing apoptosis following non-lethal TBI. Cold-stressed mice have elevated levels of norepinephrine, a key molecule of the sympathetic nervous system that binds to β-adrenergic receptors. We show that blocking this signaling pathway in vivo through use of the β-blocker propanolol completely mitigates the protective effect of cold-stress on HSPC apoptosis. Collectively this study demonstrates that chronic stress endured by the standard housing conditions of laboratory mice increases the resistance of HSPCs to TBI-induced apoptosis through a mechanism that depends upon β-adrenergic signaling. Since β-blockers are commonly prescribed to a wide variety of patients, this information could be important when predicting the clinical impact of HSPC sensitivity to TBI.

Standard Sub-Thermoneutral Caging Temperature Influences Radiosensitivity of Hematopoietic Stem and Progenitor Cells

PubMed Central

Eng, Jason W.-L.; Dougher, Christopher W.; Curtin, Leslie; Capitano, Maegan L.; Sailsbury-Ruf, Christi T.; Repasky, Elizabeth A.; Nemeth, Michael J.

2015-01-01

The production of new blood cells relies on a hierarchical network of hematopoietic stem and progenitor cells (HSPCs). To maintain lifelong hematopoiesis, HSPCs must be protected from ionizing radiation or other cytotoxic agents. For many years, murine models have been a valuable source of information regarding factors that either enhance or reduce the survival of HSPCs after exposure of marrow to ionizing radiation. In a recent series of studies, however, it has become clear that housing-related factors such as the cool room temperature required for laboratory mice can exert a surprising influence on the outcome of experiments. Here we report that the mild, but chronic cold-stress endured by mice housed under these conditions exerts a protective effect on HSPCs after both non-lethal and lethal doses of total body irradiation (TBI). Alleviation of this cold-stress by housing mice at a thermoneutral temperature (30°C) resulted in significantly greater baseline radiosensitivity to a lethal dose of TBI with more HSPCs from mice housed at thermoneutral temperature undergoing apoptosis following non-lethal TBI. Cold-stressed mice have elevated levels of norepinephrine, a key molecule of the sympathetic nervous system that binds to β-adrenergic receptors. We show that blocking this signaling pathway in vivo through use of the β-blocker propanolol completely mitigates the protective effect of cold-stress on HSPC apoptosis. Collectively this study demonstrates that chronic stress endured by the standard housing conditions of laboratory mice increases the resistance of HSPCs to TBI-induced apoptosis through a mechanism that depends upon β-adrenergic signaling. Since β-blockers are commonly prescribed to a wide variety of patients, this information could be important when predicting the clinical impact of HSPC sensitivity to TBI. PMID:25793392

Stromal derived factor 1α: A chemokine that delivers a two-pronged defence of the myocardium☆

PubMed Central

Bromage, Daniel I.; Davidson, Sean M.; Yellon, Derek M.

2014-01-01

Alleviating myocardial injury associated with ST elevation myocardial infarction is central to improving the global burden of coronary heart disease. The chemokine stromal cell-derived factor 1α (SDF-1α) has dual potential benefit in this regard. Firstly, SDF-1α is up-regulated in experimental and clinical studies of acute myocardial infarction (AMI) and regulates stem cell migration to sites of injury. SDF-1α delivery to the myocardium after AMI is associated with improved stem cell homing, angiogenesis, and left ventricular function in animal models, and improvements in heart failure and quality of life in humans. Secondly, SDF-1α may have a role in remote ischaemic conditioning (RIC), the phenomenon whereby non-lethal ischaemia–reperfusion applied to an organ or tissue remote from the heart protects the myocardium from lethal ischaemia–reperfusion injury (IRI). SDF-1α is increased in the serum of rats subjected to RIC and protects against myocardial IRI in ex vivo studies. Despite these potential pleiotropic effects, a limitation of SDF-1α is its short plasma half-life due to cleavage by dipeptidyl peptidase-4 (DPP-4). However, DPP-4 inhibitors increase the half-life of SDF-1α by preventing its degradation and are also protective against lethal IRI. In summary, SDF-1 potentially delivers a ‘two-pronged’ defence of the myocardium: acutely protecting it from IRI while simultaneously stimulating repair by recruiting stem cells to the site of injury. In this article we examine the evidence for acute and chronic cardioprotective roles of SDF-1α and discuss potential therapeutic manipulations of this mechanism with DPP-4 inhibitors to protect against lethal tissue injury in the clinical setting. PMID:24704323

Morphology-Independent Virulence of Candida Species during Polymicrobial Intra-abdominal Infections with Staphylococcus aureus

PubMed Central

Nash, Evelyn E.; Peters, Brian M.; Fidel, Paul L.

2015-01-01

Intra-abdominal polymicrobial infections cause significant morbidity and mortality. An experimental mouse model of Candida albicans-Staphylococcus aureus intra-abdominal infection (IAI) results in 100% mortality by 48 to 72 h postinoculation, while monomicrobial infections are avirulent. Mortality is associated with robust local and systemic inflammation without a requirement for C. albicans morphogenesis. However, the contribution of virulence factors coregulated during the yeast-to-hypha transition is unknown. This also raised the question of whether other Candida species that are unable to form hyphae are as virulent as C. albicans during polymicrobial IAI. Therefore, the purpose of this study was to evaluate the ability of non-albicans Candida (NAC) species with various morphologies and C. albicans transcription factor mutants (efg1/efg1 and cph1/cph1) to induce synergistic mortality and the accompanying inflammation. Results showed that S. aureus coinoculated with C. krusei or C. tropicalis was highly lethal, similar to C. albicans, while S. aureus-C. dubliniensis, S. aureus-C. parapsilosis, and S. aureus-C. glabrata coinoculations resulted in little to no mortality. Local and systemic interleukin-6 (IL-6) and prostaglandin E2 (PGE2) levels were significantly elevated during symptomatic and/or lethal coinfections, and hypothermia strongly correlated with mortality. Coinoculation with C. albicans strains deficient in the transcription factor Efg1 but not Cph1 reversed the lethal outcome. These results support previous findings and demonstrate that select Candida species, without reference to any morphological requirement, induce synergistic mortality, with IL-6 and PGE2 acting as key inflammatory factors. Mechanistically, signaling pathways controlled by Efg1 are critical for the ability of C. albicans to induce mortality from an intra-abdominal polymicrobial infection. PMID:26483410

Morphology-Independent Virulence of Candida Species during Polymicrobial Intra-abdominal Infections with Staphylococcus aureus.

PubMed

Nash, Evelyn E; Peters, Brian M; Fidel, Paul L; Noverr, Mairi C

2016-01-01

Intra-abdominal polymicrobial infections cause significant morbidity and mortality. An experimental mouse model of Candida albicans-Staphylococcus aureus intra-abdominal infection (IAI) results in 100% mortality by 48 to 72 h postinoculation, while monomicrobial infections are avirulent. Mortality is associated with robust local and systemic inflammation without a requirement for C. albicans morphogenesis. However, the contribution of virulence factors coregulated during the yeast-to-hypha transition is unknown. This also raised the question of whether other Candida species that are unable to form hyphae are as virulent as C. albicans during polymicrobial IAI. Therefore, the purpose of this study was to evaluate the ability of non-albicans Candida (NAC) species with various morphologies and C. albicans transcription factor mutants (efg1/efg1 and cph1/cph1) to induce synergistic mortality and the accompanying inflammation. Results showed that S. aureus coinoculated with C. krusei or C. tropicalis was highly lethal, similar to C. albicans, while S. aureus-C. dubliniensis, S. aureus-C. parapsilosis, and S. aureus-C. glabrata coinoculations resulted in little to no mortality. Local and systemic interleukin-6 (IL-6) and prostaglandin E2 (PGE2) levels were significantly elevated during symptomatic and/or lethal coinfections, and hypothermia strongly correlated with mortality. Coinoculation with C. albicans strains deficient in the transcription factor Efg1 but not Cph1 reversed the lethal outcome. These results support previous findings and demonstrate that select Candida species, without reference to any morphological requirement, induce synergistic mortality, with IL-6 and PGE2 acting as key inflammatory factors. Mechanistically, signaling pathways controlled by Efg1 are critical for the ability of C. albicans to induce mortality from an intra-abdominal polymicrobial infection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Embryonic Lethality Due to Arrested Cardiac Development in Psip1/Hdgfrp2 Double-Deficient Mice.

PubMed

Wang, Hao; Shun, Ming-Chieh; Dickson, Amy K; Engelman, Alan N

2015-01-01

Hepatoma-derived growth factor (HDGF) related protein 2 (HRP2) and lens epithelium-derived growth factor (LEDGF)/p75 are closely related members of the HRP2 protein family. LEDGF/p75 has been implicated in numerous human pathologies including cancer, autoimmunity, and infectious disease. Knockout of the Psip1 gene, which encodes for LEDGF/p75 and the shorter LEDGF/p52 isoform, was previously shown to cause perinatal lethality in mice. The function of HRP2 was by contrast largely unknown. To learn about the role of HRP2 in development, we knocked out the Hdgfrp2 gene, which encodes for HRP2, in both normal and Psip1 knockout mice. Hdgfrp2 knockout mice developed normally and were fertile. By contrast, the double deficient mice died at approximate embryonic day (E) 13.5. Histological examination revealed ventricular septal defect (VSD) associated with E14.5 double knockout embryos. To investigate the underlying molecular mechanism(s), RNA recovered from ventricular tissue was subjected to RNA-sequencing on the Illumina platform. Bioinformatic analysis revealed several genes and biological pathways that were significantly deregulated by the Psip1 knockout and/or Psip1/Hdgfrp2 double knockout. Among the dozen genes known to encode for LEDGF/p75 binding factors, only the expression of Nova1, which encodes an RNA splicing factor, was significantly deregulated by the knockouts. However the expression of other RNA splicing factors, including the LEDGF/p52-interacting protein ASF/SF2, was not significantly altered, indicating that deregulation of global RNA splicing was not a driving factor in the pathology of the VSD. Tumor growth factor (Tgf) β-signaling, which plays a key role in cardiac morphogenesis during development, was the only pathway significantly deregulated by the double knockout as compared to control and Psip1 knockout samples. We accordingly speculate that deregulated Tgf-β signaling was a contributing factor to the VSD and prenatal lethality of Psip1/Hdgfrp2 double-deficient mice.

Patterns of Partners' Abusive Behaviors as Reported by Latina and Non-Latina Survivors

ERIC Educational Resources Information Center

Glass, Nancy; Perrin, Nancy; Hanson, Ginger; Mankowski, Eric; Bloom, Tina; Campbell, Jacquelyn

2009-01-01

This study builds on the existing knowledge of risk factors for lethal intimate partner violence (IPV) and typologies of IPV abusers by exploring patterns of abusive partners' behaviors among known risk factors for intimate partner femicide (i.e., murder of women) and determines if groups of survivors with similar patterns of abusive behaviors…

Properties and natural occurrence of maternal-effect selfish genes ('Medea' factors) in the red flour beetle, tribolium castaneum

PubMed

Beeman; Friesen

1999-05-01

Maternally acting selfish genes, termed 'Medea' factors, were found to be widespread in wild populations of Tribolium castaneum collected in Europe, North and South America, Africa and south-east Asia, but were rare or absent in populations from Australia and the Indian subcontinent. We detected at least four distinct genetic loci in at least two different linkage groups that exhibit the Medea pattern of differential mortality of genotypes within maternal families. Although each M factor tested had similar properties of maternal lethality to larvae and zygotic self-rescue, M factors representing distinct loci did not show cross-rescue. Alleles at two of these loci, M1 and M4, were by far the most prevalent, M4 being the predominant type. M2 and M3 were each found only once, in Pakistan and Japan, respectively. Although M1 could be genetically segregated from M4 and maintained as a purified stock, the M1 factor invariably co-occurred with M4 in field populations, whereas M4 usually occurred in the absence of other Medea factors. The dominant maternal lethal action of M1 could be selectively inactivated (reverted) by gene-knockout gamma irradiation with retention of zygotic rescue activity.

When the Pain Becomes Unbearable: Case-Control Study of Mental Pain Characteristics Among Medically Serious Suicide Attempters.

PubMed

Levi-Belz, Y; Gvion, Y; Grisaru, S; Apter, A

2018-01-01

The unbearable mental pain experience is recognized as a key antecedent of suicidal behavior. We aimed to examine the precise nature of the mental pain among medically serious suicide attempters (MSSAs), a population closely resembling those who died by suicide. We evaluated various factors of mental pain from the Orbach and Mikulincer Mental Pain Scale, as well as medical lethality and suicide intent. MSSAs were higher than non-MSSAs and psychiatric controls for Irreversibility of pain. Moreover, Emptiness predicted medical lethality, while Cognitive Confusion negatively predicted suicide intent level, controlling for hopelessness and depression. high sense of Irreversibility of pain as well as high Emptiness and low Cognitive Confusion are important risk factors for more severe suicidal behavior. Implications for identification of at-risk groups for suicide as well as for suicide prevention and treatment of suicidal individuals are discussed.

Prediction of protein-peptide interactions: application of the XPairIt API to anthrax lethal factor and substrates

NASA Astrophysics Data System (ADS)

Hurley, Margaret M.; Sellers, Michael S.

2013-05-01

As software and methodology develop, key aspects of molecular interactions such as detailed energetics and flexibility are continuously better represented in docking simulations. In the latest iteration of the XPairIt API and Docking Protocol, we perform a blind dock of a peptide into the cleavage site of the Anthrax lethal factor (LF) metalloprotein. Molecular structures are prepared from RCSB:1JKY and we demonstrate a reasonably accurate docked peptide through analysis of protein motion and, using NCI Plot, visualize and characterize the forces leading to binding. We compare our docked structure to the 1JKY crystal structure and the more recent 1PWV structure, and discuss both captured and overlooked interactions. Our results offer a more detailed look at secondary contact and show that both van der Waals and electrostatic interactions from peptide residues further from the enzyme's catalytic site are significant.

GENETIC EFFECTS OF SPACEFLIGHT FACTORS

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

Glembotskii, Ya.L.; Parfenov, G.P.

1962-12-01

With the object of investigating effects of spaceflight factors on heredity, Drosophila melanogaster was carried on the second, fourth, and fifth orbital spaceships and on Vostok-1 and Vostok-2. Four different spaceflight effects were investigated. Nondisjunction of chromosomes was investigated by exposing unfertilized white-eyed Drosophila females on Vostoks 1 and 2 and mating them on their return with red-eyed males. Primary nondisjunction of chromosomes resulted in the appearance of four times as many unusual genotypes (XXY females and XO males) among the progeny of the exposed group as among offspring of the controls. However, the increase in nondisjunction cannot be ascribedmore » to radiation effects. Induced crossovers were investigated by exposing heterozygotic males (having normal phenotypes but three recessive genes in the second chromosome) on the fifth orbital spaceship and on Vostoks 1 and 2. Upon return they were mated with homozygotic females displaying the three recessive characteristics (black body, cinnabar eyes, and vestigial wings). Drosophila carried in the fifth orbital spaceship with no protection against low-frequency vibrations showed crossover incidence of 0.50 450 deg C in a 0.12%, compared to an incidence of 0.05 450 deg C in a 0.05% or none at all on Vostok spaceships, where the insect containers were cushioned against vibration. Dominant lethal mutations were investigated by exposing two strains of Drosophila melanogaster (D- 18 with a high rate of spontaneous lethal mutations, and D-32 with a low rate for the same mutations) of the five spacecraft. The number of dominant lethal mutations was found to increase somewhat in all groups exposed to space flight. Sex-linked recessive lethal mutations were investigated by exposing young males of the D-18 and D-32 strains of Drosophila melanogaster on all five vehicles. Exposure on the second and fourth orbital spaceships and on Vostok-1 resulted in statistically significant numbers of sex-linked recessive lethal mutations for spermatozoa and spermatids of both strains. However, no increase in mutations was observed following exposure on the fifth orbital spaceship and on Vostok-2. (TCO)« less

Endotoxin-induced lethality in neonatal mice is counteracted by interleukin-10 (IL-10) and exacerbated by anti-IL-10.

PubMed Central

Nicoletti, F; Mancuso, G; Ciliberti, F A; Beninati, C; Carbone, M; Franco, S; Cusumano, V

1997-01-01

The lethal effects occurring in neonatal (<24-h-old) BALB/c mice after challenge with 25 mg of lipopolysaccharide (LPS) per kg of body weight were significantly counteracted by pretreatment with recombinant interleukin-10 (rIL-10; 25 or 50 ng/mouse). Concordantly, blockage of endogenous IL-10 with the SXC1 monoclonal antibody increased LPS-induced mortality. Both IL-10 and SXC1 modulated the release of tumor necrosis factor alpha (TNF-alpha) so that, relative to controls, peak TNF-alpha values after LPS challenge were decreased by rIL-10 and increased by anti-IL-10. PMID:9302214

Quantitative high throughput screening identifies inhibitors of anthrax-induced cell death

PubMed Central

Zhu, Ping Jun; Hobson, Peyton; Southall, Noel; Qiu, Cunping; Thomas, Craig J.; Lu, Jiamo; Inglese, James; Zheng, Wei; Leppla, Stephen H.; Bugge, Thomas H.; Austin, Christopher P.; Liu, Shihui

2009-01-01

Here, we report the results of a quantitative high-throughput screen (qHTS) measuring the endocytosis and translocation of a β-lactamase-fused-lethal factor and the identification of small molecules capable of obstructing the process of anthrax toxin internalization. Several small molecules protect RAW264.7 macrophages and CHO cells from anthrax lethal toxin and protected cells from an LF-Pseudomonas exotoxin fusion protein and diphtheria toxin. Further efforts demonstrated that these compounds impaired the PA heptamer pre-pore to pore conversion in cells expressing the CMG2 receptor, but not the related TEM8 receptor, indicating that these compounds likely interfere with toxin internalization. PMID:19540764

Crystallographic studies of the Anthrax lethal toxin. Annual report

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

Frederick, C.A.

1996-07-01

The lethal form of Anthrax results from the inhalation of anthrax spores. Death is primarily due to the effects of the lethal toxin (Protective Antigen (PA) + Lethal Factor) from the causative agent, Bacillus anthracis. All the Anthrax vaccines currently in use or under development contain or produce PA, the major antigenic component of anthrax toxin, and there is a clear need for an improved vaccine for human use. In the previous report we described the first atomic resolution structure of PA, revealing that the molecule is composed largely of beta-sheets organized into four domains. This information can be usedmore » in the design. of recombinant PA vaccines. In this report we describe additional features of the full-length PA molecule derived from further crystallographic refinement and careful examination of the structure. We compare two crystal forms of PA grown at different pH values and discuss the functional implications. A complete definition of the function of each domain must await the crystal structure of the PA63 heptamer. We have grown crystals of the heptamer under both detergent and detergent-free conditions, and made substantial progress towards the crystal structure. The mechanism of anthrax intoxication in the light of our results is reviewed.« less

Knockdown of genes in the Toll pathway reveals new lethal RNA interference targets for insect pest control.

PubMed

Bingsohn, L; Knorr, E; Billion, A; Narva, K E; Vilcinskas, A

2017-02-01

RNA interference (RNAi) is a promising alternative strategy for ecologically friendly pest management. However, the identification of RNAi candidate genes is challenging owing to the absence of laboratory strains and the seasonality of most pest species. Tribolium castaneum is a well-established model, with a strong and robust RNAi response, which can be used as a high-throughput screening platform to identify potential RNAi target genes. Recently, the cactus gene was identified as a sensitive RNAi target for pest control. To explore whether the spectrum of promising RNAi targets can be expanded beyond those found by random large-scale screening, to encompass others identified using targeted knowledge-based approaches, we constructed a Cactus interaction network. We tested nine genes in this network and found that the delivery of double-stranded RNA corresponding to fusilli and cactin showed lethal effects. The silencing of cactin resulted in 100% lethality at every developmental stage from the larva to the adult. The knockdown of pelle, Dorsal-related immunity factor and short gastrulation reduced or even prevented egg hatching in the next generation. The combination of such targets with lethal and parental RNAi effects can now be tested against different pest species in field studies. © 2016 The Royal Entomological Society.

The rate of fatality and demographic characteristics associated with various suicide methods: a community-based study in Northern Taiwan.

PubMed

Lee, Chun-Yi; Wu, Ya-Wen; Chen, Chih-Ken; Wang, Liang-Jen

2014-01-01

Understanding lethality and risk factors of suicide methods is an initial step in suicide prevention. To investigate the fatality rate and demographic characteristics of various suicide methods. This study enrolled consecutive individuals with episodes of suicide attempts registered in a surveillance database in a city with a high rate of suicide mortality in Taiwan, from January 1, 2006, to December 31, 2010. In total, 3,089 suicide attempt events (including 2,583 nonfatal suicides and 506 completed suicides) occurred during the study period. Overall, the fatality rate of suicides was 16.4%. Charcoal burning accounted for the most suicide deaths (37.6%), with a fatality rate of 50.1%. Suicide by hanging carried the highest fatality rate (81.2%). Males tended to choose more lethal methods and had higher fatality rates compared with females. Elders and married persons were less likely to attempt suicide by charcoal burning. The case fatality ratio increased along with age among suicide attempts, but not in those using charcoal burning. The choice of suicide methods and lethality might be influenced by one's demographic characteristics. RESULTS from this study may provide clues for establishing suicide prevention strategies such as restricting access to common lethal suicide methods in the high-risk group.

SOCS3: an essential regulator of LIF receptor signaling in trophoblast giant cell differentiation

PubMed Central

Takahashi, Yutaka; Carpino, Nick; Cross, James C.; Torres, Miguel; Parganas, Evan; Ihle, James N.

2003-01-01

Suppressor of cytokine signaling 3 (SOCS3) binds cytokine receptors and thereby suppresses cytokine signaling. Deletion of SOCS3 causes an embryonic lethality that is rescued by a tetraploid rescue approach, demonstrating an essential role in placental development and a non-essential role in embryo development. Rescued SOCS3-deficient mice show a perinatal lethality with cardiac hypertrophy. SOCS3-deficient placentas have reduced spongiotrophoblasts and increased trophoblast secondary giant cells. Enforced expression of SOCS3 in a trophoblast stem cell line (Rcho-1) suppresses giant cell differentiation. Conversely, SOCS3-deficient trophoblast stem cells differentiate more readily to giant cells in culture, demonstrating that SOCS3 negatively regulates trophoblast giant cell differentiation. Leukemia inhibitory factor (LIF) promotes giant cell differentiation in vitro, and LIF receptor (LIFR) deficiency results in loss of giant cell differentiation in vivo. Finally, LIFR deficiency rescues the SOCS3-deficient placental defect and embryonic lethality. The results establish SOCS3 as an essential regulator of LIFR signaling in trophoblast differentiation. PMID:12554639

Survival of Escherichia coli under lethal heat stress by L-form conversion.

PubMed

Markova, Nadya; Slavchev, Georgi; Michailova, Lilia; Jourdanova, Mimi

2010-06-09

Transition of bacteria to cell wall deficient L-forms in response to stress factors has been assumed as a potential mechanism for survival of microbes under unfavorable conditions. In this article, we provide evidence of paradoxal survival through L-form conversion of E. coli high cell density population after lethal treatments (boiling or autoclaving). Light and transmission electron microscopy demonstrated conversion from classical rod to polymorphic L-form shape morphology and atypical growths of E. coli. Microcrystal formations observed at this stage were interpreted as being closely linked to the processes of L-form conversion and probably involved in the general phenomenon of protection against lethal environment. Identity of the morphologically modified L-forms as E. coli was verified by species specific DNA-based test. Our study might contribute to a better understanding of the L-form phenomenon and its importance for bacterial survival, as well as provoke reexamination of the traditional view of killing strategies against bacteria.

Survival of Escherichia coli under lethal heat stress by L-form conversion

PubMed Central

Markova, Nadya; Slavchev, Georgi; Michailova, Lilia; Jourdanova, Mimi

2010-01-01

Transition of bacteria to cell wall deficient L-forms in response to stress factors has been assumed as a potential mechanism for survival of microbes under unfavorable conditions. In this article, we provide evidence of paradoxal survival through L-form conversion of E. coli high cell density population after lethal treatments (boiling or autoclaving). Light and transmission electron microscopy demonstrated conversion from classical rod to polymorphic L-form shape morphology and atypical growths of E. coli. Microcrystal formations observed at this stage were interpreted as being closely linked to the processes of L-form conversion and probably involved in the general phenomenon of protection against lethal environment. Identity of the morphologically modified L-forms as E. coli was verified by species specific DNA-based test. Our study might contribute to a better understanding of the L-form phenomenon and its importance for bacterial survival, as well as provoke reexamination of the traditional view of killing strategies against bacteria. PMID:20582223

[Identification of new genes that affect [PSI^(+)] prion toxicity in Saccharomyces cerevisiae yeast].

PubMed

Matveenko, A G; Belousov, M V; Bondarev, S A; Moskalenko, S E; Zhouravleva, G A

2016-01-01

Translation termination is an important step in gene expression. Its correct processing is governed by eRF1 (Sup45) and eRF3 (Sup35) proteins. In Saccharomyces cerevisiae, mutations in the corresponding genes, as well as Sup35 aggregation in [PSI^(+)] cells that propagate the prion form of Sup35 lead to inaccurate stop codon recognition and, consequently, nonsense suppression. The presence of stronger prion variants results in the more efficient suppression of nonsense mutations. Previously, we proposed a synthetic lethality test that enables the identification of genes that may influence either translation termination factors or [PSI^(+)] manifestation. This is based on the fact that the combination of sup45 mutations with the strong [PSI^(+)] prion variant in diploids is lethal. In this work, a set of genes that were previously shown to enhance nonsense suppression was analyzed. It was found that ABF1, FKH2, and REB1 overexpression decreased the growth of strains in a prion-dependent manner and, thus, might influence [PSI^(+)] prion toxicity. It was also shown that the synthetic lethality of [PSI^(+)] and sup45 mutations increased with the overexpression of GLN3 and MOT3 that encode Q/N-rich transcription factors. An analysis of the effects of their expression on the transcription of the release factors genes revealed an increase in SUP35 transcription in both cases. Since SUP35 overexpression is known to be toxic in [PSI^(+)] strains, these genes apparently enhance [PSI^(+)] toxicity via the regulation of SUP35 transcription.

Heat shock modulates the subcellular localization, stability, and activity of HIPK2

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

Upadhyay, Mamta; Bhadauriya, Pratibha; Ganesh, Subramaniam, E-mail: sganesh@iitk.ac.in

2016-04-15

The homeodomain-interacting protein kinase-2 (HIPK2) is a highly conserved serine/threonine kinase and is involved in transcriptional regulation. HIPK2 is a highly unstable protein, and is kept at a low level under normal physiological conditions. However, exposure of cells to physiological stress – such as hypoxia, oxidative stress, or UV damage – is known to stabilize HIPK2, leading to the HIPK2-dependent activation of p53 and the cell death pathway. Therefore HIPK2 is also known as a stress kinase and as a stress-activated pro-apoptotic factor. We demonstrate here that exposure of cells to heat shock results in the stabilization of HIPK2 andmore » the stabilization is mediated via K63-linked ubiquitination. Intriguingly, a sub-lethal heat shock (42 °C, 1 h) results in the cytoplasmic localization of HIPK2, while a lethal heat shock (45 °C, 1 h) results in its nuclear localization. Cells exposed to the lethal heat shock showed significantly higher levels of the p53 activity than those exposed to the sub-lethal thermal stress, suggesting that both the level and the nuclear localization are essential for the pro-apoptotic activity of HIPK2 and that the lethal heat shock could retain the HIPK2 in the nucleus to promote the cell death. Taken together our study underscores the importance of HIPK2 in stress mediated cell death, and that the HIPK2 is a generic stress kinase that gets activated by diverse set of physiological stressors.« less

Industrial Noise and Tooth Wear - Experimental Study

PubMed Central

Cavacas, Maria Alzira; Tavares, Vitor; Borrecho, Gonçalo; Oliveira, Maria João; Oliveira, Pedro; Brito, José; Águas, Artur; dos Santos, José Martins

2015-01-01

Tooth wear is a complex multifactorial process that involves the loss of hard dental tissue. Parafunctional habits have been mentioned as a self-destructive process caused by stress, which results in hyperactivity of masticatory muscles. Stress manifests itself through teeth grinding, leading to progressive teeth wear. The effects of continuous exposure to industrial noise, a “stressor” agent, cannot be ignored and its effects on the teeth must be evaluated. Aims: The aim of this study was to ascertain the effects of industrial noise on dental wear over time, by identifying and quantifying crown area loss. Material and Methods: 39 Wistar rats were used. Thirty rats were divided in 3 experimental groups of 10 animals each. Animals were exposed to industrial noise, rich in LFN components, for 1, 4 and 7 months, with an average weekly exposure of 40 hours (8h/day, 5 days/week with the weekends in silence). The remaining 9 animals were kept in silence. The areas of the three main cusps of the molars were measured under light microscopy. Statistical analysis used: A two-way ANOVA model was applied at significance level of 5%. Results: The average area of the molar cusps was significantly different between exposed and non-exposed animals. The most remarkable differences occurred between month 1 and 4. The total crown loss from month 1 to month 7 was 17.3% in the control group, and 46.5% in the exposed group, and the differences between these variations were significant (p<0.001). Conclusions: Our data suggest that industrial noise is an important factor in the pathogenesis of tooth wear. PMID:25798052

Tumor Targeting and Drug Delivery by Anthrax Toxin.

PubMed

Bachran, Christopher; Leppla, Stephen H

2016-07-01

Anthrax toxin is a potent tripartite protein toxin from Bacillus anthracis. It is one of the two virulence factors and causes the disease anthrax. The receptor-binding component of the toxin, protective antigen, needs to be cleaved by furin-like proteases to be activated and to deliver the enzymatic moieties lethal factor and edema factor to the cytosol of cells. Alteration of the protease cleavage site allows the activation of the toxin selectively in response to the presence of tumor-associated proteases. This initial idea of re-targeting anthrax toxin to tumor cells was further elaborated in recent years and resulted in the design of many modifications of anthrax toxin, which resulted in successful tumor therapy in animal models. These modifications include the combination of different toxin variants that require activation by two different tumor-associated proteases for increased specificity of toxin activation. The anthrax toxin system has proved to be a versatile system for drug delivery of several enzymatic moieties into cells. This highly efficient delivery system has recently been further modified by introducing ubiquitin as a cytosolic cleavage site into lethal factor fusion proteins. This review article describes the latest developments in this field of tumor targeting and drug delivery.

Practical Advice on Calculating Confidence Intervals for Radioprotection Effects and Reducing Animal Numbers in Radiation Countermeasure Experiments

PubMed Central

Landes, Reid D.; Lensing, Shelly Y.; Kodell, Ralph L.; Hauer-Jensen, Martin

2014-01-01

The dose of a substance that causes death in P% of a population is called an LDP, where LD stands for lethal dose. In radiation research, a common LDP of interest is the radiation dose that kills 50% of the population by a specified time, i.e., lethal dose 50 or LD50. When comparing LD50 between two populations, relative potency is the parameter of interest. In radiation research, this is commonly known as the dose reduction factor (DRF). Unfortunately, statistical inference on dose reduction factor is seldom reported. We illustrate how to calculate confidence intervals for dose reduction factor, which may then be used for statistical inference. Further, most dose reduction factor experiments use hundreds, rather than tens of animals. Through better dosing strategies and the use of a recently available sample size formula, we also show how animal numbers may be reduced while maintaining high statistical power. The illustrations center on realistic examples comparing LD50 values between a radiation countermeasure group and a radiation-only control. We also provide easy-to-use spreadsheets for sample size calculations and confidence interval calculations, as well as SAS® and R code for the latter. PMID:24164553

Trophic cascades in rocky shore tide pools: distinguishing lethal and nonlethal effects.

PubMed

Trussell, Geoffrey C; Ewanchuk, Patrick J; Bertness, Mark D; Silliman, Brian R

2004-05-01

The effects of predators on the density of their prey can have positive indirect effects on the abundance of the prey's resource via a trophic cascade. This concept has strongly influenced contemporary views of how communities are structured. However, predators also can transmit indirect effects by inducing changes in prey traits. We show that the mere presence of predator risk cues can initiate a trophic cascade in rocky shore tide pools. In large (mean surface area =9 m2), natural tide pools, we manipulated crab density and their foraging ability to examine the relative importance of lethal (density-mediated) and non-lethal (trait-mediated) predator effects to algal community development. We found that perceived predation risk reduced snail density as much as the direct predation treatment, showing that green crab predation was not an important factor regulating local snail density. Instead, snail emigration away from resident crabs appears to be the most important factor regulating local snail density. As a result, the abundance of ephemeral green algae was similar in the predation risk and direct predation treatments, suggesting that the consumption of snails by crabs plays a minimal role in mediating the trophic cascade. Increased attention to trait-mediated effects that are transmitted by predator-induced changes in prey behavior may change our view of how predators exert their strong influence on community structure.

Anthrax biosensor, protective antigen ion channel asymmetric blockade.

PubMed

Halverson, Kelly M; Panchal, Rekha G; Nguyen, Tam L; Gussio, Rick; Little, Stephen F; Misakian, Martin; Bavari, Sina; Kasianowicz, John J

2005-10-07

The significant threat posed by biological agents (e.g. anthrax, tetanus, botulinum, and diphtheria toxins) (Inglesby, T. V., O'Toole, T., Henderson, D. A., Bartlett, J. G., Ascher, M. S., Eitzen, E., Friedlander, A. M., Gerberding, J., Hauer, J., Hughes, J., McDade, J., Osterholm, M. T., Parker, G., Perl, T. M., Russell, P. K., and Tonat, K. (2002) J. Am. Med. Assoc. 287, 2236-2252) requires innovative technologies and approaches to understand the mechanisms of toxin action and to develop better therapies. Anthrax toxins are formed from three proteins secreted by fully virulent Bacillus anthracis, protective antigen (PA, 83 kDa), lethal factor (LF, 90 kDa), and edema factor (EF, 89 kDa). Here we present electrophysiological measurements demonstrating that full-length LF and EF convert the current-voltage relationship of the heptameric PA63 ion channel from slightly nonlinear to highly rectifying and diode-like at pH 6.6. This effect provides a novel method for characterizing functional toxin interactions. The method confirms that a previously well characterized PA63 monoclonal antibody, which neutralizes anthrax lethal toxin in animals in vivo and in vitro, prevents the binding of LF to the PA63 pore. The technique can also detect the presence of anthrax lethal toxin complex from plasma of infected animals. The latter two results suggest the potential application of PA63 nanopore-based biosensors in anthrax therapeutics and diagnostics.

Survival in emergency escape from passenger aircraft.

DOT National Transportation Integrated Search

1970-10-01

The human factors data from three aircraft accidents involving emergency evacuations are reviewed. Of the 261 passengers aboard, 105 died in attempts to escape during the 1- to 3-minutes prior to the build-up of a lethal thermotoxic environment withi...

Non-Lethal Weapons Program

Science.gov Websites

), 26th Marine Expeditionary Unit (MEU), practice non-lethal control techniques during a non-lethal Skip to main content (Press Enter). Toggle navigation Non-Lethal Weapons Program Search Search JNLWP: Search Search JNLWP: Search Non-Lethal Weapons Program U.S. Department of Defense Non-Lethal

[Bladder tumor lethality. Results in the autonomous community of Rioja between 1975-1991].

PubMed

Fernández Fernández, A; Gil Fabra, J; Fernández Ruíz, M; Angulo Castellanos, M G; Blanco Martín, E; Otero Mauricio, G

1998-01-01

Between 1975-1991, a total of 557 cases of bladder carcinoma were identified in the Autonomous Community of La Rioja (CAR) which were followed up to December 1994. The overall lethality was 21.9%. 492 cases with 22.35% lethality were identified in males. In females, however, there was 65 cases with 18.46% lethality. The comparison of males and females lethality resulted in p = 0.525. Lethality between cases diagnosed within each 5-year period analyzed is: 1975-1981: 177 cases, lethality 23.72%. 1982-1986: 168 cases, lethality 30.95%. 1987-1991: 212 cases, lethality 13.20%. Between the first and the second 5-year periods, p = 0.132; between the first and third 5-year periods p = 0.007 and between the second and third 5-year periods p < 0.000. Bladder tumours accounts in CAR for a 22.35% lethality. Lethality is higher in males that in females but the difference is not statistically significant. In the last 5-year period assessed, 1987-1991, a reduction of lethality from bladder neoplasms has been documented.

Positron emission tomography quantification of serotonin(1A) receptor binding in suicide attempters with major depressive disorder.

PubMed

Sullivan, Gregory M; Oquendo, Maria A; Milak, Matthew; Miller, Jeffrey M; Burke, Ainsley; Ogden, R Todd; Parsey, Ramin V; Mann, J John

2015-02-01

Serotonergic system dysfunction has been associated with increased lethal suicide attempts and suicide. Dysfunction includes higher binding of serotonin(1A) autoreceptor in the brainstem raphe of individuals who die by suicide. To determine the relationships between brain serotonin(1A) binding and suicidal behavior in vivo in major depressive disorder (MDD) using positron emission tomography and the serotonin(1A) antagonist radiotracer carbon C 11 [11C]-labeled WAY-100635. Cross-sectional positron emission tomography study at an academic medical center from 1999 through 2009. We compared serotonin(1A) binding between individuals with MDD who did not attempt suicide (nonattempters) (n = 62) and those who attempted suicide (attempters) (n = 29). We subdivided the attempters into those with lower (n = 16) and higher (n = 13) levels of lethality. The binding potential (BPF) of [11C]WAY-100635 (calculated as the number of receptors available divided by affinity) in the prefrontal cortex (PFC) and brainstem, estimated by kinetic modeling with an arterial input function; the severity of suicidal behaviors, including lethality and intent of suicide attempts; and suicidal ideation. Using a linear mixed-effects model, we found no difference between attempters and nonattempters with MDD in serotonin(1A) BPF in the PFC regions (F1,88 = 0.03; P = .87) or in the raphe nuclei (F1,88 = 0.29; P = .59). Raphe nuclei serotonin(1A) BPF was 45.1% greater in higher-lethality attempters compared with lower-lethality attempters (F1,25 = 7.33; P = .01), whereas no difference was observed in the PFC regions (F1,25 = 0.12; P = .73). Serotonin(1A )BPF in the raphe nuclei of suicide attempters was positively correlated with the lethality rating (F1,25 = 10.56; P = .003) and the subjective lethal intent factor (F1,25 = 10.63; P = .003; R2 = 0.32) based on the most recent suicide attempt. Suicide ideation in participants with MDD was positively correlated with serotonin(1A) BPF in the PFC regions (F1,88 = 5.19; P = .03) and in the raphe nuclei (F1,87 = 7.38; P = .008; R2 = 0.12). Higher brainstem raphe serotonin(1A)BPF observed in higher-lethality suicide attempters with MDD is in agreement with findings in suicide studies and also with the finding of low cerebrospinal fluid levels of 5-hydroxyindoleacetic acid in higher-lethality suicide attempters. Higher brainstem raphe serotonin(1A) BPF would be consistent with lower levels of serotonin neuron firing and release and supports a model of impaired serotonin signaling in suicide and higher-lethality suicidal behavior. Severity of suicidal ideation in MDD is related to brainstem and prefrontal serotonin(1A) BPF, suggesting a role for both regions in suicidal ideation. Lower levels of serotonin release at key brain projection sites, such as the prefrontal regions, may favor more severe suicidal ideation and higher-lethality suicide attempts.

Positron Emission Tomography Quantification of Serotonin1A Receptor Binding in Suicide Attempters With Major Depressive Disorder

PubMed Central

Sullivan, Gregory M.; Oquendo, Maria A.; Milak, Matthew; Miller, Jeffrey M.; Burke, Ainsley; Ogden, R. Todd; Parsey, Ramin V.; Mann, J. John

2015-01-01

IMPORTANCE Serotonergic system dysfunction has been associated with increased lethal suicide attempts and suicide. Dysfunction includes higher binding of serotonin1A autoreceptor in the brainstem raphe of individuals who die by suicide. OBJECTIVES To determine the relationships between brain serotonin1A binding and suicidal behavior in vivo in major depressive disorder (MDD) using positron emission tomography and the serotonin1A antagonist radiotracer carbon C 11 [11C]–labeled WAY-100635. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional positron emission tomography study at an academic medical center from 1999 through 2009. We compared serotonin1A binding between individuals with MDD who did not attempt suicide (nonattempters) (n = 62) and those who attempted suicide (attempters) (n = 29). We subdivided the attempters into those with lower (n = 16) and higher (n = 13) levels of lethality. MAIN OUTCOMES AND MEASURES The binding potential (BPF) of [11C]WAY-100635 (calculated as the number of receptors available divided by affinity) in the prefrontal cortex (PFC) and brainstem, estimated by kinetic modeling with an arterial input function; the severity of suicidal behaviors, including lethality and intent of suicide attempts; and suicidal ideation. RESULTS Using a linear mixed-effects model, we found no difference between attempters and nonattempters with MDD in serotonin1A BPF in the PFC regions (F1,88 = 0.03; P = .87) or in the raphe nuclei (F1,88 = 0.29; P = .59). Raphe nuclei serotonin1A BPF was 45.1% greater in higher-lethality attempters compared with lower-lethality attempters (F1,25 = 7.33; P = .01), whereas no difference was observed in the PFC regions (F1,25 = 0.12; P = .73). Serotonin1A BPF in the raphe nuclei of suicide attempters was positively correlated with the lethality rating (F1,25 = 10.56; P = .003) and the subjective lethal intent factor (F1,25 = 10.63; P = .003; R2 = 0.32) based on the most recent suicide attempt. Suicide ideation in participants with MDD was positively correlated with serotonin1A BPF in the PFC regions (F1,88 = 5.19; P = .03) and in the raphe nuclei (F1,87 = 7.38; P = .008; R2 = 0.12). CONCLUSIONS AND RELEVANCE Higher brainstem raphe serotonin1A BPF observed in higher-lethality suicide attempters with MDD is in agreement with findings in suicide studies and also with the finding of low cerebrospinal fluid levels of 5-hydroxyindoleacetic acid in higher-lethality suicide attempters. Higher brainstem raphe serotonin1A BPF would be consistent with lower levels of serotonin neuron firing and release and supports a model of impaired serotonin signaling in suicide and higher-lethality suicidal behavior. Severity of suicidal ideation in MDD is related to brainstem and prefrontal serotonin1A BPF, suggesting a role for both regions in suicidal ideation. Lower levels of serotonin release at key brain projection sites, such as the prefrontal regions, may favor more severe suicidal ideation and higher-lethality suicide attempts. PMID:25549105

Interruption of capsule production in Streptococcus pneumonia serotype 3 by insertion of transposon Tn916.

PubMed Central

Watson, D A; Musher, D M

1990-01-01

Transposon Tn916 mutagenesis was used to produce mutant strains of Streptococcus pneumoniae serotype 3 that lacked only a polysaccharide capsule. Southern blotting, DNA-DNA hybridization, and immunochemical analyses demonstrated that the presence of a single copy of Tn916 was sufficient to produce unencapsulation. The 50% lethal dose for such mutants was greater than 5 x 10(7) CFU, as opposed to a 50% lethal dose of 1 CFU for wild-type strains. These experiments outline an effective method for targeting genes in S. pneumoniae by transposon interruption and provide molecular evidence to support the longstanding hypothesis that the capsule is the principal virulence factor in this pathogen. Images PMID:2167295

Genetics Home Reference: bladder cancer

MedlinePlus

... events in bladder tumors. Researchers believe that several genes that control cell growth and division are probably located on chromosome 9 . ... Kwast TH, Zwarthoff EC, Radvanyi F. Novel fibroblast growth factor receptor ... identified in non-lethal skeletal disorders. Eur J Hum Genet. 2002 Dec;10( ...

Lethality of Sortase Depletion in Actinomyces oris Caused by Excessive Membrane Accumulation of a Surface Glycoprotein

PubMed Central

Wu, Chenggang; Huang, I-Hsiu; Chang, Chungyu; Reardon-Robinson, Melissa Elizabeth; Das, Asis; Ton-That, Hung

2014-01-01

Sortase, a cysteine-transpeptidase conserved in Gram-positive bacteria, anchors on the cell wall many surface proteins that facilitate bacterial pathogenesis and fitness. Genetic disruption of the housekeeping sortase in several Gram-positive pathogens reported thus far attenuates virulence, but not bacterial growth. Paradoxically, we discovered that depletion of the housekeeping sortase SrtA was lethal for Actinomyces oris; yet, all of its predicted cell wall-anchored protein substrates (AcaA-N) were individually dispensable for cell viability. Using Tn5-transposon mutagenesis to identify factors that upend lethality of srtA deletion, we uncovered a set of genetic suppressors harboring transposon insertions within genes of a locus encoding AcaC and a LytR-CpsA-Psr (LCP)-like protein. AcaC was shown to be highly glycosylated and dependent on LCP for its glycosylation. Upon SrtA depletion, the glycosylated form of AcaC, hereby renamed GspA, was accumulated in the membrane. Overexpression of GspA in a mutant lacking gspA and srtA was lethal; conversely, cells overexpressing a GspA mutant missing a membrane-localization domain were viable. The results reveal a unique glycosylation pathway in A. oris that is coupled to cell wall anchoring catalyzed by sortase SrtA. Significantly, this novel phenomenon of glyco-stress provides convenient cell-based assays for developing a new class of inhibitors against Gram-positive pathogens. PMID:25230351

Androstenediol and dehydroepiandrosterone protect mice against lethal bacterial infections and lipopolysaccharide toxicity.

PubMed

Ben-Nathan, D; Padgett, D A; Loria, R M

1999-05-01

The protective effects of the hormones androstenediol (androstene-3beta, 17beta,-diol; AED) and dehydroepiandrosterone (5-androsten-3beta-ol-17-one; DHEA) on the pathophysiology of two lethal bacterial infections and endotoxin shock were examined. The infections included a gram-positive organism (Enterococcus faecalis) and a gram-negative organism (Pseudomonas aeruginosa). Both hormones protected mice from the lethal bacterial infections and from lipopolysaccharide (LPS) challenge. Treatment of animals lethally infected with P. aeruginosa with DHEA resulted in a 43% protection whereas treatment with AED gave a 67% protection. Both hormones also protected completely animals infected with an LD50 dose of E. faecalis. Similarly, the 88% mortality rate seen in LPS challenge was reduced to 17% and 8.5%, by treatment with DHEA and AED, respectively. The protective influences of both steroids were shown not to be directly antibacterial, but primarily an indirect antitoxin reaction. DHEA appears to mediate its protective effect by a mechanism that blocks the toxin-induced production of pathophysiological levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1. AED usually had greater protective effects than DHEA; however, the AED effect was independent of TNF-alpha suppression, both in vivo and in vitro. The data suggest that both DHEA and AED may have a role in the neuro-endocrine regulation of antibacterial immune resistance.

A functional and thromboelastometric-based micromethod for assessing crotoxin anticoagulant activity and antiserum relative potency against Crotalus durissus terrificus venom.

PubMed

Prezoto, B C; Tanaka-Azevedo, A M; Marcelino, J R; Tashima, A K; Nishiduka, E S; Kapronezai, J; Mota, J O; Rocha, M M T; Serino-Silva, C; Oguiura, N

2018-06-15

The assessment of the capacity of antivenoms to neutralize the lethal activity of snake venoms still relies on traditional rodent in vivo lethality assay. ED 50 and LD 50 assays require large quantities of venoms and antivenoms, and besides leading to animal suffering. Therefore, in vitro tests should be introduced for assessing antivenom neutralizing capacity in intermediary steps of antivenom production. This task is facilitated when one key lethal toxin is identified. A good example is crotoxin, a β-neurotoxin phospholipase A 2 -like toxin that presents anticoagulant activity in vitro and is responsible for the lethality of venoms of Crotalus durissus snakes. By using rotational thromboelastometry, we reported recently one sensitive coagulation assay for assessing relative potency of the anti-bothropic serum in neutralizing procoagulant activity of Bothrops jararaca venom upon recalcified factor-XII-deficient chicken plasma samples (CPS). In this study, we stablished conditions for determining relative potency of four batches of the anti-crotalic serum (ACS) (antagonist) in inactivating crotoxin anticoagulant activity in CPS (target) simultaneously treated with one classical activator of coagulation (agonists). The correlation coefficient (r) between values related the ACS potency in inactivating both in vitro crotoxin anticoagulant activity and the in vivo lethality of whole venom (ED 50 ) was 0.94 (p value < 0.05). In conclusion, slowness in spontaneous thrombin/fibrin generation even after recalcification elicit time lapse sufficient for elaboration of one dose-response curve to pro- or anti-coagulant agonists in CPS. We propose this methodology as an alternative and sensitive assay for assessing antivenom neutralizing ability in plasma of immunized horses as well as for in-process quality control. Copyright © 2018 Elsevier Ltd. All rights reserved.

Alveolar Macrophages Prevent Lethal Influenza Pneumonia By Inhibiting Infection Of Type-1 Alveolar Epithelial Cells

PubMed Central

Cardani, Amber; Boulton, Adam; Kim, Taeg S.; Braciale, Thomas J.

2017-01-01

The Influenza A virus (IAV) is a major human pathogen that produces significant morbidity and mortality. To explore the contribution of alveolar macrophages (AlvMΦs) in regulating the severity of IAV infection we employed a murine model in which the Core Binding Factor Beta gene is conditionally disrupted in myeloid cells. These mice exhibit a selective deficiency in AlvMΦs. Following IAV infection these AlvMΦ deficient mice developed severe diffuse alveolar damage, lethal respiratory compromise, and consequent lethality. Lethal injury in these mice resulted from increased infection of their Type-1 Alveolar Epithelial Cells (T1AECs) and the subsequent elimination of the infected T1AECs by the adaptive immune T cell response. Further analysis indicated AlvMΦ-mediated suppression of the cysteinyl leukotriene (cysLT) pathway genes in T1AECs in vivo and in vitro. Inhibition of the cysLT pathway enzymes in a T1AECs cell line reduced the susceptibility of T1AECs to IAV infection, suggesting that AlvMΦ-mediated suppression of this pathway contributes to the resistance of T1AECs to IAV infection. Furthermore, inhibition of the cysLT pathway enzymes, as well as blockade of the cysteinyl leukotriene receptors in the AlvMΦ deficient mice reduced the susceptibility of their T1AECs to IAV infection and protected these mice from lethal infection. These results suggest that AlvMΦs may utilize a previously unappreciated mechanism to protect T1AECs against IAV infection, and thereby reduce the severity of infection. The findings further suggest that the cysLT pathway and the receptors for cysLT metabolites represent potential therapeutic targets in severe IAV infection. PMID:28085958

Role of T Cells and Gamma Interferon during Induction of Hypersensitivity to Lipopolysaccharide by Toxic Shock Syndrome Toxin 1 in Mice

PubMed Central

Dinges, Martin M.; Schlievert, Patrick M.

2001-01-01

The superantigenic function of toxic shock syndrome toxin 1 (TSST-1) is generally regarded as an important determinant of its lethal effects in humans or experimental animals. This study examined the role of superantigenicity in a BALB/c mouse model of lethal TSST-1-induced hypersensitivity to lipopolysaccharide (LPS). In this model, TSST-1 greatly potentiated both LPS-induced lethality, as well as LPS-induced serum tumor necrosis factor alpha (TNF-α) activity. Although BALB/c-SCID mice were resistant to these LPS enhancement effects of TSST-1, BALB/c-SCID mice reconstituted with T cells were completely susceptible to the enhancement effect of TSST-1 on LPS-induced serum TNF-α. Mice pretreated with cyclosporine (Cs) or neutralizing antibodies against gamma interferon (IFN-γ) did not develop lethal LPS hypersensitivity when injected with TSST-1, and these agents reduced the enhancement effect of TSST-1 on LPS-induced serum TNF-α by 99 and 85%, respectively. Cs pretreatment also completely inhibited the known capacity of TSST-1 to amplify LPS-induced levels of IFN-γ in serum. In contrast, mice given Cs after a priming injection of TSST-1, but before LPS, still exhibited lethal hypersensitivity to LPS. Cs given after TSST-1 also did not inhibit enhancement of LPS-induced serum TNF-α by TSST-1 but inhibited the enhancement effect of TSST-1 on LPS-induced serum IFN-γ by 50%. These experiments support the theory that TSST-1-induced hypersensitivity to LPS is mediated primarily by IFN-γ derived from superantigen-activated T cells. PMID:11179286

Dietary Lycopene, Angiogenesis, and Prostate Cancer: A Prospective Study in the Prostate-Specific Antigen Era

PubMed Central

2014-01-01

Background The role of lycopene in prostate cancer prevention remains controversial. We examined the associations between dietary lycopene intake and prostate cancer, paying particular attention to the influence of prostate-specific antigen screening, and evaluated tissue biomarkers in prostate cancers in relation to lycopene intake. Methods Among 49898 male health professionals, we obtained dietary information through questionnaires and ascertained total and lethal prostate cancer cases from 1986 through January 31, 2010. Cox regression was used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs). Tissue microarrays and immunohistochemistry were used to assess tumor biomarker expression in a subset of men. Two-sided χ2 tests were used to calculate the P values. Results Higher lycopene intake was inversely associated with total prostate cancer and more strongly with lethal prostate cancer (top vs bottom quintile: HR = 0.72; 95% CI = 0.56 to 0.94; P trend = .04). In a restricted population of screened participants, the inverse associations became markedly stronger (for lethal prostate cancer: HR = 0.47; 95% CI = 0.29 to 0.75; P trend = .009). Comparing different measures of dietary lycopene, early intake, but not recent intake, was inversely associated with prostate cancer. Higher lycopene intake was associated with biomarkers in the cancer indicative of less angiogenic potential. Conclusions Dietary intake of lycopene was associated with reduced risk of lethal prostate cancer and with a lesser degree of angiogenesis in the tumor. Because angiogenesis is a strong progression factor, an endpoint of lethal prostate cancer may be more relevant than an endpoint of indolent prostate cancer for lycopene in the era of highly prevalent prostate-specific antigen screening. PMID:24463248

Pre-treatment with low-dose endotoxin prolongs survival from experimental lethal endotoxic shock: Benefit for lethal peritonitis by Escherichia coli.

PubMed

Kopanakis, Konstantinos; Tzepi, Ira-Maria; Pistiki, Aikaterini; Carrer, Dionyssia-Pinelopi; Netea, Mihai G; Georgitsi, Marianna; Lymperi, Maria; Droggiti, Dionyssia-Irini; Liakakos, Theodoros; Machairas, Anastasios; Giamarellos-Bourboulis, Evangelos J

2013-06-01

Although LPS tolerance is well-characterized, it remains unknown if it is achieved even with single doses of lipopolysaccharide (LPS) and if it offers protection against lethal bacterial infections. To this end, C57B6 mice were assigned to groups A (sham); B (saline i.p followed after 24h by i.p 30mg/kg LPS); and C (3mg/kg LPS i.p followed after 24h by i.p 30mg/kg LPS). Survival was monitored and animals were sacrificed early after lethal challenge for measurement of tumour necrosis factor-alpha (TNFα) in serum; isolation of splenocytes and cytokine stimulation; and flow-cytometry for apoptosis and TREM-1. Experiments were repeated with mice infected i.p by Escherichia coli after challenging with saline or LPS. Mortality of group B was 72.2% compared with 38.9% of group C (p: 0.020). Serum TNFα of group C was lower than group B. Expression of TREM-1 of group C on monocytes/neutrophils was greater than group B. Release of TNFα, of IFNγ and of IL-17 from splenocytes of group C was lower than group B and the opposite happened for IL-10 showing evidence of cellular reprogramming. In parallel, apoptosis of circulating lymphocytes and of splenocytes of group C was greater compared with group B. Pre-treatment of mice challenged by E. coli with low dose LPS led to 0% mortality compared with 90% of saline pre-treated mice; in these mice, splenocytes improved over-time their capacity for release of IFNγ. It is concluded that single low doses of LPS lead to early reprogramming of the innate immune response and prolong survival after lethal E. coli challenge. Copyright © 2013 Elsevier Ltd. All rights reserved.

Anthrax Lethal Factor as an Immune Target in Humans and Transgenic Mice and the Impact of HLA Polymorphism on CD4+ T Cell Immunity

PubMed Central

Ascough, Stephanie; Ingram, Rebecca J.; Chu, Karen K.; Reynolds, Catherine J.; Musson, Julie A.; Doganay, Mehmet; Metan, Gökhan; Ozkul, Yusuf; Baillie, Les; Sriskandan, Shiranee; Moore, Stephen J.; Gallagher, Theresa B.; Dyson, Hugh; Williamson, E. Diane; Robinson, John H.; Maillere, Bernard; Boyton, Rosemary J.; Altmann, Daniel M.

2014-01-01

Bacillus anthracis produces a binary toxin composed of protective antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). Most studies have concentrated on induction of toxin-specific antibodies as the correlate of protective immunity, in contrast to which understanding of cellular immunity to these toxins and its impact on infection is limited. We characterized CD4+ T cell immunity to LF in a panel of humanized HLA-DR and DQ transgenic mice and in naturally exposed patients. As the variation in antigen presentation governed by HLA polymorphism has a major impact on protective immunity to specific epitopes, we examined relative binding affinities of LF peptides to purified HLA class II molecules, identifying those regions likely to be of broad applicability to human immune studies through their ability to bind multiple alleles. Transgenics differing only in their expression of human HLA class II alleles showed a marked hierarchy of immunity to LF. Immunogenicity in HLA transgenics was primarily restricted to epitopes from domains II and IV of LF and promiscuous, dominant epitopes, common to all HLA types, were identified in domain II. The relevance of this model was further demonstrated by the fact that a number of the immunodominant epitopes identified in mice were recognized by T cells from humans previously infected with cutaneous anthrax and from vaccinated individuals. The ability of the identified epitopes to confer protective immunity was demonstrated by lethal anthrax challenge of HLA transgenic mice immunized with a peptide subunit vaccine comprising the immunodominant epitopes that we identified. PMID:24788397

Prenatal nicotinic exposure augments cardiorespiratory responses to activation of bronchopulmonary C-fibers

PubMed Central

Zhuang, Jianguo; Zhao, Lei; Zang, Na

2015-01-01

Rat pups prenatally exposed to nicotine (PNE) present apneic (lethal ventilatory arrest) responses during severe hypoxia. To clarify whether these responses are of central origin, we tested PNE effects on ventilation and diaphragm electromyography (EMGdi) during hypoxia in conscious rat pups. PNE produced apnea (lethal ventilatory arrest) identical to EMGdi silencing during hypoxia, indicating a central origin of this apneic response. We further asked whether PNE would sensitize bronchopulmonary C-fibers (PCFs), a key player in generating central apnea, with increase of the density and transient receptor potential cation channel subfamily V member 1 (TRPV1) expression of C-fibers/neurons in the nodose/jugular (N/J) ganglia and neurotrophic factors in the airways and lungs. We compared 1) ventilatory and pulmonary C-neural responses to right atrial bolus injection of capsaicin (CAP, 0.5 μg/kg), 2) bronchial substance P-immunoreactive (SP-IR) fiber density, 3) gene and protein expressions of TRPV1 in the ganglia, and 4) nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) protein in bronchoalveolar lavage fluid (BALF) and TrkA and TrkB genes in the ganglia between control and PNE pups. PNE markedly strengthened the PCF-mediated apneic response to CAP via increasing pulmonary C-neural sensitivity. PNE also enhanced bronchial SP-IR fiber density and N/J ganglia neural TRPV1 expression associated with increased gene expression of TrkA in the N/G ganglia and decreased NGF and BDNF in BALF. Our results suggest that PNE enhances PCF sensitivity likely through increasing PCF density and TRPV1 expression via upregulation of neural TrkA and downregulation of pulmonary BDNF, which may contribute to the PNE-promoted central apnea (lethal ventilatory arrest) during hypoxia. PMID:25747962

Comparative chronic toxicity of imidacloprid, clothianidin, and thiamethoxam to Chironomus dilutus and estimation of toxic equivalency factors.

PubMed

Cavallaro, Michael C; Morrissey, Christy A; Headley, John V; Peru, Kerry M; Liber, Karsten

2017-02-01

Nontarget aquatic insects are susceptible to chronic neonicotinoid insecticide exposure during the early stages of development from repeated runoff events and prolonged persistence of these chemicals. Investigations on the chronic toxicity of neonicotinoids to aquatic invertebrates have been limited to a few species and under different laboratory conditions that often preclude direct comparisons of the relative toxicity of different compounds. In the present study, full life-cycle toxicity tests using Chironomus dilutus were performed to compare the toxicity of 3 commonly used neonicotinoids: imidacloprid, clothianidin, and thiamethoxam. Test conditions followed a static-renewal exposure protocol in which lethal and sublethal endpoints were assessed on days 14 and 40. Reduced emergence success, advanced emergence timing, and male-biased sex ratios were sensitive responses to low-level neonicotinoid exposure. The 14-d median lethal concentrations for imidacloprid, clothianidin, and thiamethoxam were 1.52 μg/L, 2.41 μg/L, and 23.60 μg/L, respectively. The 40-d median effect concentrations (emergence) for imidacloprid, clothianidin, and thiamethoxam were 0.39 μg/L, 0.28 μg/L, and 4.13 μg/L, respectively. Toxic equivalence relative to imidacloprid was estimated through a 3-point response average of equivalencies calculated at 20%, 50%, and 90% lethal and effect concentrations. Relative to imidacloprid (toxic equivalency factor [TEF] = 1.0), chronic (lethality) 14-d TEFs for clothianidin and thiamethoxam were 1.05 and 0.14, respectively, and chronic (emergence inhibition) 40-d TEFs were 1.62 and 0.11, respectively. These population-relevant endpoints and TEFs suggest that imidacloprid and clothianidin exert comparable chronic toxicity to C. dilutus, whereas thiamethoxam induced comparable effects only at concentrations an order of magnitude higher. However, the authors caution that under field conditions, thiamethoxam readily degrades to clothianidin, thereby likely enhancing toxicity. Environ Toxicol Chem 2017;36:372-382. © 2016 SETAC. © 2016 SETAC.

Hope as a Predictor of Interpersonal Suicide Risk

ERIC Educational Resources Information Center

Davidson, Collin L.; Wingate, LaRicka R.; Rasmussen, Kathy A.; Slish, Meredith L.

2009-01-01

The current study hypothesized that (1) hope would negatively predict burdensomeness, thwarted belongingness, and acquired capability to enact lethal injury; (2) hope would negatively predict suicidal ideation; and (3) the interpersonal suicide risk factors would predict suicidal ideation. Results indicated that hope negatively predicted…

R-LOCUS DELETERIOUS FACTORS IN MORMONIELLA

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

Whiting, P.W.

1962-01-01

New data are presented on 37 R-locus mutant genes containing deleterious factors or crossover suppressors. Twenty-seven of these genes are among the 206 recognizable eye-color mutants previously found by others in experiments in which wild-type males were irradiated and mated, siring 11062 daughters examined, mutation rate 1.86%. With the addition of eight mutants from later simdlar tests there were 38 mutants failing to breed, probably being dominant steriles, and seven immature, probably dominant lethals. Of the l60 mutants given successful breeding test, 80 were normal and 80 contained delcterious factors of different types - lethals, near-steriles, femalesteriles, and male-stertles. Ratemore » of deleterious factor productdon differs according to the factor mutating to produce the eye-color marker. Among the l07 genes changed in factor S alone, 68 were also deleterious (63.6%) but for the 45 in O, there were only nine (20.0%), suggesting a more sensitive region near S. More than one deleterious factor may be produced simultaneously with an eye-color change and one defeet may mask others. The gene which forms a temporary unit of segregation in heterozygotes is of a higher order of magnitude than units of heredity (gene elements, cistrons) which may be permanently present dn the germ plasm. Because of the high mutation rate to the marker eye colors scarlet and oyster white, the genetical structure of the R region may be easily studied. (auth)« less

Transcription factor activating protein 4 is synthetically lethal and a master regulator of MYCN-amplified neuroblastoma.

PubMed

Boboila, Shuobo; Lopez, Gonzalo; Yu, Jiyang; Banerjee, Debarshi; Kadenhe-Chiweshe, Angela; Connolly, Eileen P; Kandel, Jessica J; Rajbhandari, Presha; Silva, Jose M; Califano, Andrea; Yamashiro, Darrell J

2018-06-07

Despite the identification of MYCN amplification as an adverse prognostic marker in neuroblastoma, MYCN inhibitors have yet to be developed. Here, by integrating evidence from a whole-genome shRNA library screen and the computational inference of master regulator proteins, we identify transcription factor activating protein 4 (TFAP4) as a critical effector of MYCN amplification in neuroblastoma, providing a novel synthetic lethal target. We demonstrate that TFAP4 is a direct target of MYCN in neuroblastoma cells, and that its expression and activity strongly negatively correlate with neuroblastoma patient survival. Silencing TFAP4 selectively inhibits MYCN-amplified neuroblastoma cell growth both in vitro and in vivo, in xenograft mouse models. Mechanistically, silencing TFAP4 induces neuroblastoma differentiation, as evidenced by increased neurite outgrowth and upregulation of neuronal markers. Taken together, our results demonstrate that TFAP4 is a key regulator of MYCN-amplified neuroblastoma and may represent a valuable novel therapeutic target.

Lower lethal temperatures for nonnative freshwater fishes in Everglades National Park, Florida

USGS Publications Warehouse

Schofield, Pam; Kline, Jeffrey L.

2018-01-01

Temperature is an important factor that shapes biogeography and species composition. In southern Florida, the tolerance of nonnative freshwater fishes to low temperatures is a critical factor in delineating their geographic spread. In this study, we provide empirical information on experimentally derived low-temperature tolerance limits of Banded Cichlid Heros severus and Spotfin Spiny Eel Macrognathus siamensis, two nonnative Everglades fishes that were lacking data, and African Jewelfish Hemichromis letourneuxi and Mayan Cichlid Cichlasoma urophthalmus, species for which previous results were derived from studies with small sample sizes. We also provide a literature review summarizing the current state of knowledge of low-temperature tolerances for all 17 nonnative freshwater fishes that have been found in Everglades National Park. Mean lower lethal temperature tolerances ranged from 4°C (Orinoco Sailfin Catfish Pterygoplichthys multiradiatus) to 16.1°C (Butterfly Peacock Bass Cichla ocellaris). These low-temperature limits may inform the understanding of the ecological role or influence of nonnative fishes and may lead to potential management opportunities and applications.

Serious adverse events associated with yellow fever vaccine.

PubMed

de Menezes Martins, Reinaldo; Fernandes Leal, Maria da Luz; Homma, Akira

2015-01-01

Yellow fever vaccine was considered one of the safest vaccines, but in recent years it was found that it could rarely cause invasive and disseminated disease in some otherwise healthy individuals, with high lethality. After extensive studies, although some risk factors have been identified, the real cause of causes of this serious adverse event are largely unknown, but findings point to individual host factors. Meningoencephalitis, once considered to happen only in children less than 6 months of age, has also been identified in older children and adults, but with good prognosis. Efforts are being made to develop a safer yellow fever vaccine, and an inactivated vaccine or a vaccine prepared with the vaccine virus envelope produced in plants are being tested. Even with serious and rare adverse events, yellow fever vaccine is the best way to avoid yellow fever, a disease of high lethality and should be used routinely in endemic areas, and on people from non-endemic areas that could be exposed, according to a careful risk-benefit analysis.

Molecular determinants for a cardiovascular collapse in anthrax

PubMed Central

Brojatsch, Jurgen; Casadevall, Arturo; Goldman, David L.

2015-01-01

Bacillus anthracis releases two bipartite proteins, lethal toxin and edema factor, that contribute significantly to the progression of anthrax-associated shock. As blocking the anthrax toxins prevents disease, the toxins are considered the main virulence factors of the bacterium. The anthrax bacterium and the anthrax toxins trigger multiorgan failure associated with enhanced vascular permeability, hemorrhage and cardiac dysfunction in animal challenge models. A recent study using mice that either lacked the anthrax toxin receptor in specific cells and corresponding mice expressing the receptor in specific cell types demonstrated that cardiovascular cells are critical for disease mediated by anthrax lethal toxin. These studies are consistent with involvement of the cardiovascular system, and with an increase of cardiac failure markers observed in human anthrax and in animal models using B. anthracis and anthrax toxins. This review discusses the current state of knowledge regarding the pathophysiology of anthrax and tries to provide a mechanistic model and molecular determinants for the circulatory shock in anthrax. PMID:24389148

Hypoxia inducible factors in hepatocellular carcinoma

PubMed Central

Chen, Chu; Lou, Tao

2017-01-01

Hepatocellular carcinoma is one of the most prevalent and lethal cancers with limited therapeutic options. Pathogenesis of this disease involves tumor hypoxia and the activation of hypoxia inducible factors. In this review, we describe the current understanding of hypoxia signaling pathway and summarize the expression, function and target genes of hypoxia inducible factors in hepatocellular carcinoma. We also highlight the recent progress in hypoxia-targeted therapeutic strategies in hepatocellular carcinoma and discuss further the future efforts for the study of hypoxia and/or hypoxia inducible factors in this deadly disease. PMID:28493839

Induction of tumor necrosis factor alpha by the group- and type-specific polysaccharides from type III group B streptococci.

PubMed Central

Mancuso, G; Tomasello, F; von Hunolstein, C; Orefici, G; Teti, G

1994-01-01

Previous studies suggested that circulating tumor necrosis factor alpha (TNF-alpha) may have a pathophysiologic role in experimental neonatal sepsis induced by group B streptococci (GBS). This study was undertaken to investigate the ability of the type III and group-specific polysaccharides of GBS to induce TNF-alpha production and TNF-alpha-dependent lethality in neonatal rats. The cytokine was detected in plasma samples by the L929 cytotoxicity assay. Intracardiac injections of either polysaccharide induced dose-dependent, transient elevations in plasma TNF-alpha levels that returned to baseline values after 5 h. The group-specific antigen induced significantly higher mean peak TNF-alpha levels than the type III antigen (125 +/- 47 versus 44 +/- 15 U/ml with 70 mg/kg of body weight). Glycogen (70 mg/kg), used as a negative control, did not induce TNF-alpha. The lipopolysaccharide-neutralizing agent polymyxin B did not decrease TNF-alpha levels induced by either polysaccharide, ruling out contamination with endotoxin as a possible cause of TNF-alpha induction. Fifty percent lethal doses of the type III and group-specific antigens given as intracardiac injections were 105 and 16 mg/kg, respectively. Salmonella endotoxin, used as a positive control, had a 50% lethal dose of 0.1 mg/kg. The lethal activities of GBS polysaccharides, as well as endotoxin, were completely prevented by pretreatment of neonatal rats with the respective specific antibodies or anti-murine TNF-alpha serum. To assess the relative importance of the type-specific substance in TNF-alpha induction by whole bacteria, two unrelated GBS transposon mutants devoid of only the type-specific capsular polysaccharide (COH1-13 and COH31-15) were employed. Each of the heat-killed unencapsulated mutants was able to produce plasma TNF-alpha level elevations or TNF-alpha-dependent lethality but was significantly less efficient in these activities than the corresponding encapsulated wild-type strain. These data suggest that the presence of type-specific material on GBS is not necessary for the stimulation of TNF-alpha production. Type III capsular polysaccharide, however, can significantly increase the ability of GBS to induce TNF-alpha. Further studies will be needed to assess the importance of TNF-alpha induction by the group- and type-specific antigens in the pathophysiology of GBS disease. PMID:8005664

American Visceral Leishmaniasis: Factors Associated with Lethality in the State of São Paulo, Brazil

PubMed Central

Madalosso, Geraldine; Fortaleza, Carlos Magno; Ribeiro, Ana Freitas; Cruz, Lisete Lage; Nogueira, Péricles Alves; Lindoso, José Angelo Lauletta

2012-01-01

Objectives. To identify factors associated with death in visceral leishmaniasis (VL) cases. Patients and Methodology. We evaluated prognostic factors for death from VL in São Paulo state, Brazil, from 1999 to 2005. A prognostic study nested in a clinical cohort was carried out by data analysis of 376 medical files. A comparison between VL fatal cases and survivors was performed for clinical, laboratory, and biological features. Association between variables and death was assessed by univariate analysis, and the multiple logistic regression model was used to determine adjusted odds ratio for death, controlling confounding factors. Results. Data analysis identified 53 fatal cases out of 376 patients, between 1999 and 2005 in São Paulo state. Lethality was 14.1% (53/376), being higher in patients older than fifty years. The main causes of death were sepsis, bleeding, liver failure, and cardiotoxicity due to treatment. Variables significantly associated with death were severe anemia, bleeding, heart failure, jaundice, diarrhea, fever for more than sixty days, age older than fifty years, and antibiotic use. Conclusion. Educational health measures are needed for the general population and continuing education programs for health professionals working in the affected areas with the purpose of identifying and treating early cases, thus preventing the disease evolution towards death. PMID:23024661

Quantitative Determination of Lethal Toxin Proteins in Culture Supernatant of Human Live Anthrax Vaccine Bacillus anthracis A16R.

PubMed

Zai, Xiaodong; Zhang, Jun; Liu, Ju; Liu, Jie; Li, Liangliang; Yin, Ying; Fu, Ling; Xu, Junjie; Chen, Wei

2016-02-25

Bacillus anthracis (B. anthracis) is the etiological agent of anthrax affecting both humans and animals. Anthrax toxin (AT) plays a major role in pathogenesis. It includes lethal toxin (LT) and edema toxin (ET), which are formed by the combination of protective antigen (PA) and lethal factor (LF) or edema factor (EF), respectively. The currently used human anthrax vaccine in China utilizes live-attenuated B. anthracis spores (A16R; pXO1+, pXO2-) that produce anthrax toxin but cannot produce the capsule. Anthrax toxins, especially LT, have key effects on both the immunogenicity and toxicity of human anthrax vaccines. Thus, determining quantities and biological activities of LT proteins expressed by the A16R strain is meaningful. Here, we explored LT expression patterns of the A16R strain in culture conditions using another vaccine strain Sterne as a control. We developed a sandwich ELISA and cytotoxicity-based method for quantitative detection of PA and LF. Expression and degradation of LT proteins were observed in culture supernatants over time. Additionally, LT proteins expressed by the A16R and Sterne strains were found to be monomeric and showed cytotoxic activity, which may be the main reason for side effects of live anthrax vaccines. Our work facilitates the characterization of anthrax vaccines components and establishment of a quality control standard for vaccine production which may ultimately help to ensure the efficacy and safety of the human anthrax vaccine A16R.

Concomitant Lethal Mutagenesis of Human Immunodeficiency Virus Type 1

PubMed Central

Dapp, Michael J.; Holtz, Colleen M.; Mansky, Louis M.

2012-01-01

RNA virus population dynamics is complex, and sophisticated approaches are needed in many cases for therapeutic intervention. One such approach, termed lethal mutagenesis, is directed at targeting the virus population structure for extinction or error catastrophe. Previous studies have demonstrated the concept of this approach with human immunodeficiency virus type 1 (HIV-1) by use of chemical mutagens (i.e., 5-azacytidine) as well as by host factors with mutagenic properties (i.e., APOBEC3G). In this study, these two unrelated mutagenic agents were used concomitantly to investigate the interplay of these distinct mutagenic mechanisms. Specifically, an HIV-1 was produced from APOBEC3G (A3G)-expressing cells and used to infect permissive target cells treated with 5-azacytidine (5-AZC). Reduced viral infectivity and increased viral mutagenesis was observed with both the viral mutagen (i.e., G-to-C mutations) and the host restriction factor (i.e., G-to-A mutations); however, when combined, had complex interactions. Intriguingly, nucleotide sequence analysis revealed that concomitant HIV-1 exposure to both 5-AZC and A3G resulted in an increase of G-to-A viral mutagenesis at the expense of G-to-C mutagenesis. A3G catalytic activity was required for the diminution in G-to-C mutagenesis. Taken together, our findings provide the first demonstration for potentiation of the mutagenic effect of a cytosine analog by A3G expression, resulting in concomitant HIV-1 lethal mutagenesis. PMID:22426127

Bacillus anthracis Cell Wall Peptidoglycan but Not Lethal or Edema Toxins Produces Changes Consistent With Disseminated Intravascular Coagulation in a Rat Model

PubMed Central

Qiu, Ping; Li, Yan; Shiloach, Joseph; Cui, Xizhong; Sun, Junfeng; Trinh, Loc; Kubler-Kielb, Joanna; Vinogradov, Evgeny; Mani, Haresh; Al-Hamad, Mariam; Fitz, Yvonne; Eichacker, Peter Q.

2013-01-01

Background. Disseminated intravascular coagulation (DIC) appears to be important in the pathogenesis of Bacillus anthracis infection, but its causes are unclear. Although lethal toxin (LT) and edema toxin (ET) could contribute, B. anthracis cell wall peptidoglycan (PGN), not the toxins, stimulates inflammatory responses associated with DIC. Methods and Results. To better understand the pathogenesis of DIC during anthrax, we compared the effects of 24-hour infusions of PGN, LT, ET, or diluent (control) on coagulation measures 6, 24, or 48 hours after infusion initiation in 135 rats. No control recipient died. Lethality rates (approximately 30%) did not differ among PGN, LT, and ET recipients (P = .78). Thirty-three of 35 deaths (94%) occurred between 6 and 24 hours after the start of challenge. Among challenge components, PGN most consistently altered coagulation measures. Compared with control at 6 hours, PGN decreased platelet and fibrinogen levels and increased prothrombin and activated partial thromboplastin times and tissue factor, tissue factor pathway inhibitor, protein C, plasminogen activator inhibitor (PAI), and thrombin-antithrombin complex levels, whereas LT and ET only decreased the fibrinogen level or increased the PAI level (P ≤ .05). Nearly all effects associated with PGN infusion significantly differed from changes associated with toxin infusion (P ≤ .05 for all comparisons except for PAI level). Conclusion. DIC during B. anthracis infection may be related more to components such as PGN than to LT or ET. PMID:23737601

Fox transcription factors: from development to disease.

PubMed

Golson, Maria L; Kaestner, Klaus H

2016-12-15

Forkhead box (Fox) transcription factors are evolutionarily conserved in organisms ranging from yeast to humans. They regulate diverse biological processes both during development and throughout adult life. Mutations in many Fox genes are associated with human disease and, as such, various animal models have been generated to study the function of these transcription factors in mechanistic detail. In many cases, the absence of even a single Fox transcription factor is lethal. In this Primer, we provide an overview of the Fox family, highlighting several key Fox transcription factor families that are important for mammalian development. © 2016. Published by The Company of Biologists Ltd.

REGRESSION ON MEDIANS OF PROBABILITY DISTRIBUTIONS

EPA Science Inventory

The median is a fundamental parameter in the area of lifetime and survival statistics. n toxicodynamics the LD50, lethal dose that results in 50% mortality, is frequently used. he median is also used to describe the incidence of cancer and other disease states. Factors such as nu...

[Evaluation of the diagnostic usefulness for ultrasonographic and echocardiographic lethal markers in fetal pulmonary hypoplasia. Analysis of 11 cases].

PubMed

Kieszek, S; Kaczmarek, P; Czichos, E; Respondek, M

1996-07-01

Results of ultrasonographic and echocardiographic studies of 11 fetuses were analysed retrospectively in relation to their pulmonary hypoplasia. Congenital malformations, quality of hydramnios and echocardiographical measurements of fetal chest were estimated. The best symptoms of pulmonary hypoplasia were: oligo/ahydramnios, absence of fetal breathing movements and malformations in fetal chest cavity (diaphragmatic hernia, cardiomegaly, hydrothorax). Systemic malformations were present in each case. The measurements such as CC, CA, HA, (CA-HA) x 100/CA were not accurate enough and we did not find any statistical differences between the control and the studied group. Finding several factors predisposing to lung hypoplasia means that its lethal form may be present in fetus.

Preventing Staphylococcus aureus sepsis through the inhibition of its agglutination in blood.

PubMed

McAdow, Molly; Kim, Hwan Keun; Dedent, Andrea C; Hendrickx, Antoni P A; Schneewind, Olaf; Missiakas, Dominique M

2011-10-01

Staphylococcus aureus infection is a frequent cause of sepsis in humans, a disease associated with high mortality and without specific intervention. When suspended in human or animal plasma, staphylococci are known to agglutinate, however the bacterial factors responsible for agglutination and their possible contribution to disease pathogenesis have not yet been revealed. Using a mouse model for S. aureus sepsis, we report here that staphylococcal agglutination in blood was associated with a lethal outcome of this disease. Three secreted products of staphylococci--coagulase (Coa), von Willebrand factor binding protein (vWbp) and clumping factor (ClfA)--were required for agglutination. Coa and vWbp activate prothrombin to cleave fibrinogen, whereas ClfA allowed staphylococci to associate with the resulting fibrin cables. All three virulence genes promoted the formation of thromboembolic lesions in heart tissues. S. aureus agglutination could be disrupted and the lethal outcome of sepsis could be prevented by combining dabigatran-etexilate treatment, which blocked Coa and vWbp activity, with antibodies specific for ClfA. Together these results suggest that the combined administration of direct thrombin inhibitors and ClfA-antibodies that block S. aureus agglutination with fibrin may be useful for the prevention of staphylococcal sepsis in humans.

Flt1/VEGFR1 heterozygosity causes transient embryonic edema.

PubMed

Otowa, Yasunori; Moriwaki, Kazumasa; Sano, Keigo; Shirakabe, Masanori; Yonemura, Shigenobu; Shibuya, Masabumi; Rossant, Janet; Suda, Toshio; Kakeji, Yoshihiro; Hirashima, Masanori

2016-06-02

Vascular endothelial growth factor-A is a major player in vascular development and a potent vascular permeability factor under physiological and pathological conditions by binding to a decoy receptor Flt1 and its primary receptor Flk1. In this study, we show that Flt1 heterozygous (Flt1(+/-)) mouse embryos grow up to adult without life-threatening abnormalities but exhibit a transient embryonic edema around the nuchal and back regions, which is reminiscent of increased nuchal translucency in human fetuses. Vascular permeability is enhanced and an intricate infolding of the plasma membrane and huge vesicle-like structures are seen in Flt1(+/-) capillary endothelial cells. Flk1 tyrosine phosphorylation is elevated in Flt1(+/-) embryos, but Flk1 heterozygosity does not suppress embryonic edema caused by Flt1 heterozygosity. When Flt1 mutants are crossed with Aspp1(-/-) mice which exhibit a transient embryonic edema with delayed formation and dysfunction of lymphatic vessels, only 5.7% of Flt1(+/-); Aspp1(-/-) mice survive, compared to expected ratio (25%). Our results demonstrate that Flt1 heterozygosity causes a transient embryonic edema and can be a risk factor for embryonic lethality in combination with other mutations causing non-lethal vascular phenotype.

Aggression-impulsivity, mental pain, and communication difficulties in medically serious and medically non-serious suicide attempters.

PubMed

Gvion, Yari; Horresh, Netta; Levi-Belz, Yossi; Fischel, Tsvi; Treves, Ilan; Weiser, Mark; David, Haim Shem; Stein-Reizer, Orit; Apter, Alan

2014-01-01

Unbearable mental pain, depression, and hopelessness have been associated with suicidal behavior in general, while difficulties with social communication and loneliness have been associated with highly lethal suicide attempts in particular. The literature also links aggression and impulsivity with suicidal behavior but raises questions about their influence on the lethality and outcome of the suicide attempt. To evaluate the relative effects of aggression and impulsivity on the lethality of suicide attempts we hypothesized that impulsivity and aggression differentiate between suicide attempters and non-attempters and between medically serious and medically non-serious suicide attempters. The study group included 196 participants divided into four groups: 43 medically serious suicide attempters; 49 medically non-serious suicide attempters, 47 psychiatric patients who had never attempted suicide; and 57 healthy control subjects. Data on sociodemographic parameters, clinical history, and details of the suicide attempts were collected. Participants completed a battery of instruments for assessment of aggression-impulsivity, mental pain, and communication difficulties. The medically serious and medically non-serious suicide attempters scored significantly higher than both control groups on mental pain, depression, and hopelessness (p<.001 for all) and on anger-in, anger-out, violence, and impulsivity (p<.05 for all), with no significant difference between the two suicide attempter groups. Medically serious suicide attempters had significantly lower self-disclosure (p<.05) and more schizoid tendencies (p<.001) than the other three groups and significantly more feelings of loneliness than the medically non-serious suicide attempters and nonsuicidal psychiatric patients (p<.05). Analysis of aggression-impulsivity, mental pain, and communication variables with suicide lethality yielded significant correlations for self-disclosure, schizoid tendency, and loneliness. The interaction between mental pain and schizoid traits explained some of the variance in suicide lethality, over and above the contribution of each component alone. Aggression-impulsivity and mental pain are risk factors for suicide attempts. However, only difficulties in communication differentiate medically serious from medically non-serious suicide attempters. The combination of unbearable mental pain and difficulties in communication has a magnifying effect on the risk of lethal suicidal behavior. © 2014.

Lethality of sortase depletion in Actinomyces oris caused by excessive membrane accumulation of a surface glycoprotein.

PubMed

Wu, Chenggang; Huang, I-Hsiu; Chang, Chungyu; Reardon-Robinson, Melissa Elizabeth; Das, Asis; Ton-That, Hung

2014-12-01

Sortase, a cysteine-transpeptidase conserved in Gram-positive bacteria, anchors on the cell wall many surface proteins that facilitate bacterial pathogenesis and fitness. Genetic disruption of the housekeeping sortase in several Gram-positive pathogens reported thus far attenuates virulence, but not bacterial growth. Paradoxically, we discovered that depletion of the housekeeping sortase SrtA was lethal for Actinomyces oris; yet, all of its predicted cell wall-anchored protein substrates (AcaA-N) were individually dispensable for cell viability. Using Tn5-transposon mutagenesis to identify factors that upend lethality of srtA deletion, we uncovered a set of genetic suppressors harbouring transposon insertions within genes of a locus encoding AcaC and a LytR-CpsA-Psr (LCP)-like protein. AcaC was shown to be highly glycosylated and dependent on LCP for its glycosylation. Upon SrtA depletion, the glycosylated form of AcaC, hereby renamed GspA, was accumulated in the membrane. Overexpression of GspA in a mutant lacking gspA and srtA was lethal; conversely, cells overexpressing a GspA mutant missing a membrane-localization domain were viable. The results reveal a unique glycosylation pathway in A. oris that is coupled to cell wall anchoring catalysed by sortase SrtA. Significantly, this novel phenomenon of glyco-stress provides convenient cell-based assays for developing a new class of inhibitors against Gram-positive pathogens. © 2014 John Wiley & Sons Ltd.

Metabolic Response of Escherichia coli upon Treatment with Hypochlorite at Sub-Lethal Concentrations

PubMed Central

Winter, Jeannette; Eisenreich, Wolfgang

2015-01-01

Hypochlorite is a reactive oxygen species that is worldwide as an antibacterial disinfectant. Hypochlorite exposure is known to cause oxidative damage to DNA and proteins. As a response to these effects, the metabolite profiles of organisms treated with sub-lethal doses of hypochlorite are assumed to be severely modified; however, the nature of these changes is hardly understood. Therefore, using nuclear magnetic resonance spectroscopy and gas chromatography-coupled mass spectrometry, we analyzed the time-dependent impact of hypochlorite exposure with a sub-lethal concentration (50 µM) on the metabolite profile of the Escherichia coli strain MG1655. Principle component analysis clearly distinguished between the metabolite profiles of bacteria treated for 0, 5,10, 20, 40, or 60 min. Major changes in the relative amounts of fatty acids, acetic acid, and formic acid occurred within the first 5 min. Comparative gas chromatography-coupled mass spectrometry analyses revealed that the amounts of free methionine and alanine were significantly decreased in the treated cells, demonstrating their susceptibility to hypochlorite exposure. The concentrations of succinate, urea, orotic acid, 2-aminobutyric acid, and 2-hydroxybutyric acid were also severely affected, indicating general changes in the metabolic network by hypochlorite. However, most metabolite levels relaxed to the reference values of untreated cells after 40–60 min, reflecting the capability of E. coli to rapidly adapt to environmental stress factors such as the presence of sub-lethal oxidant levels. PMID:25932918

Suicide and Firearm Means Restriction: Can Training Make a Difference?

ERIC Educational Resources Information Center

Slovak, Karen; Brewer, Thomas W.

2010-01-01

Along with physician education in depression recognition and treatment, restricting lethal methods is an effective suicide prevention strategy. The present study surveyed a random sample (N = 697) of Ohio licensed social workers regarding client firearm assessment and safety counseling. Analyses sought to determine what independent factors would…

A Call for Research on Planned vs. Unplanned Suicidal Behavior

ERIC Educational Resources Information Center

Conner, Kenneth R.

2004-01-01

Unplanned acts of suicidal behavior involve little preparation or forethought whereas planned acts may be carefully conceived and implemented. Planned acts are associated with greater depression, hopelessness, and lethality, but there are meager data on other factors associated with planning. The prevention of planned and unplanned acts may…

Photoreactivation of Ultraviolet-Irradiated, Plasmid-Bearing and Plasmid-Free Strains of Bacillus anthracis

DTIC Science & Technology

1985-12-19

positive bacterium Bacillus anthracis, is a virulent and highly contagious disease to which most warm-blooded animals, including man, are susceptible... Virulent strains of B. anthracis produce a capsule composed of poly-0-glutamic acid and an exotoxin. The toxin is composed of three proteins identified...as ederma factor (EF), protective antigen (PA), and lethal factor (LF) (17). Anthrax toxin and capsule production are associated with two separate

Synthetic Lethal Networks for Precision Oncology: Promises and Pitfalls.

PubMed

Shen, John Paul; Ideker, Trey

2018-06-19

Synthetic lethal interactions, in which the simultaneous loss-of-function of two genes produces a lethal phenotype, are being explored as a means to therapeutically exploit cancer-specific vulnerabilities and expand the scope of precision oncology. Currently, three FDA approved drugs work by targeting the synthetic lethal interaction between BRCA1/2 and PARP. This review examines additional efforts to discover networks of synthetic lethal interactions and discusses both challenges and opportunities regarding the translation of new synthetic lethal interactions into the clinic. Copyright © 2018. Published by Elsevier Ltd.

Rancher-reported efficacy of lethal and non-lethal livestock predation mitigation strategies for a suite of carnivores.

PubMed

Scasta, J D; Stam, B; Windh, J L

2017-10-26

Pastoralists have dealt with livestock losses from predators for millennia, yet effective mitigation strategies that balance wildlife conservation and sustainable agriculture are still needed today. In Wyoming, USA, 274 ranchers responded to a retrospective survey, and rated the efficacy of predation mitigation strategies for foxes, dogs, coyotes, wolves, bobcats, mountain lions, bears, and birds (buzzards, eagles, hawks, ravens). Rancher reported efficacy of mitigation varied by predator species, mitigation strategy, and lethality of strategies, but not livestock type. Ranchers perceive they were most effective at mitigating predation by foxes and coyotes, moderately effective at mitigating large carnivores, and the least effective at mitigating birds. Ranchers also reported that avian predators seem to be the most challenging predator type. The general perception was lethal mitigation strategies were more effective than non-lethal strategies, with guard animals showing the most potential among the non-lethal options. In general, ranchers did not perceive non-lethal strategies as a proxy for lethal strategies. However, a few ranchers reported being successful with non-lethal options such as herding, fencing, and stalling at night but more details about such successful applications are needed. Innovation in current or novel non-lethal mitigation strategies, and examples of efficacy, are needed to justify producer adoption.

Issues surrounding lethal injection as a means of capital punishment.

PubMed

Romanelli, Frank; Whisman, Tyler; Fink, Joseph L

2008-12-01

Lethal injection as a method of state-sanctioned capital punishment was initially proposed in the United States in 1977 and used for the first time in 1982. Most lethal injection protocols use a sequential drug combination of sodium thiopental, pancuronium bromide, and potassium chloride. Lethal injection was originally introduced as a more humane form of execution compared with existing mechanical methods such as electrocution, toxic gassing, hanging, or firing squad. Lethal injection has not, however, been without controversy. Several states are considering whether lethal injection meets constitutional scrutiny forbidding cruel and unusual punishment. Recently in the case of Ralph Baze and Thomas C. Bowling, Petitioners, v John D. Rees, Commissioner, Kentucky Department of Corrections et al, the United States Supreme Court upheld the constitutionality of the lethal injection protocol as carried out in the Commonwealth of Kentucky. Most of the debate has surrounded the dosing and procedures used in lethal injection and whether the drug combinations and measures for administering the drugs truly produce a timely, pain-free, and fail-safe death. Many have also raised issues regarding the "medicalization" of execution and the ethics of health care professionals' participation in any part of the lethal injection process. As a result of all these issues, the future of lethal injection as a means of execution in the United States is under significant scrutiny. Outcomes of ongoing legislative and judicial reviews might result in cessation of lethal injection in totality or in alterations involving specific drug combinations or administration procedures.

Inferring the distribution of mutational effects on fitness in Drosophila.

PubMed

Loewe, Laurence; Charlesworth, Brian

2006-09-22

The properties of the distribution of deleterious mutational effects on fitness (DDME) are of fundamental importance for evolutionary genetics. Since it is extremely difficult to determine the nature of this distribution, several methods using various assumptions about the DDME have been developed, for the purpose of parameter estimation. We apply a newly developed method to DNA sequence polymorphism data from two Drosophila species and compare estimates of the parameters of the distribution of the heterozygous fitness effects of amino acid mutations for several different distribution functions. The results exclude normal and gamma distributions, since these predict too few effectively lethal mutations and power-law distributions as a result of predicting too many lethals. Only the lognormal distribution appears to fit both the diversity data and the frequency of lethals. This DDME arises naturally in complex systems when independent factors contribute multiplicatively to an increase in fitness-reducing damage. Several important parameters, such as the fraction of effectively neutral non-synonymous mutations and the harmonic mean of non-neutral selection coefficients, are robust to the form of the DDME. Our results suggest that the majority of non-synonymous mutations in Drosophila are under effective purifying selection.

Response of Leuconostoc strains against technological stress factors: Growth performance and volatile profiles.

PubMed

Cicotello, Joaquín; Wolf, Irma V; D'Angelo, Luisa; Guglielmotti, Daniela M; Quiberoni, Andrea; Suárez, Viviana B

2018-08-01

The ability of twelve strains belonging to three Leuconostoc species (Leuconostoc mesenteroides, Leuconostoc lactis and Leuconostoc pseudomesenteroides) to grow under diverse sub-lethal technological stress conditions (cold, acidic, alkaline and osmotic) was evaluated in MRS broth. Two strains, Leuconostoc lactis Ln N6 and Leuconostoc mesenteroides Ln MB7, were selected based on their growth under sub-lethal conditions, and volatile profiles in RSM (reconstituted skim milk) at optimal and under stress conditions were analyzed. Growth rates under sub-lethal conditions were strain- and not species-dependent. Volatilomes obtained from the two strains studied were rather diverse. Particularly, Ln N6 (Ln. lactis) produced more ethanol and acetic acid than Ln MB7 (Ln. mesenteroides) and higher amounts and diversity of the rest of volatile compounds as well, at all times of incubation. For the two strains studied, most of stress conditions applied diminished the amounts of ethanol and acetic acid produced and the diversity and levels of the rest of volatile compounds. These results were consequence of the different capacity of the strains to grow under each stress condition tested. Copyright © 2018 Elsevier Ltd. All rights reserved.

Toxicity and bioconcentration evaluation of RDX and HMX using sheepshead minnows in water exposures.

PubMed

Lotufo, Guilherme R; Gibson, Alfreda B; Yoo, J Leslie

2010-10-01

Lethal effects of the explosives RDX and HMX were assessed using ten-day water exposures to juvenile sheepshead minnows (Cyprinodon variegatus). For RDX, maximum mortality occurred during the first two days of exposure with a 10-d median lethal concentration (LC50) of 9.9 mg L(-1). The RDX 10-d median lethal residue (LR50) was 9.6 mg kg(-1) (34.9 μmol kg(-1)) wet weight (ww), the first RDX critical body residue reported for fish. Previous investigations reported that RDX body residues in marine amphipods up to 96 μmol kg(-1) ww and in marine mussels up to 86 μmol kg(-1) ww failed to result in significant mortality. The highest HMX concentration tested, corresponding to its apparent solubility limit in seawater (2.0 mg L(-1)), and the associated mean body residue (3 mg kg(-1) or 14 μmol kg(-1) ww) resulted in no significant mortality for exposed minnows. The mean 10-d bioconcentration factors for RDX (0.6-0.9 L kg(-1)) and HMX (0.3-1.6 L kg(-1)) were typically lower than 1, reflecting the low bioaccumulative potential for these compounds. Published by Elsevier Inc.

FGFR3-related condition: a skeletal dysplasia with similarities to thanatophoric dysplasia and SADDAN due to Lys650Met.

PubMed

Farmakis, Shannon G; Shinawi, Marwan; Miller-Thomas, Michelle; Radmanesh, Alireza; Herman, Thomas E

2015-03-01

Mutations in the fibroblast growth factor receptor 3 (FGFR3) gene account for six related skeletal dysplasia conditions: achondroplasia, hypochondroplasia, thanatophoric dysplasia types 1 and 2, SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans), and platyspondylic lethal skeletal dysplasia, San Diego type. This group of disorders has very characteristic clinical and radiologic features, which distinguish them from other skeletal dysplasias. They display a spectrum of severity in the skeletal findings, ranging from relatively mild hypochondroplasia to lethal thanatophoric dysplasia. We report a patient who has the missense FGFR3 mutation, Lys650Met, previously reported in association only with SADDAN, who exhibits some findings similar to both thanatophoric dysplasia (types 1 and 2) in addition to those findings characteristic of SADDAN.

The solar UV environment and bacterial spore UV resistance: considerations for Earth-to-Mars transport by natural processes and human spaceflight.

PubMed

Nicholson, Wayne L; Schuerger, Andrew C; Setlow, Peter

2005-04-01

The environment in space and on planets such as Mars can be lethal to microorganisms because of the high vacuum and high solar radiation flux, in particular UV radiation, in such environments. Spores of various Bacillus species are among the organisms most resistant to the lethal effects of high vacuum and UV radiation, and as a consequence are of major concern for planetary contamination via unmanned spacecraft or even natural processes. This review focuses on the spores of various Bacillus species: (i) their mechanisms of UV resistance; (ii) their survival in unmanned spacecraft, space flight and simulated space flight and Martian conditions; (iii) the UV flux in space and on Mars; (iv) factors affecting spore survival in such high UV flux environments.

Organophosphorus insecticides in honey, pollen and bees (Apis mellifera L.) and their potential hazard to bee colonies in Egypt.

PubMed

Al Naggar, Yahya; Codling, Garry; Vogt, Anja; Naiem, Elsaied; Mona, Mohamed; Seif, Amal; Giesy, John P

2015-04-01

There is no clear single factor to date that explains colony loss in bees, but one factor proposed is the wide-spread application of agrochemicals. Concentrations of 14 organophosphorous insecticides (OPs) in honey bees (Apis mellifera) and hive matrices (honey and pollen) were measured to assess their hazard to honey bees. Samples were collected during spring and summer of 2013, from 5 provinces in the middle delta of Egypt. LC/MS-MS was used to identify and quantify individual OPs by use of a modified Quick Easy Cheap Effective Rugged Safe (QuEChERS) method. Pesticides were detected more frequently in samples collected during summer. Pollen contained the greatest concentrations of OPs. Profenofos, chlorpyrifos, malation and diazinon were the most frequently detected OPs. In contrast, ethoprop, phorate, coumaphos and chlorpyrifos-oxon were not detected. A toxic units approach, with lethality as the endpoint was used in an additive model to assess the cumulative potential for adverse effects posed by OPs. Hazard quotients (HQs) in honey and pollen ranged from 0.01-0.05 during spring and from 0.02-0.08 during summer, respectively. HQs based on lethality due to direct exposure of adult worker bees to OPs during spring and summer ranged from 0.04 to 0.1 for best and worst case respectively. It is concluded that direct exposure and/or dietary exposure to OPs in honey and pollen pose little threat due to lethality of bees in Egypt. Copyright © 2014 Elsevier Inc. All rights reserved.

Quantitative Determination of Lethal Toxin Proteins in Culture Supernatant of Human Live Anthrax Vaccine Bacillus anthracis A16R

PubMed Central

Zai, Xiaodong; Zhang, Jun; Liu, Ju; Liu, Jie; Li, Liangliang; Yin, Ying; Fu, Ling; Xu, Junjie; Chen, Wei

2016-01-01

Bacillus anthracis (B. anthracis) is the etiological agent of anthrax affecting both humans and animals. Anthrax toxin (AT) plays a major role in pathogenesis. It includes lethal toxin (LT) and edema toxin (ET), which are formed by the combination of protective antigen (PA) and lethal factor (LF) or edema factor (EF), respectively. The currently used human anthrax vaccine in China utilizes live-attenuated B. anthracis spores (A16R; pXO1+, pXO2−) that produce anthrax toxin but cannot produce the capsule. Anthrax toxins, especially LT, have key effects on both the immunogenicity and toxicity of human anthrax vaccines. Thus, determining quantities and biological activities of LT proteins expressed by the A16R strain is meaningful. Here, we explored LT expression patterns of the A16R strain in culture conditions using another vaccine strain Sterne as a control. We developed a sandwich ELISA and cytotoxicity-based method for quantitative detection of PA and LF. Expression and degradation of LT proteins were observed in culture supernatants over time. Additionally, LT proteins expressed by the A16R and Sterne strains were found to be monomeric and showed cytotoxic activity, which may be the main reason for side effects of live anthrax vaccines. Our work facilitates the characterization of anthrax vaccines components and establishment of a quality control standard for vaccine production which may ultimately help to ensure the efficacy and safety of the human anthrax vaccine A16R. PMID:26927174

Epigenome-Wide Tumor DNA Methylation Profiling Identifies Novel Prognostic Biomarkers of Metastatic-Lethal Progression in Men Diagnosed with Clinically Localized Prostate Cancer.

PubMed

Zhao, Shanshan; Geybels, Milan S; Leonardson, Amy; Rubicz, Rohina; Kolb, Suzanne; Yan, Qingxiang; Klotzle, Brandy; Bibikova, Marina; Hurtado-Coll, Antonio; Troyer, Dean; Lance, Raymond; Lin, Daniel W; Wright, Jonathan L; Ostrander, Elaine A; Fan, Jian-Bing; Feng, Ziding; Stanford, Janet L

2017-01-01

Aside from Gleason sum, few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential. Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of prostate cancer patients followed prospectively for at least 5 years. Metastasis was confirmed by positive bone scan, MRI, CT, or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from nonrecurrent tumors, and which were complementary to Gleason sum. Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P < 0.05) AUC (range, 0.66-0.75) or pAUC (range, 0.007-0.009). The biomarkers that improved discrimination of patients with metastatic-lethal prostate cancer include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset, the AUC for Gleason sum alone (0.82) significantly increased with the addition of four individual CpGs (range, 0.86-0.89; all P <0.05). Eight differentially methylated CpGs that distinguish patients with metastatic-lethal from nonrecurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. Clin Cancer Res; 23(1); 311-9. ©2016 AACR. ©2016 American Association for Cancer Research.

Species Profiles: Life Histories and Environmental Requirements of Coastal Fishes and Invertebrates (Pacific Southwest): Striped Bass

DTIC Science & Technology

1988-03-01

no ill effects (Table 5). Juve- Temperature niles acclimated to higher tempera- tures had higher lethal limits than Striped bass eggs have a broad fish...decrease was gradual (4 C/h). Adult tween 14 and 23 °C (Albrecht 1964). preferred temperatures varied with Table 3. Effects of selected environmental...34.% .N~ Table 4. Effects of selected environmental factors on striped bass larval stages. 0 Environmental Experimental factor conditions Tolerance

Peptide Probes Reveal a Hydrophobic Steric Ratchet in the Anthrax Toxin Protective Antigen Translocase.

PubMed

Colby, Jennifer M; Krantz, Bryan A

2015-11-06

Anthrax toxin is a tripartite virulence factor produced by Bacillus anthracis during infection. Under acidic endosomal pH conditions, the toxin's protective antigen (PA) component forms a transmembrane channel in host cells. The PA channel then translocates its two enzyme components, lethal factor and edema factor, into the host cytosol under the proton motive force. Protein translocation under a proton motive force is catalyzed by a series of nonspecific polypeptide binding sites, called clamps. A 10-residue guest/host peptide model system, KKKKKXXSXX, was used to functionally probe polypeptide-clamp interactions within wild-type PA channels. The guest residues were Thr, Ala, Leu, Phe, Tyr, and Trp. In steady-state translocation experiments, the channel blocked most tightly with peptides that had increasing amounts of nonpolar surface area. Cooperative peptide binding was observed in the Trp-containing peptide sequence but not the other tested sequences. Trp substitutions into a flexible, uncharged linker between the lethal factor amino-terminal domain and diphtheria toxin A chain expedited translocation. Therefore, peptide-clamp sites in translocase channels can sense large steric features (like tryptophan) in peptides, and while these steric interactions may make a peptide translocate poorly, in the context of folded domains, they can make the protein translocate more rapidly presumably via a hydrophobic steric ratchet mechanism. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

A selfish gene chastened: Tribolium castaneum Medea M4 is silenced by a complementary gene.

PubMed

Thomson, M Scott

2014-04-01

Maternal-effect dominant embryonic arrest (Medea) of Tribolium castaneum are autosomal factors that act maternally to cause the death of any progeny that do not inherit them. This selfish behavior is thought to result from a maternally expressed poison and zygotically expressed antidote. Medea factors and the hybrid incompatibility factor, H, have a negative interaction consistent with complementary genes of the Dobzhansky-Muller model for post-zygotic isolation. This negative interaction may result from H suppression of Medea zygotic antidote, leaving zygotes incompletely protected from maternal poison. I report here a test of the hypothesis that H also suppresses the Medea maternal poison. Viable F1 females were generated from a cross of Medea M4 strain males to H strain females. These females, heterozygous for both M4 and H, failed to express M4 maternal lethal activity when crossed to their male sibs. Transmission of non-M4 homologues from these females was confirmed using a dominant transgenic enhanced green fluorescent protein eye color marker, tightly linked in cis to M4. M4 beetles, lacking H, were selected from the F2 population. Female descendants of these clearly expressed M4 maternal lethal activity, indicating restoration of this activity after H was segregated away. I conclude that H, or a factor tightly linked to H, suppresses Medea M4 maternal poison.

Impact of myxomatosis in relation to local persistence in wild rabbit populations: the role of waning immunity and the reproductive period.

PubMed

Fouchet, David; Guitton, Jean-Sébastien; Marchandeau, Stéphane; Pontier, Dominique

2008-02-21

Many diseases are less severe when they are contracted in early life. For highly lethal diseases, such as myxomatosis in rabbits, getting infected early in life can represent the best chance for an individual to survive the disease. For myxomatosis, early infections are attenuated by maternal antibodies. This may lead to the immunisation of the host, preventing the subsequent development of the lethal form of the disease. But early infection of young individuals requires specific demographic and epidemiological contexts, such as a high transmission rate of the pathogen agent. To investigate other factors involved in the impact of such diseases, we have built a stochastic model of a rabbit metapopulation infected by myxomatosis. We show that the impact of the pathogen agent can be reduced by early infections only when the agent has a long local persistence time and/or when the host subpopulations are highly connected. The length of the reproductive period and the duration of acquired immunity are also important factors influencing the persistence of the pathogen and thus, the impact of the disease. Besides confirming the role of classical factors in the persistence of a pathogen agent, such as the size of the subpopulation or the degree of connectivity, our results highlight novel factors that can modulate the impact of diseases whose severity increase with age.

Lethality of Rendang packaged in multilayer retortable pouch with sterilization process

NASA Astrophysics Data System (ADS)

Praharasti, A. S.; Kusumaningrum, A.; Frediansyah, A.; Nurhikmat, A.; Khasanah, Y.; Suprapedi

2017-01-01

Retort Pouch had become a choice to preserve foods nowadays, besides the used of the can. Both had their own advantages, and Retort Pouch became more popular for the reason of cheaper and easier to recycle. General Method usually used to estimate the lethality of commercial heat sterilization process. Lethality value wa s used for evaluating the efficacy of the thermal process. This study aimed to find whether different layers of pouch materials affect the lethality value and to find differences lethality in two types of multilayer retort pouch, PET/Aluminum Foil/Nylon/RCPP and PET/Nylon/Modified Aluminum/CPP. The result showed that the different layer arrangement was resulted different Sterilization Value (SV). PET/Nylon/Modified Aluminum/CPP had better heat penetration, implied by the higher value of lethality. PET/Nylon/Modified Aluminum/CPP had the lethality value of 6,24 minutes, whereas the lethality value of PET/Aluminum Foil/Nylon/RCPP was 3,54 minutes.

40 CFR Appendix A to Part 300 - The Hazard Ranking System

Code of Federal Regulations, 2011 CFR

2011-07-01

... control groups. For HRS purposes, the response considered is cancer. [milligrams toxicant per kilogram...-2Containment factor values for surface water migration pathway. 4-3Drainage area values. 4-4Soil group... a group of exposed organisms. The LC50 is used in the HRS in assessing acute toxicity. LD 50 (lethal...

40 CFR Appendix A to Part 300 - The Hazard Ranking System

Code of Federal Regulations, 2012 CFR

2012-07-01

... control groups. For HRS purposes, the response considered is cancer. [milligrams toxicant per kilogram...-2Containment factor values for surface water migration pathway. 4-3Drainage area values. 4-4Soil group... a group of exposed organisms. The LC50 is used in the HRS in assessing acute toxicity. LD 50 (lethal...

Combined effects of Corexit EC 9500A with secondary abiotic and biotic factors in the rotifer Brachionus plicatilis.

PubMed

Williams, Michael B; Powell, Mickie L; Watts, Stephen A

2016-10-01

We examined lethality and behavioral effects of Corexit EC 9500A (C-9500A) exposure on the model marine zooplankton Brachionus plicatilis singularly and in combination with abiotic and biotic factors. C-9500A exposure at standard husbandry conditions (17.5ppt, 24°C, 200 rotifer*mL(-1) density) identified the 24h median lethal concentration, by Probit analysis, to be 107ppm for cultured B. plicatilis. Rotifers surviving exposure to higher concentrations (100 and 150ppm) exhibited a decreased swimming velocity and a reduced net to gross movement ratio. Significant interaction between C-9500A exposure and temperature or salinity was observed. Upper thermal range was reduced and maximal salinity stress was seen as ca. 25ppt. Increased or decreased nutritional availability over the exposure period did not significantly alter mortality of B. plicatilis populations at the concentrations tested. Results from this study may be useful for predicting possible outcomes on marine zooplankton following dispersant application under diverse natural conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

An Allele of Sequoia Dominantly Enhances a Trio Mutant Phenotype to Influence Drosophila Larval Behavior

PubMed Central

Liebl, Eric C.

2013-01-01

The transition of Drosophila third instar larvae from feeding, photo-phobic foragers to non-feeding, photo-neutral wanderers is a classic behavioral switch that precedes pupariation. The neuronal network responsible for this behavior has recently begun to be defined. Previous genetic analyses have identified signaling components for food and light sensory inputs and neuropeptide hormonal outputs as being critical for the forager to wanderer transition. Trio is a Rho-Guanine Nucleotide Exchange Factor integrated into a variety of signaling networks including those governing axon pathfinding in early development. Sequoia is a pan-neuronally expressed zinc-finger transcription factor that governs dendrite and axon outgrowth. Using pre-pupal lethality as an endpoint, we have screened for dominant second-site enhancers of a weakly lethal trio mutant background. In these screens, an allele of sequoia has been identified. While these mutants have no obvious disruption of embryonic central nervous system architecture and survive to third instar larvae similar to controls, they retain forager behavior and thus fail to pupariate at high frequency. PMID:24376789

An allele of sequoia dominantly enhances a trio mutant phenotype to influence Drosophila larval behavior.

PubMed

Dean, Kathryn E; Fields, April; Geer, Marcus J; King, Eric C; Lynch, Brian T; Manohar, Rohan R; McCall, Julianne R; Palozola, Katherine C; Zhang, Yan; Liebl, Eric C

2013-01-01

The transition of Drosophila third instar larvae from feeding, photo-phobic foragers to non-feeding, photo-neutral wanderers is a classic behavioral switch that precedes pupariation. The neuronal network responsible for this behavior has recently begun to be defined. Previous genetic analyses have identified signaling components for food and light sensory inputs and neuropeptide hormonal outputs as being critical for the forager to wanderer transition. Trio is a Rho-Guanine Nucleotide Exchange Factor integrated into a variety of signaling networks including those governing axon pathfinding in early development. Sequoia is a pan-neuronally expressed zinc-finger transcription factor that governs dendrite and axon outgrowth. Using pre-pupal lethality as an endpoint, we have screened for dominant second-site enhancers of a weakly lethal trio mutant background. In these screens, an allele of sequoia has been identified. While these mutants have no obvious disruption of embryonic central nervous system architecture and survive to third instar larvae similar to controls, they retain forager behavior and thus fail to pupariate at high frequency.

Impulsivity, aggression and brain structure in high and low lethality suicide attempters with borderline personality disorder.

PubMed

Soloff, Paul; White, Richard; Diwadkar, Vaibhav A

2014-06-30

Impulsivity and aggressiveness are trait dispositions associated with the vulnerability to suicidal behavior across diagnoses. They are associated with structural and functional abnormalities in brain networks involved in regulation of mood, impulse and behavior. They are also core characteristics of borderline personality disorder (BPD), a disorder defined, in part, by recurrent suicidal behavior. We assessed the relationships between personality traits, brain structure and lethality of suicide attempts in 51 BPD attempters using multiple regression analyses on structural MRI data. BPD was diagnosed by the Diagnostic Interview for Borderline Patients-revised, impulsivity by the Barratt Impulsiveness Scale (BIS), aggression by the Brown-Goodwin Lifetime History of Aggression (LHA), and high lethality by a score of 4 or more on the Lethality Rating Scale (LRS). Sixteen High Lethality attempters were compared to 35 Low Lethality attempters, with no significant differences noted in gender, co-morbidity, childhood abuse, BIS or LHA scores. Degree of medical lethality (LRS) was negatively related to gray matter volumes across multiple fronto-temporal-limbic regions. Effects of impulsivity and aggression on gray matter volumes discriminated High from Low Lethality attempters and differed markedly within lethality groups. Lethality of suicide attempts in BPD may be related to the mediation of these personality traits by specific neural networks. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Weapon Involvement in the Victimization of Children.

PubMed

Mitchell, Kimberly J; Hamby, Sherry L; Turner, Heather A; Shattuck, Anne; Jones, Lisa M

2015-07-01

To report the prevalence of weapons involved in the victimization of youth with particular emphasis on weapons with a "high lethality risk" and how such exposure fits into the broader victimization and life experiences of children and adolescents. Data were collected as part of the Second National Survey of Children's Exposure to Violence, a nationally representative telephone survey of youth ages 2 to 17 years and caregivers (N = 4114) conducted in 2011. Estimates from the Second National Survey of Children's Exposure to Violence indicate that almost 14 million youth, ages 2–17, in the United States have been exposed to violence involving a weapon in their lifetimes as witnesses or victims,or .1 in 5 children in this age group [corrected]. More than 2 million youth in the United States (1 in 33) have been directly assaulted in incidents where the high lethality risk weapons of guns and knives were used. Differences were noted between victimizations involving higher and lower lethality risk weapons as well as between any weapon involvement versus none. Poly-victims, youth with 7 or more victimization types, were particularly likely to experience victimization with any weapon, as well as victimization with a highly lethal weapon compared with nonpoly-victims. Findings add to the field's broadening conceptualization of youth victimization highlighting the potentially highly consequential risk factor of weapon exposure as a component of victimization experiences on the mental health of youth. Further work on improving gun safety practices and taking steps to reduce children's exposure to weapon-involved violence is warranted to reduce this problem. Copyright © 2015 by the American Academy of Pediatrics.

Estimation of effectiveness of three methods of feral cat population control by use of a simulation model.

PubMed

McCarthy, Robert J; Levine, Stephen H; Reed, J Michael

2013-08-15

To predict effectiveness of 3 interventional methods of population control for feral cat colonies. Population model. Estimates of vital data for feral cats. Data were gathered from the literature regarding the demography and mating behavior of feral cats. An individual-based stochastic simulation model was developed to evaluate the effectiveness of trap-neuter-release (TNR), lethal control, and trap-vasectomy-hysterectomy-release (TVHR) in decreasing the size of feral cat populations. TVHR outperformed both TNR and lethal control at all annual capture probabilities between 10% and 90%. Unless > 57% of cats were captured and neutered annually by TNR or removed by lethal control, there was minimal effect on population size. In contrast, with an annual capture rate of ≥ 35%, TVHR caused population size to decrease. An annual capture rate of 57% eliminated the modeled population in 4,000 days by use of TVHR, whereas > 82% was required for both TNR and lethal control. When the effect of fraction of adult cats neutered on kitten and young juvenile survival rate was included in the analysis, TNR performed progressively worse and could be counterproductive, such that population size increased, compared with no intervention at all. TVHR should be preferred over TNR for management of feral cats if decrease in population size is the goal. This model allowed for many factors related to the trapping program and cats to be varied and should be useful for determining the financial and person-effort commitments required to have a desired effect on a given feral cat population.

Biological damage induced by ionizing cosmic rays in dry Arabidopsis seeds.

PubMed

Kranz, A R; Bork, U; Bucker, H; Reitz, G

1990-01-01

In September 1987 dry seeds containing embryos of the crucifer plant Arabidopsis thaliana (L.) Heynh, were flown in orbit for 13 days on the Kosmos 1887 satellite. The seeds were fixed on CNd detectors and stored in units of Biorack type I/O. One unit was exposed inside, another one outside the satellite. The temperature profile of the flown seeds inside the satellite was simulated on earth in an identical backup control sample (BC). An additional control (SC) was studied with the original seeds sample. By use of the CNd-detector, HZE-tracks were measured with a PC-assisted microscope. The biological damages were investigated by growing the seeds under controlled climatic conditions. The following biological endpoints of the cosmic radiation damage were studied: germination, radicle length, sublethality, morphological aberrations, flower development, tumorization, embryo lethality inside the siliques. The summarized damage (D) and the mutation frequencies of embyronic lethal genes were calculated. The following results were obtained: the damages increase significantly in orbit at all biological endpoints; germination and fiowerings especially, as well as embryo lethality of fruits and lethal mutation frequency, were maximum mostly for HZE-hit seeds. Additionally, an increase of damage was observed for the seeds of the outside-exposed Biorack in comparison to the inside ones, which was probably caused by less radiation shielding and free space vacuum. The significance of the results obtained is discussed with respect to stress and risk and, thus, the quality of the RBE-factors and heavy ionizing radiation all needed for the very definition of radiation protection standards in space.

Mitigative Effects of a Combination of Multiple Pharmaceutical Drugs on the Survival of Mice Exposed to Lethal Ionizing Radiation.

PubMed

Hirouchi, Tokuhisa; Ito, Koichi; Nakano, Manabu; Monzen, Satoru; Yoshino, Hironori; Chiba, Mitsuru; Hazawa, Masaharu; Nakano, Akira; Ishikawa, Junya; Yamaguchi, Masaru; Tanaka, Kimio; Kashiwakura, Ikuo

2015-01-01

It is important to establish an easy-to-use therapeutic protocol for the emergency medical care of patients involved in radiation accidents to reduce the radiation-related casualties. The present study aimed to establish an optimum therapeutic protocol using currently approved pharmaceutical drugs to increase the survival of victims exposed to lethal radiation. Different combinations of four drugs-recombinant human erythropoietin (EPO), granulocyte-colony stimulating factor (G-CSF), c-mpl receptor agonist romiplostim (RP) and nandrolone decanoate (ND)-were administered to mice within 2 h after exposure to a lethal 7 Gy dose of γ-irradiation. On day 30 after irradiation, the condition of the mice was analyzed using various hematological parameters, such as the number of peripheral blood cells, bone marrow cells, hematopoietic progenitor cells and the expression of cell surface antigens. Approximately 10% of the untreated irradiated control mice survived for 21 days, but all of the control mice died by day 30. The combined administration of G-CSF, EPO and RP for five days immediately after irradiation led to a complete survival of the irradiated mice until day 30. However, the treatment with G-CSF, EPO and RP with ND led to only 75% survival at day 30. The hematological analyses showed that the numbers of almost all of hematopoietic cells in the surviving mice treated with effective medications recovered to the levels of non-irradiated mice. The present findings show that the combination of G-CSF, EPO and RP may be a useful countermeasure for victims exposed to accidental lethal irradiation.

From tails to toes: developing nonlethal tissue indicators of mercury exposure in five amphibian species.

PubMed

Pfleeger, Adam Z; Eagles-Smith, Collin A; Kowalski, Brandon M; Herring, Garth; Willacker, James J; Jackson, Allyson K; Pierce, John R

2016-04-01

Exposure to environmental contaminants has been implicated as a factor in global amphibian decline. Mercury (Hg) is a particularly widespread contaminant that biomagnifies in amphibians and can cause a suite of deleterious effects. However, monitoring contaminant exposure in amphibian tissues may conflict with conservation goals if lethal take is required. Thus, there is a need to develop non-lethal tissue sampling techniques to quantify contaminant exposure in amphibians. Some minimally invasive sampling techniques, such as toe-clipping, are common in population-genetic research, but it is unclear if these methods can adequately characterize contaminant exposure. We examined the relationships between mercury (Hg) concentrations in non-lethally sampled tissues and paired whole-bodies in five amphibian species. Specifically, we examined the utility of three different tail-clip sections from four salamander species and toe-clips from one anuran species. Both tail and toe-clips accurately predicted whole-body THg concentrations, but the relationships differed among species and the specific tail-clip section or toe that was used. Tail-clips comprised of the distal 0-2 cm segment performed the best across all salamander species, explaining between 82 and 92% of the variation in paired whole-body THg concentrations. Toe-clips were less effective predictors of frog THg concentrations, but THg concentrations in outer rear toes accounted for up to 79% of the variability in frog whole-body THg concentrations. These findings suggest non-lethal sampling of tails and toes has potential applications for monitoring contaminant exposure and risk in amphibians, but care must be taken to ensure consistent collection and interpretation of samples.

Coho salmon Oncorhynchus kisutch strain differences in disease resistance and non-specific immunity, following immersion challenges with Vibrio anguillarum

USGS Publications Warehouse

Balfry, Shannon K.; Maule, Alec G.; Iwama, George K.

2001-01-01

Two strains of freshwater-reared coho salmon Oncorhynchus kisutch were compared for differences in the activity of selected non-specific immune factors before and after lethal and non-lethal immersion challenges with the marine bacterial pathogen Vibrio anguillarum (Vang). Two disease challenge experiments were performed. The first experimental challenge resulted in no mortality; however, significant strain and challenge treatment effects were detected at Day 16 post-challenge. Strain differences in plasma lysozyme activity were found in pre-challenge samples. The second challenge experiment compared the same strains of coho salmon following immersion challenges in different doses of Vang. The fish were sampled at Days 0, 2, 7, and 18 post-challenge and mortality, plasma lysozyme, and anterior kidney phagocyte respiratory burst activity were compared. There were significant strain differences in mortality in the high dose group. The more disease-resistant strain was found to have higher levels of plasma lysozyme and anterior kidney phagocyte respiratory burst activity. These strain differences were detected at various times in the lethal (high dose) and non-lethal challenge groups. There was a clear relationship between the enhanced survival of the more disease-resistant strain and a more sustained, elevated non-specific immune response following the experimental disease challenges. The results of this study suggest that the basis for strain differences in innate disease resistance is related to the ability of the fish to respond quickly to the initial infection and to maintain the response until the infection is quelled.

Green tea polyphenol (−)-epigallocatechin-3-gallate triggered hepatotoxicity in mice: Responses of major antioxidant enzymes and the Nrf2 rescue pathway

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

Wang, Dongxu; Wang, Yijun; Wan, Xiaochun

(−)-Epigallocatechin-3-gallate (EGCG), a constituent of green tea, has been suggested to have numerous health-promoting effects. On the other hand, high-dose EGCG is able to evoke hepatotoxicity. In the present study, we elucidated the responses of hepatic major antioxidant enzymes and nuclear factor erythroid 2-related factor 2 (Nrf2) rescue pathway to high-dose levels of EGCG in Kunming mice. At a non-lethal toxic dose (75 mg/kg, i.p.), repeated EGCG treatments markedly decreased the levels of superoxide dismutase, catalase, and glutathione peroxidase. As a rescue response, the nuclear distribution of Nrf2 was significantly increased; a battery of Nrf2-target genes, including heme oxygenase 1more » (HO1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), and those involved in glutathione and thioredoxin systems, were all up-regulated. At the maximum tolerated dose (45 mg/kg, i.p.), repeated EGCG treatments did not disturb the major antioxidant defense. Among the above-mentioned genes, only HO1, NQO1, and GST genes were significantly but modestly up-regulated, suggesting a comprehensive and extensive activation of Nrf2-target genes principally occurs at toxic levels of EGCG. At a lethal dose (200 mg/kg, i.p.), a single EGCG treatment dramatically decreased not only the major antioxidant defense but also the Nrf2-target genes, demonstrating that toxic levels of EGCG are able to cause a biphasic response of Nrf2. Overall, the mechanism of EGCG-triggered hepatotoxicity involves suppression of major antioxidant enzymes, and the Nrf2 rescue pathway plays a vital role for counteracting EGCG toxicity. - Highlights: • EGCG at maximum tolerated dose does not disturb hepatic major antioxidant defense. • EGCG at maximum tolerated dose modestly upregulates hepatic Nrf2 target genes. • EGCG at toxic dose suppresses hepatic major antioxidant enzymes. • EGCG at non-lethal toxic dose pronouncedly activates hepatic Nrf2 rescue response. • EGCG at lethal dose substantially suppresses hepatic Nrf2 pathway.« less

Preventing Staphylococcus aureus Sepsis through the Inhibition of Its Agglutination in Blood

PubMed Central

McAdow, Molly; Kim, Hwan Keun; DeDent, Andrea C.; Hendrickx, Antoni P. A.; Schneewind, Olaf; Missiakas, Dominique M.

2011-01-01

Staphylococcus aureus infection is a frequent cause of sepsis in humans, a disease associated with high mortality and without specific intervention. When suspended in human or animal plasma, staphylococci are known to agglutinate, however the bacterial factors responsible for agglutination and their possible contribution to disease pathogenesis have not yet been revealed. Using a mouse model for S. aureus sepsis, we report here that staphylococcal agglutination in blood was associated with a lethal outcome of this disease. Three secreted products of staphylococci - coagulase (Coa), von Willebrand factor binding protein (vWbp) and clumping factor (ClfA) – were required for agglutination. Coa and vWbp activate prothrombin to cleave fibrinogen, whereas ClfA allowed staphylococci to associate with the resulting fibrin cables. All three virulence genes promoted the formation of thromboembolic lesions in heart tissues. S. aureus agglutination could be disrupted and the lethal outcome of sepsis could be prevented by combining dabigatran-etexilate treatment, which blocked Coa and vWbp activity, with antibodies specific for ClfA. Together these results suggest that the combined administration of direct thrombin inhibitors and ClfA-antibodies that block S. aureus agglutination with fibrin may be useful for the prevention of staphylococcal sepsis in humans. PMID:22028651

Bacillus anthracis lethal toxin induces TNF-α–independent hypoxia-mediated toxicity in mice

PubMed Central

Moayeri, Mahtab; Haines, Diana; Young, Howard A.; Leppla, Stephen H.

2003-01-01

Bacillus anthracis lethal toxin (LT) is the major virulence factor of anthrax and reproduces most of the laboratory manifestations of the disease in animals. We studied LT toxicity in BALB/cJ and C57BL/6J mice. BALB/cJ mice became terminally ill earlier and with higher frequency than C57BL/6J mice. Timed histopathological analysis identified bone marrow, spleen, and liver as major affected organs in both mouse strains. LT induced extensive hypoxia. Crisis was due to extensive liver necrosis accompanied by pleural edema. There was no evidence of disseminated intravascular coagulation or renal dysfunction. Instead, analyses revealed hepatic dysfunction, hypoalbuminemia, and vascular/oxygenation insufficiency. Of 50 cytokines analyzed, BALB/cJ mice showed rapid but transitory increases in specific factors including KC, MCP-1/JE, IL-6, MIP-2, G-CSF, GM-CSF, eotaxin, FasL, and IL-1β. No changes in TNF-α occurred. The C57BL/6J mice did not mount a similar cytokine response. These factors were not induced in vitro by LT treatment of toxin-sensitive macrophages. The evidence presented shows that LT kills mice through a TNF-α–independent, FasL-independent, noninflammatory mechanism that involves hypoxic tissue injury but does not require macrophage sensitivity to toxin. PMID:12952916

Airpower’s Emasculation? -- Non-lethal Weapons in Joint Urban Operations

DTIC Science & Technology

2005-02-14

Lethal, Subdue the Enemy Without Killing,” 14, US Military Non-Lethal Weapons, 10 November 1997, <http://www.geocities.com/ Area51 /Shadowlands/6583...37 “Non-Lethal, Subdue the Enemy Without Killing,” 10-11, US Military Non-Lethal Weapons, 10 November 1997, <http://www.geocities.com/ Area51 ... Area51 /Shadowlands/6583/project035.html> [15 December 2004]. 42 “US Plans for Use of Gas in Iraq,” The Sunshine Project, 7 February 2003, <http

Heterochromatin position effects on circularized sex chromosomes cause filicidal embryonic lethality in Drosophila melanogaster.

PubMed

Ferree, Patrick M; Gomez, Karina; Rominger, Peter; Howard, Dagnie; Kornfeld, Hannah; Barbash, Daniel A

2014-04-01

Some circularized X-Y chromosomes in Drosophila melanogaster are mitotically unstable and induce early embryonic lethality, but the genetic basis is unknown. Our experiments suggest that a large region of X-linked satellite DNA causes anaphase bridges and lethality when placed into a new heterochromatic environment within certain circularized X-Y chromosomes. These results reveal that repetitive sequences can be incompatible with one another in cis. The lethal phenotype also bears a remarkable resemblance to a case of interspecific hybrid lethality.

A Strategy To Isolate Modifiers of Caenorhabditis elegans Lethal Mutations: Investigating the Endoderm Specifying Ability of the Intestinal Differentiation GATA Factor ELT-2.

PubMed

Wiesenfahrt, Tobias; Duanmu, Jingjie; Snider, Frances; Moerman, Don; Au, Vinci; Li-Leger, Erica; Flibotte, Stephane; Parker, Dylan M; Marshall, Craig J; Nishimura, Erin Osborne; Mains, Paul E; McGhee, James D

2018-05-04

The ELT-2 GATA factor normally functions in differentiation of the C. elegans endoderm, downstream of endoderm specification. We have previously shown that, if ELT-2 is expressed sufficiently early, it is also able to specify the endoderm and to replace all other members of the core GATA-factor transcriptional cascade (END-1, END-3, ELT-7). However, such rescue requires multiple copies (and presumably overexpression) of the end-1p :: elt-2 cDNA transgene; a single copy of the transgene does not rescue. We have made this observation the basis of a genetic screen to search for genetic modifiers that allow a single copy of the end-1p :: elt-2 cDNA transgene to rescue the lethality of the end-1 end-3 double mutant. We performed this screen on a strain that has a single copy insertion of the transgene in an end-1 end-3 background. These animals are kept alive by virtue of an extrachromosomal array containing multiple copies of the rescuing transgene; the extrachromosomal array also contains a toxin under heat shock control to counterselect for mutagenized survivors that have been able to lose the rescuing array. A screen of ∼14,000 mutagenized haploid genomes produced 17 independent surviving strains. Whole genome sequencing was performed to identify genes that incurred independent mutations in more than one surviving strain. The C. elegans gene tasp-1 was mutated in four independent strains. tasp-1 encodes the C. elegans homolog of Taspase, a threonine-aspartic acid protease that has been found, in both mammals and insects, to cleave several proteins involved in transcription, in particular MLL1/trithorax and TFIIA. A second gene, pqn-82 , was mutated in two independent strains and encodes a glutamine-asparagine rich protein. tasp-1 and pqn-82 were verified as loss-of-function modifiers of the end-1p :: elt-2 transgene by RNAi and by CRISPR/Cas9-induced mutations. In both cases, gene loss leads to modest increases in the level of ELT-2 protein in the early endoderm although ELT-2 levels do not strictly correlate with rescue. We suggest that tasp-1 and pqn-82 represent a class of genes acting in the early embryo to modulate levels of critical transcription factors or to modulate the responsiveness of critical target genes. The screen's design, rescuing lethality with an extrachromosomal transgene followed by counterselection, has a background survival rate of <10 -4 without mutagenesis and should be readily adapted to the general problem of identifying suppressors of C. elegans lethal mutations. Copyright © 2018 Wiesenfahrt et al.

Lethal Zika Virus Disease Models in Young and Older Interferon α/β Receptor Knock Out Mice.

PubMed

Marzi, Andrea; Emanuel, Jackson; Callison, Julie; McNally, Kristin L; Arndt, Nicolette; Chadinha, Spencer; Martellaro, Cynthia; Rosenke, Rebecca; Scott, Dana P; Safronetz, David; Whitehead, Stephen S; Best, Sonja M; Feldmann, Heinz

2018-01-01

The common small animal disease models for Zika virus (ZIKV) are mice lacking the interferon responses, but infection of interferon receptor α/β knock out (IFNAR -/- ) mice is not uniformly lethal particularly in older animals. Here we sought to advance this model in regard to lethality for future countermeasure efficacy testing against more recent ZIKV strains from the Asian lineage, preferably the American sublineage. We first infected IFNAR -/- mice subcutaneously with the contemporary ZIKV-Paraiba strain resulting in predominantly neurological disease with ~50% lethality. Infection with ZIKV-Paraiba by different routes established a uniformly lethal model only in young mice (4-week old) upon intraperitoneal infection. However, intraperitoneal inoculation of ZIKV-French Polynesia resulted in uniform lethality in older IFNAR -/- mice (10-12-weeks old). In conclusion, we have established uniformly lethal mouse disease models for efficacy testing of antivirals and vaccines against recent ZIKV strains representing the Asian lineage.

28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

Code of Federal Regulations, 2014 CFR

2014-07-01

... 28 Judicial Administration 2 2014-07-01 2014-07-01 false Use of less-than-lethal weapons... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is such...

28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

Code of Federal Regulations, 2012 CFR

2012-07-01

... 28 Judicial Administration 2 2012-07-01 2012-07-01 false Use of less-than-lethal weapons... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is such...

28 CFR 552.25 - Use of less-than-lethal weapons, including chemical agents.

Code of Federal Regulations, 2013 CFR

2013-07-01

... 28 Judicial Administration 2 2013-07-01 2013-07-01 false Use of less-than-lethal weapons... Use of less-than-lethal weapons, including chemical agents. (a) The Warden may authorize the use of less-than-lethal weapons, including those containing chemical agents, only when the situation is such...

Calculating Hematopoietic-Mode-Lethality Risk Avoidance Associated with Radionuclide Decorporation Countermeasures Related to a Radiological Terrorism Incident

PubMed Central

Scott, Bobby R.

2009-01-01

This paper provides theoretical health-risk-assessment tools that are designed to facilitate planning for and managing radiological terrorism incidents that involve ingestion exposure to bone-seeking radionuclides (e.g., radiostrontium nuclides). The focus is on evaluating lethality risk avoidance (RAV; i.e., the decrease in risk) that is associated with radionuclide decorporation countermeasures employed to remove ingested bone-seeking beta and/or gamma-emitting radionuclides from the body. To illustrate the application of tools presented, hypothetical radiostrontium decorporation scenarios were considered that involved evaluating the hematopoietic-mode-lethality RAV. For evaluating the efficacy of specific decorporation countermeasures, the lethality risk avoidance proportion (RAP; which is the RAV divided by the total lethality risk in the absence of protective countermeasures) is introduced. The lethality RAP is expected to be a useful tool for designing optimal radionuclide decorporation schemes and for identifying green, yellow and red dose-rate zones. For the green zone, essentially all of the lethality risk is expected to be avoided (RAP = 1) as a consequence of the radionuclide decorporation scheme used. For the yellow zone, some but not all of the lethality risk is expected to be avoided. For the red zone, none of the lethality risk (which equals 1) is expected to be avoided. PMID:20011652

Anthrax toxin: the long and winding road that leads to the kill.

PubMed

Abrami, Laurence; Reig, Nuria; van der Goot, F Gisou

2005-02-01

The past five years have led to a tremendous increase in our molecular understanding of the mode of action of the anthrax toxin, one of the two main virulence factors produced by Bacillus anthracis. The structures of each of the three components of the toxin--lethal factor (LF), edema factor (EF) and protective antigen (PA)--have been solved not only in their monomeric forms but, depending on the subunit, in a heptameric form, bound to their substrate, co-factor or receptor. The endocytic route followed by the toxin has also been unraveled and the enzymatic mechanisms of EF and LF elucidated.

ANOTHER "LETHAL TRIAD"-RISK FACTORS FOR VIOLENT INJURY AND LONG-TERM MORTALITY AMONG ADULT VICTIMS OF VIOLENT INJURY.

PubMed

Laytin, Adam D; Shumway, Martha; Boccellari, Alicia; Juillard, Catherine J; Dicker, Rochelle A

2018-05-01

Mental illness, substance abuse, and poverty are risk factors for violent injury, and violent injury is a risk factor for early mortality that can be attenuated through hospital-based violence intervention programs. Most of these programs focus on victims under the age of 30 years. Little is known about risk factors or long-term mortality among older victims of violent injury. To explore the prevalence of risk factors for violent injury among younger (age < 30 years) and older (age 30 ≥ years) victims of violent injury, to determine the long-term mortality rates in these age groups, and to explore the association between risk factors for violent injury and long-term mortality. Adults with violent injuries were enrolled between 2001 and 2004. Demographic and injury data were recorded on enrollment. Ten-year mortality rates were measured. Descriptive analysis and logistic regression were used to compare older and younger subjects. Among 541 subjects, 70% were over age 30. The overall 10-year mortality rate was 15%, and was much higher than in the age-matched general population in both age groups. Risk factors for violent injury including mental illness, substance abuse, and poverty were prevalent, especially among older subjects, and were each independently associated with increased risk of long-term mortality. Mental illness, substance abuse, and poverty constitute a "lethal triad" that is associated with an increased risk of long-term mortality among victims of violent injury, including both younger adults and those over age 30 years. Both groups may benefit from targeted risk-reduction efforts. Emergency department visits offer an invaluable opportunity to engage these vulnerable patients. Copyright © 2018 Elsevier Inc. All rights reserved.

Engineering species-like barriers to sexual reproduction.

PubMed

Maselko, Maciej; Heinsch, Stephen C; Chacón, Jeremy M; Harcombe, William R; Smanski, Michael J

2017-10-12

Controlling the exchange of genetic information between sexually reproducing populations has applications in agriculture, eradication of disease vectors, control of invasive species, and the safe study of emerging biotechnology applications. Here we introduce an approach to engineer a genetic barrier to sexual reproduction between otherwise compatible populations. Programmable transcription factors drive lethal gene expression in hybrid offspring following undesired mating events. As a proof of concept, we target the ACT1 promoter of the model organism Saccharomyces cerevisiae using a dCas9-based transcriptional activator. Lethal overexpression of actin results from mating this engineered strain with a strain containing the wild-type ACT1 promoter.Genetic isolation of a genetically modified organism represents a useful strategy for biocontainment. Here the authors use dCas9-VP64-driven gene expression to construct a 'species-like' barrier to reproduction between two otherwise compatible populations.

Microbial survival in deep space environment.

NASA Technical Reports Server (NTRS)

Silverman, G. J.

1971-01-01

Review of the knowledge available on the extent to which microorganisms (mainly microbial spores, vegetative cells, and fungi) are capable of surviving the environment of deep space, based on recent simulation experiments of deep space. A description of the experimental procedures used is followed by a discussion of deep space ecology, the behavior of microorganisms in ultrahigh vacuum, and factors influencing microbial survival. It is concluded that, so far, simulation experiments have proved far less lethal to microorganisms than to other forms of life. There are, however, wide gaps in the knowledge available, and no accurate predictions can as yet be made on the degree of lethality that might be incurred by a microbial population on a given mission. Therefore, sterilization of spacecraft surfaces is deemed necessary if induced panspermia (i.e., interplanetary life propagation) is to be avoided.

EFFECTS OF SINGLE, BINARY AND TERTIARY COMBINATIONS WITH Jatropha gossypifolia AND OTHER PLANT-DERIVED MOLLUSCICIDES ON REPRODUCTION AND SURVIVAL OF THE SNAIL Lymnaea acuminata

PubMed Central

Yadav, Ram P.; Singh, Ajay

2014-01-01

The effect of sub-lethal doses (40% and 80% of LC50/24h) of plant derived molluscicides of singly, binary (1:1) and tertiary (1:1:1) combinations of the Rutin, Ellagic acid, Betulin and taraxerol with J. gossypifolia latex, leaf and stem bark powder extracts and their active component on the reproduction of freshwater snail Lymnaea acuminata have been studied. It was observed that the J. gossypifolia latex, stem bark, individual leaf and their combinations with other plant derived active molluscicidal components caused a significant reduction in fecundity, hatchability and survival of young snails. It is believed that sub-lethal exposure of these molluscicides on snail reproduction is a complex process involving more than one factor in reducing the reproductive capacity. PMID:25229223

Lethal acrodysgenital dwarfism: a severe lethal condition resembling Smith-Lemli-Opitz syndrome.

PubMed Central

Merrer, M L; Briard, M L; Girard, S; Mulliez, N; Moraine, C; Imbert, M C

1988-01-01

We report eight cases of a lethal association of failure to thrive, facial dysmorphism, ambiguous genitalia, syndactyly, postaxial polydactyly, and internal developmental anomalies (Hirschsprung's disease, cardiac and renal malformation). This syndrome is likely to be autosomal recessive and resembles Smith-Lemli-Opitz (SLO) syndrome. However, the lethality, the common occurrence of polydactyly, and the sexual ambiguity distinguishes this condition from SLO syndrome. A review of published reports supports the separate classification of this syndrome for which we propose the name lethal acrodysgenital dwarfism. Images PMID:2831368

Evolution of a zoonotic pathogen: investigating prophage diversity in enterohaemorrhagic E. coli O157 by long-read sequencing

USDA-ARS?s Scientific Manuscript database

Enterohaemorrhagic Escherichia Coli (EHEC) is a zoonotic pathogen known to be potentially lethal in humans. Its main animal reservoir is ruminants, specifically cattle, and yearly outbreaks occur worldwide with the most prevalent serotype being EHEC O157:H7. Most virulence factors of EHEC O157, incl...

Report of a factor VIII inhibitor in a patient with autoimmune lymphoproliferative syndrome.

PubMed

Fang, B S; Sneller, M C; Straus, S E; Frenkel, L; Dale, J K; Rick, M E

2000-07-01

The occurrence of factor VIII inhibitors in non-hemophilic patients is a rare event with a potentially lethal outcome. Despite its infrequent occurrence, the association of this inhibitor with multiple autoimmune diseases is well recognized. We report the case of a patient with the recently described autoimmune lymphoproliferative syndrome (ALPS) who developed an inhibitor to factor VIII. ALPS is a disease characterized by defective lymphocyte apoptosis due to inherited mutations in genes that regulate apoptosis, with the resulting enlargement of lymphoid organs and a variety of autoimmune manifestations. Published 2000 Wiley-Liss, Inc.

Essential but partially redundant roles for POU4F1/Brn-3a and POU4F2/Brn-3b transcription factors in the developing heart

PubMed Central

Maskell, Lauren J; Qamar, Kashif; Babakr, Aram A; Hawkins, Thomas A; Heads, Richard J; Budhram-Mahadeo, Vishwanie S

2017-01-01

Congenital heart defects contribute to embryonic or neonatal lethality but due to the complexity of cardiac development, the molecular changes associated with such defects are not fully understood. Here, we report that transcription factors (TFs) Brn-3a (POU4F1) and Brn-3b (POU4F2) are important for normal cardiac development. Brn-3a directly represses Brn-3b promoter in cardiomyocytes and consequently Brn-3a knockout (KO) mutant hearts express increased Brn-3b mRNA during mid-gestation, which is linked to hyperplastic growth associated with elevated cyclin D1, a known Brn-3b target gene. However, during late gestation, Brn-3b can cooperate with p53 to enhance transcription of pro-apoptotic genes e.g. Bax, thereby increasing apoptosis and contribute to morphological defects such as non-compaction, ventricular wall/septal thinning and increased crypts/fissures, which may cause lethality of Brn-3a KO mutants soon after birth. Despite this, early embryonic lethality in e9.5 double KO (Brn-3a−/− : Brn-3b−/−) mutants indicate essential functions with partial redundancy during early embryogenesis. High conservation between mammals and zebrafish (ZF) Brn-3b (87%) or Brn-3a (76%) facilitated use of ZF embryos to study potential roles in developing heart. Double morphant embryos targeted with morpholino oligonucleotides to both TFs develop significant cardiac defects (looping abnormalities and valve defects) suggesting essential roles for Brn-3a and Brn-3b in developing hearts. PMID:28594399

Insulin-Like Growth Factor 1 Mitigates Hematopoietic Toxicity After Lethal Total Body Irradiation

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

Zhou, Dunhua; Deoliveira, Divino; Kang, Yubin

2013-03-15

Purpose: To investigate whether and how insulin-like growth factor 1 (IGF-1) mitigates hematopoietic toxicity after total body irradiation. Methods and Materials: BALB/c mice were irradiated with a lethal dose of radiation (7.5 Gy) and treated with IGF-1 at a dose of 100 μg/dose intravenously once a day for 5 consecutive days starting within 1 hour after exposure. Survival and hematopoietic recovery were monitored. The mechanisms by which IGF-1 promotes hematopoietic recovery were also studied by use of an in vitro culture system. Results: IGF-1 protected 8 of 20 mice (40%) from lethal irradiation, whereas only 2 of 20 mice (10%) inmore » the saline control group survived for more than 100 days after irradiation. A single dose of IGF-1 (500 μg) was as effective as daily dosing for 5 days. Positive effects were noted even when the initiation of treatment was delayed as long as 6 hours after irradiation. In comparison with the saline control group, treatment with IGF-1 significantly accelerated the recovery of both platelets and red blood cells in peripheral blood, total cell numbers, hematopoietic stem cells, and progenitor cells in the bone marrow when measured at day 14 after irradiation. IGF-1 protected both hematopoietic stem cells and progenitor cells from radiation-induced apoptosis and cell death. In addition, IGF-1 was able to facilitate the proliferation and differentiation of nonirradiated and irradiated hematopoietic progenitor cells. Conclusions: IGF-1 mitigates radiation-induced hematopoietic toxicity through protecting hematopoietic stem cells and progenitor cells from apoptosis and enhancing proliferation and differentiation of the surviving hematopoietic progenitor cells.« less

Gammaherpesvirus Co-infection with Malaria Suppresses Anti-parasitic Humoral Immunity

PubMed Central

Matar, Caline G.; Anthony, Neil R.; O’Flaherty, Brigid M.; Jacobs, Nathan T.; Priyamvada, Lalita; Engwerda, Christian R.; Speck, Samuel H.; Lamb, Tracey J.

2015-01-01

Immunity to non-cerebral severe malaria is estimated to occur within 1-2 infections in areas of endemic transmission for Plasmodium falciparum. Yet, nearly 20% of infected children die annually as a result of severe malaria. Multiple risk factors are postulated to exacerbate malarial disease, one being co-infections with other pathogens. Children living in Sub-Saharan Africa are seropositive for Epstein Barr Virus (EBV) by the age of 6 months. This timing overlaps with the waning of protective maternal antibodies and susceptibility to primary Plasmodium infection. However, the impact of acute EBV infection on the generation of anti-malarial immunity is unknown. Using well established mouse models of infection, we show here that acute, but not latent murine gammaherpesvirus 68 (MHV68) infection suppresses the anti-malarial humoral response to a secondary malaria infection. Importantly, this resulted in the transformation of a non-lethal P. yoelii XNL infection into a lethal one; an outcome that is correlated with a defect in the maintenance of germinal center B cells and T follicular helper (Tfh) cells in the spleen. Furthermore, we have identified the MHV68 M2 protein as an important virus encoded protein that can: (i) suppress anti-MHV68 humoral responses during acute MHV68 infection; and (ii) plays a critical role in the observed suppression of anti-malarial humoral responses in the setting of co-infection. Notably, co-infection with an M2-null mutant MHV68 eliminates lethality of P. yoelii XNL. Collectively, our data demonstrates that an acute gammaherpesvirus infection can negatively impact the development of an anti-malarial immune response. This suggests that acute infection with EBV should be investigated as a risk factor for non-cerebral severe malaria in young children living in areas endemic for Plasmodium transmission. PMID:25996913

Maternal Vaccination with a Fimbrial Tip Adhesin and Passive Protection of Neonatal Mice against Lethal Human Enterotoxigenic Escherichia coli Challenge

PubMed Central

Luiz, Wilson B.; Rodrigues, Juliana F.; Crabb, Joseph H.

2015-01-01

Globally, enterotoxigenic Escherichia coli (ETEC) is a leading cause of childhood and travelers' diarrhea, for which an effective vaccine is needed. Prevalent intestinal colonization factors (CFs) such as CFA/I fimbriae and heat-labile enterotoxin (LT) are important virulence factors and protective antigens. We tested the hypothesis that donor strand-complemented CfaE (dscCfaE), a stabilized form of the CFA/I fimbrial tip adhesin, is a protective antigen, using a lethal neonatal mouse ETEC challenge model and passive dam vaccination. For CFA/I-ETEC strain H10407, which has been extensively studied in volunteers, an inoculum of 2 × 107 bacteria resulted in 50% lethal doses (LD50) in neonatal DBA/2 mice. Vaccination of female DBA/2 mice with CFA/I fimbriae or dscCfaE, each given with a genetically attenuated LT adjuvant (LTK63) by intranasal or orogastric delivery, induced high antigen-specific serum IgG and fecal IgA titers and detectable milk IgA responses. Neonates born to and suckled by dams antenatally vaccinated with each of these four regimens showed 78 to 93% survival after a 20× LD50 challenge with H10407, compared to 100% mortality in pups from dams vaccinated with sham vaccine or LTK63 only. Crossover experiments showed that high pup survival rates after ETEC challenge were associated with suckling but not birthing from vaccinated dams, suggesting that vaccine-specific milk antibodies are protective. In corroboration, preincubation of the ETEC inoculum with antiadhesin and antifimbrial bovine colostral antibodies conferred a dose-dependent increase in pup survival after challenge. These findings indicate that the dscCfaE fimbrial tip adhesin serves as a protective passive vaccine antigen in this small animal model and merits further evaluation. PMID:26371126

Elimination of water pathogens with solar radiation using an automated sequential batch CPC reactor.

PubMed

Polo-López, M I; Fernández-Ibáñez, P; Ubomba-Jaswa, E; Navntoft, C; García-Fernández, I; Dunlop, P S M; Schmid, M; Byrne, J A; McGuigan, K G

2011-11-30

Solar disinfection (SODIS) of water is a well-known, effective treatment process which is practiced at household level in many developing countries. However, this process is limited by the small volume treated and there is no indication of treatment efficacy for the user. Low cost glass tube reactors, together with compound parabolic collector (CPC) technology, have been shown to significantly increase the efficiency of solar disinfection. However, these reactors still require user input to control each batch SODIS process and there is no feedback that the process is complete. Automatic operation of the batch SODIS process, controlled by UVA-radiation sensors, can provide information on the status of the process, can ensure the required UVA dose to achieve complete disinfection is received and reduces user work-load through automatic sequential batch processing. In this work, an enhanced CPC photo-reactor with a concentration factor of 1.89 was developed. The apparatus was automated to achieve exposure to a pre-determined UVA dose. Treated water was automatically dispensed into a reservoir tank. The reactor was tested using Escherichia coli as a model pathogen in natural well water. A 6-log inactivation of E. coli was achieved following exposure to the minimum uninterrupted lethal UVA dose. The enhanced reactor decreased the exposure time required to achieve the lethal UVA dose, in comparison to a CPC system with a concentration factor of 1.0. Doubling the lethal UVA dose prevented the need for a period of post-exposure dark inactivation and reduced the overall treatment time. Using this reactor, SODIS can be automatically carried out at an affordable cost, with reduced exposure time and minimal user input. Copyright © 2011 Elsevier B.V. All rights reserved.

General Medical, Mental Health, and Demographic Risk Factors Associated With Suicide by Firearm Compared With Other Means.

PubMed

Boggs, Jennifer M; Beck, Arne; Hubley, Sam; Peterson, Edward L; Hu, Yong; Williams, L Keoki; Prabhakar, Deepak; Rossom, Rebecca C; Lynch, Frances L; Lu, Christine Y; Waitzfelder, Beth E; Owen-Smith, Ashli A; Simon, Gregory E; Ahmedani, Brian K

2018-06-01

Mitigation of suicide risk by reducing access to lethal means, such as firearms and potentially lethal medications, is a highly recommended practice. To better understand groups of patients at risk of suicide in medical settings, the authors compared demographic and clinical risk factors between patients who died by suicide by using firearms or other means with matched patients who did not die by suicide (control group). In a case-control study in 2016 from eight health care systems within the Mental Health Research Network, 2,674 suicide cases from 2010-2013 were matched to a control group (N=267,400). The association between suicide by firearm or other means and medical record information on demographic characteristics, general medical disorders, and mental disorders was assessed. The odds of having a mental disorder were higher among cases of suicide involving a method other than a firearm. Fourteen general medical disorders were associated with statistically significant (p<.001) greater odds of suicide by firearm, including traumatic brain injury (TBI) (odds ratio [OR]=23.53), epilepsy (OR=3.17), psychogenic pain (OR=2.82), migraine (OR=2.35), and stroke (OR=2.20). Fifteen general medical disorders were associated with statistically significant (p<.001) greater odds of suicide by other means, with particularly high odds for TBI (OR=7.74), epilepsy (OR=3.28), HIV/AIDS (OR=6.03), and migraine (OR=3.17). Medical providers should consider targeting suicide risk screening for patients with any mental disorder, TBI, epilepsy, HIV, psychogenic pain, stroke, and migraine. When suicide risk is detected, counseling on reducing access to lethal means should include both firearms and other means for at-risk groups.

Pregnancy interruption after second trimester diagnosis of fetal structural anomalies: the New Jersey Fetal Abnormalities Registry.

PubMed

Rauch, Eden R; Smulian, John C; DePrince, Kristin; Ananth, Cande V; Marcella, Stephen W

2005-10-01

The purpose of this study was to identify factors that predict a decision to interrupt a pregnancy in which there are fetal anomalies in the second trimester. The New Jersey Fetal Abnormalities Registry prospectively recruits and collects information on pregnancies (> or = 15 weeks of gestation) from New Jersey residents in whom a fetal structural anomaly has been suspected by maternal-fetal medicine specialists. Enrolled pregnancies that have major fetal structural abnormalities identified from 15 to 23 weeks of gestation were included. Outcomes were classified as either elective interruption or a natural pregnancy course, which might include a spontaneous fetal death or live birth. Predictors of elective interruption of pregnancy were examined with univariable and multivariable logistic regression analyses. Of the 97 cases, 33% of the women (n = 32) interrupted the pregnancy. Significant variables in the regression model that were associated with a decision to interrupt a pregnancy were earlier identification of fetal anomalies (19.0 +/- 2 weeks of gestation vs 20.5 +/- 2 weeks of gestation; P = .003), the presence of multiple anomalies (78% [25/32] vs 52% [33/63]; P = .01], and a presumption of lethality (56% [18/32] vs 14% [9/65]; P = .0001). These variables corresponded to an odds ratio for pregnancy interruption of 4.2 (95% CI, 1.0, 17.0) for multiple anomalies, 0.8 (95% CI, 0.7, 1.0) for each week of advancing gestational age, and 36.1 (95% CI, 2.9, 450.7) for presumed lethal abnormalities. Early diagnosis, the identification of multiple abnormalities, and an assessment of likely lethality of fetal anomalies are important factors for the optimization of parental autonomy in deciding pregnancy management.

Lethal trap trees and semiochemical repellents as area host protection strategies for spruce beetle (Coleoptera: Curculionidae, Scolytinae) in Utah

Treesearch

Matt Hansen; A. Steven Munson; Darren C. Blackford; David Wakarchuk; Scott Baggett

2016-01-01

We tested lethal trap trees and repellent semiochemicals as area treatments to protect host trees from spruce beetle (Dendroctonus rufipennis Kirby) attacks. Lethal trap tree treatments ("spray treatment") combined a spruce beetle bait with carbaryl treatment of the baited spruce. Repellent treatments ("spray-repellent”) combined a baited lethal...

[Prognostic value of the lethal triad among patients with multiple trauma].

PubMed

González Balverde, María; Ramírez Lizardo, Ernesto J; Cardona Muñoz, Ernesto G; Totsuka Sutto, Sylvia E; García Benavides, Leonel

2013-11-01

Patients who have suffered multiple traumatic injuries, have a serious risk for death. Hypothermia, acidosis and coagulopathy are three complications in these patients, whose presence is known as lethal triad and indicates bad prognosis. To determine if the lethal triad in multiple trauma patients is associated with higher mortality and Injury Score Severity (ISS). One hundred multiple trauma patients aged 26 to 56 years (90 males), admitted to an emergency room, were studied. Body temperature, prothrombin time, partial thromboplastin time, platelet count and blood gases were determined on admission. Twenty six patients had the lethal triad and 15% died in the emergency room within the first 6 hours. No death was recorded among the 74 patients without the lethal triad. The mean ISS among patients with and without the lethal triad was 31.7 and 25.6, respectively (p < 0.05). The presence of the lethal triad among patients with multiple trauma is associated with a higher mortality and ISS.

Effect of lethality on the extinction and on the error threshold of quasispecies.

PubMed

Tejero, Hector; Marín, Arturo; Montero, Francisco

2010-02-21

In this paper the effect of lethality on error threshold and extinction has been studied in a population of error-prone self-replicating molecules. For given lethality and a simple fitness landscape, three dynamic regimes can be obtained: quasispecies, error catastrophe, and extinction. Using a simple model in which molecules are classified as master, lethal and non-lethal mutants, it is possible to obtain the mutation rates of the transitions between the three regimes analytically. The numerical resolution of the extended model, in which molecules are classified depending on their Hamming distance to the master sequence, confirms the results obtained in the simple model and shows how an error catastrophe regime changes when lethality is taken in account. (c) 2009 Elsevier Ltd. All rights reserved.

In vivo postirradiation protection by a vitamin E analog, alpha-TMG.

PubMed

Satyamitra, Merriline; Uma Devi, P; Murase, Hironobu; Kagiya, V T

2003-12-01

The water-soluble vitamin E derivative alpha-TMG is an excellent radical scavenger. A dose of 600 mg/kg TMG significantly reduced radiation clastogenicity in mouse bone marrow when administered after irradiation. The present study was aimed at investigating the radioprotective effect of postirradiation treatment with alpha-TMG against a range of whole-body lethal (8.5-12 Gy) and sublethal (1-5 Gy) doses of radiation in adult Swiss albino mice. Protection against lethal irradiation was evaluated from 30-day mouse survival and against sublethal doses was assessed from micronuclei and chromosomal aberrations in the bone marrow 24 h after irradiation. An intraperitoneal injection of 600 mg/kg TMG within 10 min of lethal irradiation increased survival, giving a dose modification factor (DMF) of 1.09. TMG at doses of 400 mg/kg and 600 mg/kg significantly reduced the percentage of aberrant metaphases, the different types of aberrations, and the number of micronucleated erythrocytes. DMFs of 1.22 and 1.48 for percentage aberrant metaphases and 1.6 and 1.98 for micronuclei were obtained for 400 mg/kg and 600 mg/kg TMG, respectively. No drug toxicity was observed at these doses. The effectiveness of TMG when administered postirradiation suggests its possible utility for protection against unplanned radiation exposures.

Properties of proteolytic toxin of Vibrio anguilolarum from diseased flounder

NASA Astrophysics Data System (ADS)

Mo, Zhao-Lan; Chen, Shi-Yong; Zhang, Pei-Jun

2002-12-01

Extracellular products (ECP) produced by Vibrio anguillarum strain M3 originally isolated from diseased flounder ( Paralichthys olivaceus) were prepared. ECP of M3 showed gelatinase, casinase, amylase and haemolytic activity on agarose plates. High protease activity against azocasin was detected. Bacterium M2 showed highest growth and protease activity at 25°C. The protease present in ECP showed maximal activity at pH 8 and 55°C; was completely inactivated by application of 80°C heat for 30 min; was completely inhibited by EDTA and HgCl2, and was partially inhibited by PMSF, SDS, MnCl2 and iodoacetic acid; but not inhibited by CaCl2 and MgCl2. The ECP was toxic to flounder fish at LD50 values of 3.1 μg protein/g body weight. The addition of HgCl2 and application of heat at 50°C decreased the lethal toxicity of ECP. When heated at 100°C, ECP lethality to flounder was completely inhibited. After intramuscular injection of ECP into flounder, it showed evident histopathological changes including necrosis of muscle, extensive deposition of haemosiderin in the spleen, dilated blood vessels congested with numerious lymphocytes in the liver. These results showed that ECP protease was a lethal factor produced by the bacterium V. anguillarum M3.

Predictive Factors of Mortality in Burn Patients

PubMed Central

Fazeli, Shahram; Karami-Matin, Reza; Kakaei, Neda; Pourghorban, Samira; Safari-Faramani, Roya; Safari-Faramani, Bahare

2014-01-01

Background: Burn injuries impose a considerable burden on healthcare systems in Iran. It is among the top ten causes of mortality and a main cause of disability. Objectives: This study aimed to examine factors influencing mortality in burn patients admitted to the main educational tertiary referral hospital in Kermanshah. Patients and Methods: All patients admitted to the Imam Khomeini Hospital (from March 2011 to March 2012), due to thermal burn injuries were included in the study. We applied multiple logistic regressions to identify risk and protective factors of mortality. Also we calculated lethal area fifty percent (LA50), as an aggregate index for hospital quality. Results: During the study period, 540 burn patients were admitted. Male to female ratio was 1.12:1. Twenty three percent of the patients were less than 15 years-old. Median of age was 25 years (Inter Quartile Range, 16 - 37). Overall, probability of death was 25.8%. Lethal area fifty percent (LA50) was 50.82 (CI 95%: 47.76 - 54.48). In the final model, after adjustment of sex, age, total body surface area (TBSA), cause of burn and it’s severity, female gender (P < 0.05), age ≥ 60 years (in comparison with age less than 15 years, P < 0.05) and larger burn size (P < 0.0001) were identified as the main risk factors of death in these patients. Conclusions: Findings showed that the main risk factors of death were female gender, burn size and old age. Directing more attention to these vulnerable patients is required to reduce mortality and improve patient survival. PMID:24719826

Essential functions of the Williams-Beuren syndrome-associated TFII-I genes in embryonic development.

PubMed

Enkhmandakh, Badam; Makeyev, Aleksandr V; Erdenechimeg, Lkhamsuren; Ruddle, Frank H; Chimge, Nyam-Osor; Tussie-Luna, Maria Isabel; Roy, Ananda L; Bayarsaihan, Dashzeveg

2009-01-06

GTF2I and GTF2IRD1 encoding the multifunctional transcription factors TFII-I and BEN are clustered at the 7q11.23 region hemizygously deleted in Williams-Beuren syndrome (WBS), a complex multisystemic neurodevelopmental disorder. Although the biochemical properties of TFII-I family transcription factors have been studied in depth, little is known about the specialized contributions of these factors in pathways required for proper embryonic development. Here, we show that homozygous loss of either Gtf2ird1 or Gtf2i function results in multiple phenotypic manifestations, including embryonic lethality; brain hemorrhage; and vasculogenic, craniofacial, and neural tube defects in mice. Further analyses suggest that embryonic lethality may be attributable to defects in yolk sac vasculogenesis and angiogenesis. Microarray data indicate that the Gtf2ird1 homozygous phenotype is mainly caused by an impairment of the genes involved in the TGFbetaRII/Alk1/Smad5 signal transduction pathway. The effect of Gtf2i inactivation on this pathway is less prominent, but downregulation of the endothelial growth factor receptor-2 gene, resulting in the deterioration of vascular signaling, most likely exacerbates the severity of the Gtf2i mutant phenotype. A subset of Gtf2ird1 and Gtf2i heterozygotes displayed microcephaly, retarded growth, and skeletal and craniofacial defects, therefore showing that haploinsufficiency of TFII-I proteins causes various developmental anomalies that are often associated with WBS.

DefenseLink.mil - Special Report - Soldiers Train with Non-lethal Weapons

Science.gov Websites

Training 10th Mountain Division soldiers feel the effects of a Taser during non-lethal weapons training Nov soldiers feel the effects of a Taser during non-lethal weapons training Nov. 19, 2008, at Fort Drum, N.Y situation can be resolved without lethal measures, Army Staff Sgt. Eric Johnson said during training and

Regular Aspirin Use and the Risk of Lethal Prostate Cancer in the Physicians' Health Study.

PubMed

Downer, Mary K; Allard, Christopher B; Preston, Mark A; Gaziano, J Michael; Stampfer, Meir J; Mucci, Lorelei A; Batista, Julie L

2017-11-01

Regular aspirin use probably protects against some malignancies including prostate cancer (PC), but its impact on lethal PC is particularly unclear. To investigate the association between regular aspirin and (1) the risk of lethal PC in a large prospective cohort and (2) survival after PC diagnosis. In 1981/82, the Physicians' Health Study randomized 22 071 healthy male physicians to aspirin, β-carotene, both, or placebo. After the trial ended in 1988, annual questionnaires have obtained data on aspirin use, cancer diagnoses, and outcomes up to 2009 for the whole cohort, and to 2015 for PC patients. We evaluated the relationship between regular aspirin (>3 tablets/week) and lethal PC (metastases or PC death). Cox proportional-hazards models estimated hazard ratios (HRs) for the risk of lethal PC in the whole cohort and postdiagnosis survival among men initially diagnosed with nonlethal PC. Risk analysis revealed that 502 men developed lethal PC by 2009. Current and past regular aspirin was associated with a lower risk of lethal PC (current: HR 0.68, 95% confidence interval [CI] 0.52-0.89; past: HR 0.54, 95% CI 0.40-0.74) compared to never users. In the survival analysis, 407/3277 men diagnosed with nonlethal PC developed lethal disease by 2015. Current postdiagnostic aspirin was associated with lower risks of lethal PC (HR 0.68, 95% CI 0.52-0.90) and overall mortality (HR 0.72, 95% CI 0.61-0.9). We could not assess aspirin dose, and inconsistencies were observed in some sensitivity analyses. Current regular aspirin use was associated with a lower risk of lethal PC among all participants. Current postdiagnostic use was associated with improved survival after diagnosis, consistent with a potential inhibitory effect of aspirin on PC progression. A randomized trial is warranted to confirm or refute these findings. We examined the potential effect of regular aspirin use on lethal prostate cancer. We found that taking aspirin was associated with a lower risk of lethal prostate cancer, and taking it after diagnosis may help to prevent prostate cancer from becoming fatal. Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Conditioning the heart to prevent myocardial reperfusion injury during PPCI

PubMed Central

2012-01-01

For patients presenting with a ST-segment elevation myocardial infarction (STEMI), early myocardial reperfusion by primary percutaneous coronary intervention (PPCI) remains the most effective treatment strategy for limiting myocardial infarct size, preserving left ventricular systolic function, and preventing the onset of heart failure. Recent advances in PCI technology to improve myocardial reperfusion and the introduction of novel anti-platelet and anti-thrombotic agents to maintain the patency of the infarct-related coronary artery continue to optimize PPCI procedure. However, despite these improvements, STEMI patients still experience significant major adverse cardiovascular events. One major contributing factor has been the inability to protect the heart against the lethal myocardial reperfusion injury, which accompanies PPCI. Past attempts to translate cardioprotective strategies, discovered in experimental studies to prevent lethal myocardial reperfusion injury, into the clinical setting of PPCI have been disappointing. However, a number of recent proof-of-concept clinical studies suggest that the heart can be ‘conditioned’ to protect itself against lethal myocardial reperfusion injury, as evidenced by a reduction in myocardial infarct size. This can be achieved using either mechanical (such as ischaemic postconditioning, remote ischaemic preconditioning, therapeutic hypothermia, or hyperoxaemia) or pharmacological (such as cyclosporin-A, natriuretic peptide, exenatide) ‘conditioning’ strategies as adjuncts to PPCI. Furthermore, recent developments in cardiac magnetic resonance (CMR) imaging can provide a non-invasive imaging strategy for assessing the efficacy of these novel adjunctive therapies to PPCI in terms of key surrogate clinical endpoints such as myocardial infarct size, myocardial salvage, left ventricular ejection fraction, and the presence of microvascular obstruction or intramyocardial haemorrhage. In this article, we review the therapeutic potential of ‘conditioning’ to protect the heart against lethal myocardial reperfusion injury in STEMI patients undergoing PPCI. PMID:24062884

A single phosphorodiamidate morpholino oligomer targeting VP24 protects rhesus monkeys against lethal Ebola virus infection.

PubMed

Warren, Travis K; Whitehouse, Chris A; Wells, Jay; Welch, Lisa; Heald, Alison E; Charleston, Jay S; Sazani, Pete; Reid, St Patrick; Iversen, Patrick L; Bavari, Sina

2015-02-10

Ebola viruses (EBOV) cause severe disease in humans and nonhuman primates with high mortality rates and continue to emerge in new geographic locations, including several countries in West Africa, the site of a large ongoing outbreak. Phosphorodiamidate morpholino oligomers (PMOs) are synthetic antisense molecules that are able to target mRNAs in a sequence-specific fashion and suppress translation through steric hindrance. We previously showed that the use of PMOs targeting a combination of VP35 and VP24 protected rhesus monkeys from lethal EBOV infection. Surprisingly, the present study revealed that a PMOplus compound targeting VP24 alone was sufficient to confer protection from lethal EBOV infection but that a PMOplus targeting VP35 alone resulted in no protection. This study further substantiates recent data demonstrating that VP24 may be a key virulence factor encoded by EBOV and suggests that VP24 is a promising target for the development of effective anti-EBOV countermeasures. Several West African countries are currently being ravaged by an outbreak of Ebola virus (EBOV) that has become a major epidemic affecting not only these African countries but also Europe and the United States. A better understanding of the mechanism of virulence of EBOV is important for the development of effective treatments, as no licensed treatments or vaccines for EBOV disease are currently available. This study of phosphorodiamidate morpholino oligomers (PMOs) targeting the mRNAs of two different EBOV proteins, alone and in combination, demonstrated that targeting a single protein was effective at conferring a significant survival benefit in an EBOV lethal primate model. Future development of PMOs with efficacy against EBOV will be simplified if only one PMO is required instead of a combination, particularly in terms of regulatory approval. Copyright © 2015 Warren et al.

From tails to toes: developing nonlethal tissue indicators of mercury exposure in five amphibian species

USGS Publications Warehouse

Pfleeger, Adam Z.; Eagles-Smith, Collin A.; Kowalski, Brandon M.; Herring, Garth; Willacker, James J.; Jackson, Allyson K.; Pierce, John

2016-01-01

Exposure to environmental contaminants has been implicated as a factor in global amphibian decline. Mercury (Hg) is a particularly widespread contaminant that biomagnifies in amphibians and can cause a suite of deleterious effects. However, monitoring contaminant exposure in amphibian tissues may conflict with conservation goals if lethal take is required. Thus, there is a need to develop non-lethal tissue sampling techniques to quantify contaminant exposure in amphibians. Some minimally invasive sampling techniques, such as toe-clipping, are common in population-genetic research, but it is unclear if these methods can adequately characterize contaminant exposure. We examined the relationships between mercury (Hg) concentrations in non-lethally sampled tissues and paired whole-bodies in five amphibian species. Specifically, we examined the utility of three different tail-clip sections from four salamander species and toe-clips from one anuran species. Both tail and toe-clips accurately predicted whole-body THg concentrations, but the relationships differed among species and the specific tail-clip section or toe that was used. Tail-clips comprised of the distal 0–2 cm segment performed the best across all salamander species, explaining between 82 and 92 % of the variation in paired whole-body THg concentrations. Toe-clips were less effective predictors of frog THg concentrations, but THg concentrations in outer rear toes accounted for up to 79 % of the variability in frog whole-body THg concentrations. These findings suggest non-lethal sampling of tails and toes has potential applications for monitoring contaminant exposure and risk in amphibians, but care must be taken to ensure consistent collection and interpretation of samples.

Relative Risks for Lethal Prostate Cancer Based on Complete Family History of Prostate Cancer Death.

PubMed

Albright, Frederick S; Stephenson, Robert A; Agarwal, Neeraj; Cannon-Albright, Lisa A

2017-01-01

There are few published familial relative risks (RR) for lethal prostate cancer. This study estimates RRs for lethal prostate cancer based on comprehensive family history data, with the goal of improving identification of those men at highest risk of dying from prostate cancer. We used a population-based genealogical resource linked to a statewide electronic SEER cancer registry and death certificates to estimate relative risks (RR) for death from prostate cancer based upon family history. Over 600,000 male probands were analyzed, representing a variety of family history constellations of lethal prostate cancer. RR estimates were based on the ratio of the observed to the expected number of lethal prostate cancer cases using internal rates. RRs for lethal prostate cancer based on the number of affected first-degree relatives (FDR) ranged from 2.49 (95% CI: 2.27, 2.73) for exactly 1 FDR to 5.30 (2.13, 10.93) for ≥3 affected FDRs. In an absence of affected FDRs, increased risk was also significant for increasing numbers of affected second-degree or third degree relatives. Equivalent risks were observed for similar maternal and paternal family history. This study provides population-based estimates of lethal prostate cancer risk based on lethal prostate cancer family history. Many family history constellations associated with two to greater than five times increased risk for lethal prostate cancer were identified. These lethal prostate cancer risk estimates hold potential for use in identification, screening, early diagnosis, and treatment of men at high risk for death from prostate cancer. Prostate77:41-48, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Choline intake and risk of lethal prostate cancer: incidence and survival123

PubMed Central

Richman, Erin L; Kenfield, Stacey A; Stampfer, Meir J; Giovannucci, Edward L; Zeisel, Steven H; Willett, Walter C; Chan, June M

2012-01-01

Background: Meat, milk, and eggs have been inconsistently associated with the risk of advanced prostate cancer. These foods are sources of choline—a nutrient that may affect prostate cancer progression through cell membrane function and one-carbon metabolism. No study has examined dietary choline and the risk of lethal prostate cancer. Objective: Our objective was to examine whether dietary choline, choline-containing compounds, and betaine (a choline metabolite) increase the risk of lethal prostate cancer. Design: We prospectively examined the intake of these nutrients and the risk of lethal prostate cancer among 47,896 men in the Health Professionals Follow-Up Study. In a case-only survival analysis, we examined the postdiagnostic intake of these nutrients and the risk of lethal prostate cancer among 4282 men with an initial diagnosis of nonmetastatic disease during follow-up. Diet was assessed with a validated questionnaire 6 times during 22 y of follow-up. Results: In the incidence analysis, we observed 695 lethal prostate cancers during 879,627 person-years. Men in the highest quintile of choline intake had a 70% increased risk of lethal prostate cancer (HR: 1.70; 95% CI: 1.18, 2.45; P-trend = 0.005). In the case-only survival analysis, we observed 271 lethal cases during 33,679 person-years. Postdiagnostic choline intake was not statistically significantly associated with the risk of lethal prostate cancer (HR for quintile 5 compared with quintile 1: 1.69; 95% CI: 0.93, 3.09; P-trend = 0.20). Conclusion: Of the 47,896 men in our study population, choline intake was associated with an increased risk of lethal prostate cancer. PMID:22952174

Lethal and sub-lethal responses of native freshwater mussels exposed to granular Bayluscide®, a sea lamprey larvicide

USGS Publications Warehouse

Newton, Teresa; Boogaard, Michael A.; Gray, Brian R.; Hubert, Terrance D.; Schloesser, Nicholas

2017-01-01

The invasive sea lamprey (Petromyzon marinus) poses a substantial threat to fish communities in the Great Lakes. Efforts to control sea lamprey populations typically involve treating tributary streams with lampricides on a recurring cycle. The presence of a substantial population of larval sea lampreys in the aquatic corridor between Lakes Huron and Erie prompted managers to propose a treatment using the granular formulation of Bayluscide® that targets larval sea lampreys that reside in sediments. However, these treatments could cause adverse effects on native freshwater mussels—imperiled animals that also reside in sediments. We estimated the risk of mortality and sub-lethal effects among eight species of adult and sub-adult mussels exposed to Bayluscide® for durations up to 8 h to mimic field applications. Mortality was appreciable in some species, especially in sub-adults (range, 23–51%). The lethal and sub-lethal effects were positively associated with the duration of exposure in most species and life stage combinations. Estimates of the median time of exposure that resulted in lethal and sub-lethal effects suggest that sub-adults were often affected by Bayluscide® earlier than adults. Siphoning activity and burrowing position of mussels during exposure may have moderated the uptake of Bayluscide® and may have influenced lethal and sub-lethal responses. Given that the various species and life stages were differentially affected, it will be difficult to predict the effects of Bayluscide® treatments on mussels.

Modeling Conventional Land Combat in a Multi-Agent System Using Generalization of the Different Combat Entities and Combat Operations

DTIC Science & Technology

2001-09-01

Blue and Red Death Rates for Red Lethality = 1 ..........................66 xi Figure 23 Blue and Red Death Rates for Red Lethality = 2...67 Figure 24 Blue and Red Death Rates for Red Lethality = 3 ..........................67 Figure 25 Blue and Red Casualties...vs. Red Lethality....................................68 Figure 26 Blue and Red Death Rates for Blue Training = 100%...................69 Figure

Haploinsufficiency of E-selectin ligand-1 is Associated with Reduced Atherosclerotic Plaque Macrophage Content while Complete Deficiency Leads to Early Embryonic Lethality in Mice

PubMed Central

Luo, Wei; Wang, Hui; Guo, Chiao; Wang, Jintao; Kwak, Jeffrey; Bahrou, Kristina L; Eitzman, Daniel T.

2012-01-01

E-selectin-1 (ESL-1), also known as golgi complex-localized glycoprotein-1 (GLG1), homocysteine-rich fibroblast growth factor receptor (CGR-1), and latent transforming growth factor-β complex protein 1 (LTCP-1), is a multifunctional protein with widespread tissue distribution. To determine the functional consequences of ESL-1 deficiency, mice were generated carrying an ESL-1 gene trap. After backcrossing to C57BL6/J for 6 generations, mice heterozygous for the gene trap (ESL-1+/-) were intercrossed to produce ESL-1-/- mice, however ESL-1-/- mice were not viable, even at embryonic day E10.5. To determine the effect of heterozygous ESL-1 deficiency on atherosclerosis, apolipoprotein E deficient (ApoE-/-), ESL-1+/- mice were generated and fed western diet. Compared to ApoE-/-, ESL-1++ mice, atherosclerotic lesions from ApoE-/-, ESL-1+/- contained more collagen and fewer macrophages, suggesting increased plaque stability. In conclusion, heterozygous deficiency of ESL-1 is associated with features of increased atherosclerotic plaque stability while complete deficiency of ESL-1 leads to embryonic lethality. PMID:22939356

Cross-Regulation of Two Type I Interferon Signaling Pathways in Plasmacytoid Dendritic Cells Controls Anti-malaria Immunity and Host Mortality.

PubMed

Yu, Xiao; Cai, Baowei; Wang, Mingjun; Tan, Peng; Ding, Xilai; Wu, Jian; Li, Jian; Li, Qingtian; Liu, Pinghua; Xing, Changsheng; Wang, Helen Y; Su, Xin-Zhuan; Wang, Rong-Fu

2016-11-15

Type I interferon (IFN) is critical for controlling pathogen infection; however, its regulatory mechanisms in plasmacytoid cells (pDCs) still remain unclear. Here, we have shown that nucleic acid sensors cGAS-, STING-, MDA5-, MAVS-, or transcription factor IRF3-deficient mice produced high amounts of type I IFN-α and IFN-β (IFN-α/β) in the serum and were resistant to lethal plasmodium yoelii YM infection. Robust IFN-α/β production was abolished when gene encoding nucleic acid sensor TLR7, signaling adaptor MyD88, or transcription factor IRF7 was ablated or pDCs were depleted. Further, we identified SOCS1 as a key negative regulator to inhibit MyD88-dependent type I IFN signaling in pDCs. Finally, we have demonstrated that pDCs, cDCs, and macrophages were required for generating IFN-α/β-induced subsequent protective immunity. Thus, our findings have identified a critical regulatory mechanism of type I IFN signaling in pDCs and stage-specific function of immune cells in generating potent immunity against lethal YM infection. Copyright © 2016 Elsevier Inc. All rights reserved.

Apoptosis inducing factor (AIF) mediates lethal redox stress induced by menadione.

PubMed

Wiraswati, Hesti Lina; Hangen, Emilie; Sanz, Ana Belén; Lam, Ngoc-Vy; Reinhardt, Camille; Sauvat, Allan; Mogha, Ariane; Ortiz, Alberto; Kroemer, Guido; Modjtahedi, Nazanine

2016-11-22

Mitochondrial apoptosis inducing factor (AIF) is a redox-active enzyme that participates to the biogenesis/maintenance of complex I of the respiratory chain, yet also contributes to catabolic reactions in the context of regulated cell death when AIF translocates to the cytosol and to the nucleus. Here we explore the contribution of AIF to cell death induced by menadione (2-methyl-1,4-naphtoquinone; also called vitamin K3) in conditions in which this pro-oxidant does not cause the mitochondrial release of AIF, yet causes caspase-independent cell killing. Depletion of AIF from human cancer cells reduced the cytotoxicity of menadione. This cytoprotective effect was accompanied by the maintenance of high levels of reduced glutathione (GSH), which are normally depleted by menadione. In addition, AIF depletion reduced the arylation of cellular proteins induced by menadione. This menadione-triggered arylation, which can be measured by a fluorescence assay, is completely suppressed by addition of exogenous glutathione or N-acetyl cysteine. Complex I inhibition by Rotenone did not mimic the cytoprotective action of AIF depletion. Altogether, these results are compatible with the hypothesis that mitochondrion-sessile AIF facilitates lethal redox cycling of menadione, thereby precipitating protein arylation and glutathione depletion.

Apoptosis inducing factor (AIF) mediates lethal redox stress induced by menadione

PubMed Central

Wiraswati, Hesti Lina; Hangen, Emilie; Sanz, Ana Belén; Lam, Ngoc-Vy; Reinhardt, Camille; Sauvat, Allan; Mogha, Ariane; Ortiz, Alberto

2016-01-01

Mitochondrial apoptosis inducing factor (AIF) is a redox-active enzyme that participates to the biogenesis/maintenance of complex I of the respiratory chain, yet also contributes to catabolic reactions in the context of regulated cell death when AIF translocates to the cytosol and to the nucleus. Here we explore the contribution of AIF to cell death induced by menadione (2-methyl-1,4-naphtoquinone; also called vitamin K3) in conditions in which this pro-oxidant does not cause the mitochondrial release of AIF, yet causes caspase-independent cell killing. Depletion of AIF from human cancer cells reduced the cytotoxicity of menadione. This cytoprotective effect was accompanied by the maintenance of high levels of reduced glutathione (GSH), which are normally depleted by menadione. In addition, AIF depletion reduced the arylation of cellular proteins induced by menadione. This menadione-triggered arylation, which can be measured by a fluorescence assay, is completely suppressed by addition of exogenous glutathione or N-acetyl cysteine. Complex I inhibition by Rotenone did not mimic the cytoprotective action of AIF depletion. Altogether, these results are compatible with the hypothesis that mitochondrion-sessile AIF facilitates lethal redox cycling of menadione, thereby precipitating protein arylation and glutathione depletion. PMID:27738311

The Drosophila mitochondrial translation elongation factor G1 contains a nuclear localization signal and inhibits growth and DPP signaling.

PubMed

Trivigno, Catherine; Haerry, Theodor E

2011-02-25

Mutations in the human mitochondrial elongation factor G1 (EF-G1) are recessive lethal and cause death shortly after birth. We have isolated mutations in iconoclast (ico), which encodes the highly conserved Drosophila orthologue of EF-G1. We find that EF-G1 is essential during fly development, but its function is not required in every tissue. In contrast to null mutations, missense mutations exhibit stronger, possibly neomorphic phenotypes that lead to premature death during embryogenesis. Our experiments show that EF-G1 contains a secondary C-terminal nuclear localization signal. Expression of missense mutant forms of EF-G1 can accumulate in the nucleus and cause growth and patterning defects and animal lethality. We find that transgenes that encode mutant human EF-G1 proteins can rescue ico mutants, indicating that the underlying problem of the human disease is not just the loss of enzymatic activity. Our results are consistent with a model where EF-G1 acts as a retrograde signal from mitochondria to the nucleus to slow down cell proliferation if mitochondrial energy output is low.

The Drosophila Mitochondrial Translation Elongation Factor G1 Contains a Nuclear Localization Signal and Inhibits Growth and DPP Signaling

PubMed Central

Trivigno, Catherine; Haerry, Theodor E.

2011-01-01

Mutations in the human mitochondrial elongation factor G1 (EF-G1) are recessive lethal and cause death shortly after birth. We have isolated mutations in iconoclast (ico), which encodes the highly conserved Drosophila orthologue of EF-G1. We find that EF-G1 is essential during fly development, but its function is not required in every tissue. In contrast to null mutations, missense mutations exhibit stronger, possibly neomorphic phenotypes that lead to premature death during embryogenesis. Our experiments show that EF-G1 contains a secondary C-terminal nuclear localization signal. Expression of missense mutant forms of EF-G1 can accumulate in the nucleus and cause growth and patterning defects and animal lethality. We find that transgenes that encode mutant human EF-G1 proteins can rescue ico mutants, indicating that the underlying problem of the human disease is not just the loss of enzymatic activity. Our results are consistent with a model where EF-G1 acts as a retrograde signal from mitochondria to the nucleus to slow down cell proliferation if mitochondrial energy output is low. PMID:21364917

Anthrax Lethal Toxin Impairs Innate Immune Functions of Alveolar Macrophages and Facilitates Bacillus anthracis Survival

PubMed Central

Ribot, Wilson J.; Panchal, Rekha G.; Brittingham, Katherine C.; Ruthel, Gordon; Kenny, Tara A.; Lane, Douglas; Curry, Bob; Hoover, Timothy A.; Friedlander, Arthur M.; Bavari, Sina

2006-01-01

Alveolar macrophages (AM) are very important for pulmonary innate immune responses against invading inhaled pathogens because they directly kill the organisms and initiate a cascade of innate and adaptive immune responses. Although several factors contribute to inhalational anthrax, we hypothesized that unimpeded infection of Bacillus anthracis is directly linked to disabling the innate immune functions contributed by AM. Here, we investigated the effects of lethal toxin (LT), one of the binary complex virulence factors produced by B. anthracis, on freshly isolated nonhuman primate AM. Exposure of AM to doses of LT that killed susceptible macrophages had no effect on the viability of AM, despite complete MEK1 cleavage. Intoxicated AM remained fully capable of B. anthracis spore phagocytosis. However, pretreatment of AM with LT resulted in a significant decrease in the clearance of both the Sterne strain and the fully virulent Ames strain of B. anthracis, which may have been a result of impaired AM secretion of proinflammatory cytokines. Our data imply that cytolysis does not correlate with MEK1 cleavage, and this is the first report of LT-mediated impairment of nonhuman primate AM bactericidal activity against B. anthracis. PMID:16926394

The m6A pathway facilitates sex determination in Drosophila

PubMed Central

Kan, Lijuan; Grozhik, Anya V.; Vedanayagam, Jeffrey; Patil, Deepak P.; Pang, Nan; Lim, Kok-Seong; Huang, Yi-Chun; Joseph, Brian; Lin, Ching-Jung; Despic, Vladimir; Guo, Jian; Yan, Dong; Kondo, Shu; Deng, Wu-Min; Dedon, Peter C.; Jaffrey, Samie R.; Lai, Eric C.

2017-01-01

The conserved modification N6-methyladenosine (m6A) modulates mRNA processing and activity. Here, we establish the Drosophila system to study the m6A pathway. We first apply miCLIP to map m6A across embryogenesis, characterize its m6A ‘writer’ complex, validate its YTH ‘readers’ CG6422 and YT521-B, and generate mutants in five m6A factors. While m6A factors with additional roles in splicing are lethal, m6A-specific mutants are viable but present certain developmental and behavioural defects. Notably, m6A facilitates the master female determinant Sxl, since multiple m6A components enhance female lethality in Sxl sensitized backgrounds. The m6A pathway regulates Sxl processing directly, since miCLIP data reveal Sxl as a major intronic m6A target, and female-specific Sxl splicing is compromised in multiple m6A pathway mutants. YT521-B is a dominant m6A effector for Sxl regulation, and YT521-B overexpression can induce female-specific Sxl splicing. Overall, our transcriptomic and genetic toolkit reveals in vivo biologic function for the Drosophila m6A pathway. PMID:28675155

Identification of lethal cluster of genes in the yeast transcription network

NASA Astrophysics Data System (ADS)

Rho, K.; Jeong, H.; Kahng, B.

2006-05-01

Identification of essential or lethal genes would be one of the ultimate goals in drug designs. Here we introduce an in silico method to select the cluster with a high population of lethal genes, called lethal cluster, through microarray assay. We construct a gene transcription network based on the microarray expression level. Links are added one by one in the descending order of the Pearson correlation coefficients between two genes. As the link density p increases, two meaningful link densities pm and ps are observed. At pm, which is smaller than the percolation threshold, the number of disconnected clusters is maximum, and the lethal genes are highly concentrated in a certain cluster that needs to be identified. Thus the deletion of all genes in that cluster could efficiently lead to a lethal inviable mutant. This lethal cluster can be identified by an in silico method. As p increases further beyond the percolation threshold, the power law behavior in the degree distribution of a giant cluster appears at ps. We measure the degree of each gene at ps. With the information pertaining to the degrees of each gene at ps, we return to the point pm and calculate the mean degree of genes of each cluster. We find that the lethal cluster has the largest mean degree.

Risk-taking behaviors and subgrouping of suicide in Iran: A latent class analysis of national registries data.

PubMed

Hajebi, Ahmad; Abbasi-Ghahramanloo, Abbas; Hashemian, Seyed Sepehr; Khatibi, Seyed Reza; Ghasemzade, Masomeh; Khodadost, Mahmoud

2017-09-01

Suicide is one the most important public health problem which is rapidly growing concerns. The aim of this study was to subgroup suicide using LCA method. This cross-sectional study was conducted in Iran based on 66990 records registered in Ministry of Health in 2014. A case report questionnaire in the form of software was used for case registries. Latent class analysis was used to achieve the research objectives. Four latent classes were identified; (a) Non-lethal attempters without a history of psychiatric disorders, (b) Non-lethal attempters with a history of psychiatric disorders, (c) Lethal attempters without a history of psychiatric disorders, (d) Lethal attempters with a history of psychiatric disorders. The probability of completed/an achieved suicide is high in lethal attempter classes. Being male increases the risk of inclusion in lethal attempters' classes (OR = 4.93). Also, being single (OR = 1.16), having an age lower than 25 years (OR = 1.14) and being a rural citizen (OR = 2.36) associate with lethal attempters classes. The males tend to use more violent methods and have more completed suicide. Majority of the individuals are non-lethal attempters who need to be addressed by implementing preventive interventions and mental support provision. Copyright © 2017. Published by Elsevier B.V.

Clostridium sordellii lethal toxin kills mice by inducing a major increase in lung vascular permeability.

PubMed

Geny, Blandine; Khun, Huot; Fitting, Catherine; Zarantonelli, Leticia; Mazuet, Christelle; Cayet, Nadège; Szatanik, Marek; Prevost, Marie-Christine; Cavaillon, Jean-Marc; Huerre, Michel; Popoff, Michel R

2007-03-01

When intraperitoneally injected into Swiss mice, Clostridium sordellii lethal toxin reproduces the fatal toxic shock syndrome observed in humans and animals after natural infection. This animal model was used to study the mechanism of lethal toxin-induced death. Histopathological and biochemical analyses identified lung and heart as preferential organs targeted by lethal toxin. Massive extravasation of blood fluid in the thoracic cage, resulting from an increase in lung vascular permeability, generated profound modifications such as animal dehydration, increase in hematocrit, hypoxia, and finally, cardiorespiratory failure. Vascular permeability increase induced by lethal toxin resulted from modifications of lung endothelial cells as evidenced by electron microscopy. Immunohistochemical analysis demonstrated that VE-cadherin, a protein participating in intercellular adherens junctions, was redistributed from membrane to cytosol in lung endothelial cells. No major sign of lethal toxin-induced inflammation was observed that could participate in the toxic shock syndrome. The main effect of the lethal toxin is the glucosylation-dependent inactivation of small GTPases, in particular Rac, which is involved in actin polymerization occurring in vivo in lungs leading to E-cadherin junction destabilization. We conclude that the cells most susceptible to lethal toxin are lung vascular endothelial cells, the adherens junctions of which were altered after intoxication.

Clostridium sordellii Lethal Toxin Kills Mice by Inducing a Major Increase in Lung Vascular Permeability

PubMed Central

Geny, Blandine; Khun, Huot; Fitting, Catherine; Zarantonelli, Leticia; Mazuet, Christelle; Cayet, Nadège; Szatanik, Marek; Prevost, Marie-Christine; Cavaillon, Jean-Marc; Huerre, Michel; Popoff, Michel R.

2007-01-01

When intraperitoneally injected into Swiss mice, Clostridium sordellii lethal toxin reproduces the fatal toxic shock syndrome observed in humans and animals after natural infection. This animal model was used to study the mechanism of lethal toxin-induced death. Histopathological and biochemical analyses identified lung and heart as preferential organs targeted by lethal toxin. Massive extravasation of blood fluid in the thoracic cage, resulting from an increase in lung vascular permeability, generated profound modifications such as animal dehydration, increase in hematocrit, hypoxia, and finally, cardiorespiratory failure. Vascular permeability increase induced by lethal toxin resulted from modifications of lung endothelial cells as evidenced by electron microscopy. Immunohistochemical analysis demonstrated that VE-cadherin, a protein participating in intercellular adherens junctions, was redistributed from membrane to cytosol in lung endothelial cells. No major sign of lethal toxin-induced inflammation was observed that could participate in the toxic shock syndrome. The main effect of the lethal toxin is the glucosylation-dependent inactivation of small GTPases, in particular Rac, which is involved in actin polymerization occurring in vivo in lungs leading to E-cadherin junction destabilization. We conclude that the cells most susceptible to lethal toxin are lung vascular endothelial cells, the adherens junctions of which were altered after intoxication. PMID:17322384

An adenovirus-vectored nasal vaccine confers rapid and sustained protection against anthrax in a single-dose regimen.

PubMed

Zhang, Jianfeng; Jex, Edward; Feng, Tsungwei; Sivko, Gloria S; Baillie, Leslie W; Goldman, Stanley; Van Kampen, Kent R; Tang, De-chu C

2013-01-01

Bacillus anthracis is the causative agent of anthrax, and its spores have been developed into lethal bioweapons. To mitigate an onslaught from airborne anthrax spores that are maliciously disseminated, it is of paramount importance to develop a rapid-response anthrax vaccine that can be mass administered by nonmedical personnel during a crisis. We report here that intranasal instillation of a nonreplicating adenovirus vector encoding B. anthracis protective antigen could confer rapid and sustained protection against inhalation anthrax in mice in a single-dose regimen in the presence of preexisting adenovirus immunity. The potency of the vaccine was greatly enhanced when codons of the antigen gene were optimized to match the tRNA pool found in human cells. In addition, an adenovirus vector encoding lethal factor can confer partial protection against inhalation anthrax and might be coadministered with a protective antigen-based vaccine.

An Adenovirus-Vectored Nasal Vaccine Confers Rapid and Sustained Protection against Anthrax in a Single-Dose Regimen

PubMed Central

Jex, Edward; Feng, Tsungwei; Sivko, Gloria S.; Baillie, Leslie W.; Goldman, Stanley; Van Kampen, Kent R.; Tang, De-chu C.

2013-01-01

Bacillus anthracis is the causative agent of anthrax, and its spores have been developed into lethal bioweapons. To mitigate an onslaught from airborne anthrax spores that are maliciously disseminated, it is of paramount importance to develop a rapid-response anthrax vaccine that can be mass administered by nonmedical personnel during a crisis. We report here that intranasal instillation of a nonreplicating adenovirus vector encoding B. anthracis protective antigen could confer rapid and sustained protection against inhalation anthrax in mice in a single-dose regimen in the presence of preexisting adenovirus immunity. The potency of the vaccine was greatly enhanced when codons of the antigen gene were optimized to match the tRNA pool found in human cells. In addition, an adenovirus vector encoding lethal factor can confer partial protection against inhalation anthrax and might be coadministered with a protective antigen-based vaccine. PMID:23100479

Effect of human milk and colostrum on Entamoeba histolytica.

PubMed

Akisu, Ciler; Aksoy, Umit; Cetin, Hasan; Ustun, Sebnem; Akisu, Mete

2004-03-01

Many defense factors of the mother's colostrum or milk protect infants from intestinal, respiratory and systemic infections. In the present study, we investigated the effect of colostrum and mature human milk on E. histolytica parasites in vitro. Samples of human milk were collected from 5 healthy lactating mothers. The medium with human milk at concentrations of 2%, 5% and 10% was obtained. The lethal effect of E. histolytica on the medium supplemented with different concentrations of both colostrum and mature human milk was significant during the first 30 min. We also detected that the results of colostrum and mature human milk were similar. No statistically significant differences were found between same concentrations of colostrum and mature human milk at the same times. Colostrum and mature human milk have significant lethal effect on E. histolytica and protect against its infection in breast fed children.

The staphylococcal enterotoxin (SE) family: SEB and siblings.

PubMed

Krakauer, Teresa; Stiles, Bradley G

2013-11-15

Staphylococcus aureus plays an important role in numerous human cases of food poisoning, soft tissue, and bone infections, as well as potentially lethal toxic shock. This common bacterium synthesizes various virulence factors that include staphylococcal enterotoxins (SEs). These protein toxins bind directly to major histocompatibility complex class II on antigen-presenting cells and specific Vβ regions of T-cell receptors, resulting in potentially life-threatening stimulation of the immune system. Picomolar concentrations of SEs ultimately elicit proinflammatory cytokines that can induce fever, hypotension, multi-organ failure, and lethal shock. Various in vitro and in vivo models have provided important tools for studying the biological effects of, as well as potential vaccines/therapeutics against, the SEs. This review succinctly presents known physical and biological properties of the SEs, including various intervention strategies. In particular, SEB will often be portrayed as per biodefense concerns dating back to the 1960s.

Toxicity of Imidacloprid to the Stingless Bee Scaptotrigona postica Latreille, 1807 (Hymenoptera: Apidae).

PubMed

Soares, Hellen Maria; Jacob, Cynthia Renata Oliveira; Carvalho, Stephan Malfitano; Nocelli, Roberta Cornélio Ferreira; Malaspina, Osmar

2015-06-01

The stingless bee Scaptotrigona postica is an important pollinator of native and cultivated plants in Brazil. Among the factors affecting the survival of these insects is the indiscriminate use of insecticides, including the neonicotinoid imidacloprid. This work determined the toxicity of imidacloprid as the topical median lethal dose (LD50) and the oral median lethal concentration (LC50) as tools for assessing the effects of this insecticide. The 24 and 48 h LD50 values were 25.2 and 24.5 ng of active ingredient (a.i.)/bee, respectively. The 24 and 48 h LC50 values were 42.5 and 14.3 ng a.i./µL of diet, respectively. Ours results show the hazard of imidacloprid and the vulnerability of stingless bees to it, providing relevant toxicological data that can used in mitigation programs to ensure the conservation of this species.

Novel insights for systemic inflammation in sepsis and hemorrhage.

PubMed

Cai, Bolin; Deitch, Edwin A; Ulloa, Luis

2010-01-01

The inflammatory responses in sepsis and hemorrhage remain a major cause of death. Clinically, it is generally accepted that shock in sepsis or hemorrhage differs in its mechanisms. However, the recognition of inflammatory cytokines as a common lethal pathway has become consent. Proinflammatory cytokines such as tumor necrosis factor (TNF) or high-mobility group box1 (HMGB1) are fanatically released and cause lethal multiorgan dysfunction. Inhibition of these cytokines can prevent the inflammatory responses and organ damage. In seeking potential anti-inflammatory strategies, we reported that ethyl pyruvate and alpha7 nicotinic acetylcholine receptor (alpha7nAChR) agonists effectively restrained cytokine production to provide therapeutic benefits in both experimental sepsis and hemorrhage. Here, we review the inflammatory responses and the anti-inflammatory strategies in experimental models of sepsis and hemorrhage, as they may have a consistent inflammatory pathway in spite of their different pathophysiological processes.

The staphylococcal enterotoxin (SE) family

PubMed Central

Krakauer, Teresa; Stiles, Bradley G

2013-01-01

Staphylococcus aureus plays an important role in numerous human cases of food poisoning, soft tissue, and bone infections, as well as potentially lethal toxic shock. This common bacterium synthesizes various virulence factors that include staphylococcal enterotoxins (SEs). These protein toxins bind directly to major histocompatibility complex class II on antigen-presenting cells and specific Vβ regions of T-cell receptors, resulting in potentially life-threatening stimulation of the immune system. Picomolar concentrations of SEs ultimately elicit proinflammatory cytokines that can induce fever, hypotension, multi-organ failure, and lethal shock. Various in vitro and in vivo models have provided important tools for studying the biological effects of, as well as potential vaccines/therapeutics against, the SEs. This review succinctly presents known physical and biological properties of the SEs, including various intervention strategies. In particular, SEB will often be portrayed as per biodefense concerns dating back to the 1960s. PMID:23959032

Toxicity and motor changes in Africanized honey bees (Apis mellifera L.) exposed to fipronil and imidacloprid.

PubMed

Bovi, Thaís S; Zaluski, Rodrigo; Orsi, Ricardo O

2018-01-01

This study evaluated the in vitro toxicity and motor activity changes in African-derived adult honey bees (Apis mellifera L.) exposed to lethal or sublethal doses of the insecticides fipronil and imidacloprid. Mortality of bees was assessed to determine the ingestion and contact lethal dose for 24 h using probit analysis. Motor activities in bees exposed to lethal (LD50) and sublethal doses (1/500th of the lethal dose) of both insecticides were evaluated in a behavioral observation box at 1 and 4 h. Ingestion and contact lethal doses of fipronil were 0.2316 ? 0.0626 and 0.0080 ? 0.0021 μg/bee, respectively. Ingestion and contact lethal doses of imidacloprid were 0.1079 ? 0.0375 and 0.0308 ? 0.0218 μg/bee, respectively. Motor function of bees exposed to lethal doses of fipronil and imidacloprid was impaired; exposure to sublethal doses of fipronil but not imidacloprid impaired motor function. The insecticides evaluated in this study were highly toxic to African-derived A. mellifera and caused impaired motor function in these pollinators.

Toxic shock syndrome toxin-1, not α-toxin, mediated Bundaberg fatalities.

PubMed

Mueller, Elizabeth A; Merriman, Joseph A; Schlievert, Patrick M

2015-12-01

The 1928 Bundaberg disaster is one of the greatest vaccine tragedies in history. Of 21 children immunized with a diphtheria toxin-antitoxin preparation contaminated with Staphylococcus aureus, 18 developed life-threatening disease and 12 died within 48  h. Historically, the deaths have been attributed to α-toxin, a secreted cytotoxin produced by most S. aureus strains, yet the ability of the Bundaberg contaminant microbe to produce the toxin has never been verified. For the first time, the ability of the original strain to produce α-toxin and other virulence factors is investigated. The study investigates the genetic and regulatory loci mediating α-toxin expression by PCR and assesses production of the cytotoxin in vitro using an erythrocyte haemolysis assay. This analysis is extended to other secreted virulence factors produced by the strain, and their sufficiency to cause lethality in New Zealand white rabbits is determined. Although the strain possesses a wild-type allele for α-toxin, it must have a defective regulatory system, which is responsible for the strain's minimal α-toxin production. The strain encodes and produces staphylococcal superantigens, including toxic shock syndrome toxin-1 (TSST-1), which is sufficient to cause lethality in patients. The findings cast doubt on the belief that α-toxin is the major virulence factor responsible for the Bundaberg fatalities and point to the superantigen TSST-1 as the cause of the disaster.

A Family of Indoles Regulate Virulence and Shiga Toxin Production in Pathogenic E. coli

PubMed Central

Izrayelit, Yevgeniy; Bhatt, Shantanu; Cartwright, Emily; Wang, Wei; Swimm, Alyson I.; Benian, Guy M.; Schroeder, Frank C.; Kalman, Daniel

2013-01-01

Enteropathogenic Escherichia coli (EPEC), enterohemorrhagic E. coli (EHEC) and enteroaggregative E. coli (EAEC) are intestinal pathogens that cause food and water-borne disease in humans. Using biochemical methods and NMR-based comparative metabolomics in conjunction with the nematode Caenorhabditis elegans, we developed a bioassay to identify secreted small molecules produced by these pathogens. We identified indole, indole-3-carboxaldehyde (ICA), and indole-3-acetic acid (IAA), as factors that only in combination are sufficient to kill C. elegans. Importantly, although lethal to C. elegans, these molecules downregulate several bacterial processes important for pathogenesis in mammals. These include motility, biofilm formation and production of Shiga toxins. Some pathogenic E. coli strains are known to contain a Locus of Enterocyte Effacement (LEE), which encodes virulence factors that cause “attaching and effacing” (A/E) lesions in mammals, including formation of actin pedestals. We found that these indole derivatives also downregulate production of LEE virulence factors and inhibit pedestal formation on mammalian cells. Finally, upon oral administration, ICA inhibited virulence and promoted survival in a lethal mouse infection model. In summary, the C. elegans model in conjunction with metabolomics has facilitated identification of a family of indole derivatives that broadly regulate physiology in E. coli, and virulence in pathogenic strains. These molecules may enable development of new therapeutics that interfere with bacterial small-molecule signaling. PMID:23372726

Is the Sexual Murderer a Unique Type of Offender? A Typology of Violent Sexual Offenders Using Crime Scene Behaviors.

PubMed

Healey, Jay; Beauregard, Eric; Beech, Anthony; Vettor, Shannon

2016-09-01

The empirical literature on sexual homicide has posited the sexual murderer as a unique type of offender who is qualitatively different from other types of offenders. However, recent research has suggested that sexual homicide is a dynamic crime and that sexual assaults can escalate to homicide when specific situational factors are present. This study simultaneously explored the utility of the sexual murderer as a unique type of offender hypothesis and sexual homicide as a differential outcome of sexual assaults hypothesis. This study is based on a sample of 342 males who were convicted of committing a violent sexual offense, which resulted in either physical injury or death of the victim. A series of latent class analyses were performed using crime scene indicators in an attempt to identify discrete groups of sexual offenders. In addition, the effects of modus operandi, situational factors, and offender characteristics on each group were investigated. Results suggest that both hypotheses are supported. A group of offenders was identified who almost exclusively killed their victims and demonstrated a lethal intent by the choice of their offending behavior. Moreover, three other groups of sex offenders were identified with a diverse lethality level, suggesting that these cases could end up as homicide when certain situational factors were present. © The Author(s) 2014.

Factors contributing to deep supercooling capability and cold survival in dwarf bamboo (Sasa senanensis) leaf blades.

PubMed

Ishikawa, Masaya; Oda, Asuka; Fukami, Reiko; Kuriyama, Akira

2014-01-01

Wintering Sasa senanensis, dwarf bamboo, is known to employ deep supercooling as the mechanism of cold hardiness in most of its tissues from leaves to rhizomes. The breakdown of supercooling in leaf blades has been shown to proceed in a random and scattered manner with a small piece of tissue surrounded by longitudinal and transverse veins serving as the unit of freezing. The unique cold hardiness mechanism of this plant was further characterized using current year leaf blades. Cold hardiness levels (LT20: the lethal temperature at which 20% of the leaf blades are injured) seasonally increased from August (-11°C) to December (-20°C). This coincided with the increases in supercooling capability of the leaf blades as expressed by the initiation temperature of low temperature exotherms (LTE) detected in differential thermal analyses (DTA). When leaf blades were stored at -5°C for 1-14 days, there was no nucleation of the supercooled tissue units either in summer or winter. However, only summer leaf blades suffered significant injury after prolonged supercooling of the tissue units. This may be a novel type of low temperature-induced injury in supercooled state at subfreezing temperatures. When winter leaf blades were maintained at the threshold temperature (-20°C), a longer storage period (1-7 days) increased lethal freezing of the supercooled tissue units. Within a wintering shoot, the second or third leaf blade from the top was most cold hardy and leaf blades at lower positions tended to suffer more injury due to lethal freezing of the supercooled units. LTE were shifted to higher temperatures (2-5°C) after a lethal freeze-thaw cycle. The results demonstrate that the tissue unit compartmentalized with longitudinal and transverse veins serves as the unit of supercooling and temperature- and time-dependent freezing of the units is lethal both in laboratory freeze tests and in the field. To establish such supercooling in the unit, structural ice barriers such as development of sclerenchyma and biochemical mechanisms to increase the stability of supercooling are considered important. These mechanisms are discussed in regard to ecological and physiological significance in winter survival.

Development of System Architecture to Investigate the Impact of Integrated Air and Missile Defense in a Distributed Lethality Environment

DTIC Science & Technology

2017-12-01

SYSTEM ARCHITECTURE TO INVESTIGATE THE IMPACT OF INTEGRATED AIR AND MISSILE DEFENSE IN A DISTRIBUTED LETHALITY ENVIRONMENT by Justin K. Davis...TO INVESTIGATE THE IMPACT OF INTEGRATED AIR AND MISSILE DEFENSE IN A DISTRIBUTED LETHALITY ENVIRONMENT 5. FUNDING NUMBERS 6. AUTHOR(S) Justin K...ARCHITECTURE TO INVESTIGATE THE IMPACT OF INTEGRATED AIR AND MISSILE DEFENSE IN A DISTRIBUTED LETHALITY ENVIRONMENT Justin K. Davis Lieutenant

Non-Lethal Weapons: A Technology Gap or Lack or Available Systems, Training, and Proper Application

DTIC Science & Technology

2016-06-10

Ibid., 190-191. 9 Jonathan D. Moreno, “Medical Ethics and Non-Lethal Weapons ,” The American Journal of Bioethics 4, no. 4 (Fall 2004): W1...Quarterly (Spring-Summer 2001): 18-22. Moreno, Jonathan D. “Medical Ethics and Non-Lethal Weapons .” The American Journal of Bioethics 4, no. 4 (Fall...NON-LETHAL WEAPONS : A TECHNOLOGY GAP OR LACK OF AVAILABLE SYSTEMS, TRAINING, AND PROPER APPLICATION A thesis presented to

A bacterial cocaine esterase protects against cocaine-induced epileptogenic activity and lethality.

PubMed

Jutkiewicz, Emily M; Baladi, Michelle G; Cooper, Ziva D; Narasimhan, Diwahar; Sunahara, Roger K; Woods, James H

2009-09-01

Cocaine toxicity results in cardiovascular complications, seizures, and death and accounts for approximately 20% of drug-related emergency department visits every year. Presently, there are no treatments to eliminate the toxic effects of cocaine. The present study hypothesizes that a bacterial cocaine esterase with high catalytic efficiency would provide rapid and robust protection from cocaine-induced convulsions, epileptogenic activity, and lethality. Cocaine-induced paroxysmal activity and convulsions were evaluated in rats surgically implanted with radiotelemetry devices (N=6 per treatment group). Cocaine esterase was administered 1 minute after a lethal dose of cocaine or after cocaine-induced convulsions to determine the ability of the enzyme to prevent or reverse, respectively, the effects of cocaine. The cocaine esterase prevented all cocaine-induced electroencephalographic changes and lethality. This effect was specific for cocaine because the esterase did not prevent convulsions and death induced by a cocaine analog, (-)-2beta-carbomethoxy-3beta-phenyltropane. The esterase prevented lethality even after cocaine-induced convulsions occurred. In contrast, the short-acting benzodiazepine, midazolam, prevented cocaine-induced convulsions but not the lethal effects of cocaine. The data showed that cocaine esterase successfully degraded circulating cocaine to prevent lethality and that cocaine-induced convulsions alone are not responsible for the lethal effects of cocaine in this model. Therefore, further investigation into the use of cocaine esterase for treating cocaine overdose and its toxic effects is warranted.

Testing of candidate non-lethal sampling methods for detection of Renibacterium salmoninarum in juvenile Chinook salmon Oncorhynchus tshawytscha

USGS Publications Warehouse

Elliott, Diane G.; McKibben, Constance L.; Conway, Carla M.; Purcell, Maureen K.; Chase, Dorothy M.; Applegate, Lynn M.

2015-01-01

Non-lethal pathogen testing can be a useful tool for fish disease research and management. Our research objectives were to determine if (1) fin clips, gill snips, surface mucus scrapings, blood draws, or kidney biopsies could be obtained non-lethally from 3 to 15 g Chinook salmon Oncorhynchus tshawytscha, (2) non-lethal samples could accurately discriminate between fish exposed to the bacterial kidney disease agent Renibacterium salmoninarum and non-exposed fish, and (3) non-lethal samples could serve as proxies for lethal kidney samples to assess infection intensity. Blood draws and kidney biopsies caused ≥5% post-sampling mortality (Objective 1) and may be appropriate only for larger fish, but the other sample types were non-lethal. Sampling was performed over 21 wk following R. salmoninarum immersion challenge of fish from 2 stocks (Objectives 2 and 3), and nested PCR (nPCR) and real-time quantitative PCR (qPCR) results from candidate non-lethal samples were compared with kidney tissue analysis by nPCR, qPCR, bacteriological culture, enzyme-linked immunosorbent assay (ELISA), fluorescent antibody test (FAT) and histopathology/immunohistochemistry. R. salmoninarum was detected by PCR in >50% of fin, gill, and mucus samples from challenged fish. Mucus qPCR was the only non-lethal assay exhibiting both diagnostic sensitivity and specificity estimates >90% for distinguishing between R. salmoninarum-exposed and non-exposed fish and was the best candidate for use as an alternative to lethal kidney sample testing. Mucus qPCR R. salmoninarum quantity estimates reflected changes in kidney bacterial load estimates, as evidenced by significant positive correlations with kidney R. salmoninaruminfection intensity scores at all sample times and in both fish stocks, and were not significantly impacted by environmentalR. salmoninarum concentrations.

Modeling synthetic lethality

PubMed Central

Le Meur, Nolwenn; Gentleman, Robert

2008-01-01

Background Synthetic lethality defines a genetic interaction where the combination of mutations in two or more genes leads to cell death. The implications of synthetic lethal screens have been discussed in the context of drug development as synthetic lethal pairs could be used to selectively kill cancer cells, but leave normal cells relatively unharmed. A challenge is to assess genome-wide experimental data and integrate the results to better understand the underlying biological processes. We propose statistical and computational tools that can be used to find relationships between synthetic lethality and cellular organizational units. Results In Saccharomyces cerevisiae, we identified multi-protein complexes and pairs of multi-protein complexes that share an unusually high number of synthetic genetic interactions. As previously predicted, we found that synthetic lethality can arise from subunits of an essential multi-protein complex or between pairs of multi-protein complexes. Finally, using multi-protein complexes allowed us to take into account the pleiotropic nature of the gene products. Conclusions Modeling synthetic lethality using current estimates of the yeast interactome is an efficient approach to disentangle some of the complex molecular interactions that drive a cell. Our model in conjunction with applied statistical methods and computational methods provides new tools to better characterize synthetic genetic interactions. PMID:18789146

Growth and yield of southwest pinyon-juniper woodlands: Modeling growth and drought effects

Treesearch

John D. Shaw

2008-01-01

A complex of drought, insects, and disease caused widespread mortality in the pinyon-juniper forest types of the American Southwest in recent years. Most public and scientific attention has been given to the extent of drought-related mortality and causal factors. At the same time, there has been relatively little attention given to non-lethal drought effects. As part...

A model to predict the risk of lethal nasopharyngeal necrosis after re-irradiation with intensity-modulated radiotherapy in nasopharyngeal carcinoma patients.

PubMed

Yu, Ya-Hui; Xia, Wei-Xiong; Shi, Jun-Li; Ma, Wen-Juan; Li, Yong; Ye, Yan-Fang; Liang, Hu; Ke, Liang-Ru; Lv, Xing; Yang, Jing; Xiang, Yan-Qun; Guo, Xiang

2016-06-29

For patients with nasopharyngeal carcinoma (NPC) who undergo re-irradiation with intensity-modulated radiotherapy (IMRT), lethal nasopharyngeal necrosis (LNN) is a severe late adverse event. The purpose of this study was to identify risk factors for LNN and develop a model to predict LNN after radical re-irradiation with IMRT in patients with recurrent NPC. Patients who underwent radical re-irradiation with IMRT for locally recurrent NPC between March 2001 and December 2011 and who had no evidence of distant metastasis were included in this study. Clinical characteristics, including recurrent carcinoma conditions and dosimetric features, were evaluated as candidate risk factors for LNN. Logistic regression analysis was used to identify independent risk factors and construct the predictive scoring model. Among 228 patients enrolled in this study, 204 were at risk of developing LNN based on risk analysis. Of the 204 patients treated, 31 (15.2%) developed LNN. Logistic regression analysis showed that female sex (P = 0.008), necrosis before re-irradiation (P = 0.008), accumulated total prescription dose to the gross tumor volume (GTV) ≥145.5 Gy (P = 0.043), and recurrent tumor volume ≥25.38 cm(3) (P = 0.009) were independent risk factors for LNN. A model to predict LNN was then constructed that included these four independent risk factors. A model that includes sex, necrosis before re-irradiation, accumulated total prescription dose to GTV, and recurrent tumor volume can effectively predict the risk of developing LNN in NPC patients who undergo radical re-irradiation with IMRT.

A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer.

PubMed

Wu, Yishuo; Yu, Hongjie; Zheng, S Lilly; Na, Rong; Mamawala, Mufaddal; Landis, Tricia; Wiley, Kathleen; Petkewicz, Jacqueline; Shah, Sameep; Shi, Zhuqing; Novakovic, Kristian; McGuire, Michael; Brendler, Charles B; Ding, Qiang; Helfand, Brian T; Carter, H Ballentine; Cooney, Kathleen A; Isaacs, William B; Xu, Jianfeng

2018-06-01

Germline mutations in CHEK2 have been associated with prostate cancer (PCa) risk. Our objective is to examine whether germline pathogenic CHEK2 mutations can differentiate risk of lethal from indolent PCa. A case-case study of 703 lethal PCa patients and 1455 patients with low-risk localized PCa of European, African, and Chinese origin was performed. Germline DNA samples from these patients were sequenced for CHEK2. Mutation carrier rates and their association with lethal PCa were analyzed using the Fisher exact test and Kaplan-Meier survival analysis. In the entire study population, 40 (1.85%) patients were identified as carrying one of 15 different germline CHEK2 pathogenic or likely pathogenic mutations. CHEK2 mutations were detected in 16 (2.28%) of 703 lethal PCa patients compared with 24 (1.65%) of 1455 low-risk PCa patients (P = 0.31). No association was found between CHEK2 mutation status and early-diagnosis or PCa-specific survival time. However, the most common mutation in CHEK2, c.1100delC (p.T367 fs), had a significantly higher carrier rate (1.28%) in lethal PCa patients than low-risk PCa patients of European American origin (0.16%), P = 0.0038. The estimated Odds Ratio of this mutation for lethal PCa was 7.86. The carrier rate in lethal PCa was also significantly higher than that (0.46%) in 32 461 non-Finnish European subjects from the Exome Aggregation Consortium (ExAC) (P = 0.01). While overall CHEK2 mutations were not significantly more common in men with lethal compared to low-risk PCa, the specific CHEK2 mutation, c.1100delC, appears to contribute to an increased risk of lethal PCa in European American men. © 2018 Wiley Periodicals, Inc.

Absolute probability estimates of lethal vessel strikes to North Atlantic right whales in Roseway Basin, Scotian Shelf.

PubMed

van der Hoop, Julie M; Vanderlaan, Angelia S M; Taggart, Christopher T

2012-10-01

Vessel strikes are the primary source of known mortality for the endangered North Atlantic right whale (Eubalaena glacialis). Multi-institutional efforts to reduce mortality associated with vessel strikes include vessel-routing amendments such as the International Maritime Organization voluntary "area to be avoided" (ATBA) in the Roseway Basin right whale feeding habitat on the southwestern Scotian Shelf. Though relative probabilities of lethal vessel strikes have been estimated and published, absolute probabilities remain unknown. We used a modeling approach to determine the regional effect of the ATBA, by estimating reductions in the expected number of lethal vessel strikes. This analysis differs from others in that it explicitly includes a spatiotemporal analysis of real-time transits of vessels through a population of simulated, swimming right whales. Combining automatic identification system (AIS) vessel navigation data and an observationally based whale movement model allowed us to determine the spatial and temporal intersection of vessels and whales, from which various probability estimates of lethal vessel strikes are derived. We estimate one lethal vessel strike every 0.775-2.07 years prior to ATBA implementation, consistent with and more constrained than previous estimates of every 2-16 years. Following implementation, a lethal vessel strike is expected every 41 years. When whale abundance is held constant across years, we estimate that voluntary vessel compliance with the ATBA results in an 82% reduction in the per capita rate of lethal strikes; very similar to a previously published estimate of 82% reduction in the relative risk of a lethal vessel strike. The models we developed can inform decision-making and policy design, based on their ability to provide absolute, population-corrected, time-varying estimates of lethal vessel strikes, and they are easily transported to other regions and situations.

Lethal factor is not required for Bacillus anthracis virulence in guinea pigs and rabbits.

PubMed

Levy, Haim; Weiss, Shay; Altboum, Zeev; Schlomovitz, Josef; Rothschild, Nili; Blachinsky, Eran; Kobiler, David

2011-11-01

The major virulence factor of Bacillus anthracis is the tripartite anthrax toxin, comprising the protective antigen (PA), lethal factor (LF) and edema factor (EF). The LF of B. anthracis is a metalloprotease that has been shown to play an important role in pathogenicity. Deletion of this gene (lef) in the Sterne strain was reported to dramatically reduce the pathogenicity of this strain in mice, and was reported to be as dramatic as the deletion of PA. We evaluated the effect on pathogenicity of the lef deletion in the fully virulent Vollum strain in guinea pigs and NZW rabbits by either subcutaneous injection or intranasal instillation. In guinea pigs, no major differences between the mutant strain and the wild type could be detected in the LD(50) or mean time to death values. On the other hand, the lef deletion caused death of 50-70% of all rabbits infected with the mutant spores at doses equivalent or higher than the wild type LD(50). The surviving rabbits, which were infected with spore doses higher than the wild type LD(50), developed a protective immune response that conferred resistance to challenge with the wild type strain. These findings may indicate that the mutant lacking the LF is capable of host colonization which causes death in 50-70% of the animals and a protective immune response in the others. These results indicate that unlike the data obtained in mice, the LF mutation does not abolish B. anthracis pathogenicity. Copyright © 2011 Elsevier Ltd. All rights reserved.

Risk factor profile for sudden cardiac death during mountain hiking.

PubMed

Burtscher, M; Pachinger, O; Schocke, M F H; Ulmer, H

2007-07-01

Mountain hiking is associated with a death rate of about 4 deaths per 100,000 hikers annually. About 50 % of all fatalities during mountain hiking are sudden cardiac deaths (SCDs). But there are only few data available regarding risk factors and triggers associated with SCD during mountain hiking. Thus, a case-control analysis between persons who died suddenly during mountain hiking and randomly selected controls was carried out. Risk factor profiles of 179 males over the age of 34 who suffered SCD during mountain hiking were compared to those of 537 matched controls. Hikers who died suddenly during mountain hiking were much more likely to have had a prior MI (17% vs. 0.9%; p < 0.001), known coronary artery disease (CAD) without prior MI (17 % vs. 4%; p < 0.001), diabetes (6% vs. 1 %; p < 0.001), hypercholesterolemia (54 % vs. 20%; p < 0.001), and were less engaged in regular mountain sports activities (31% vs. 58%; p < 0.001) compared to hikers from the control group. Based on the reported relationship between traditional risk factors and coronary plaque morphology, acute plaque rupture with thrombus formation and subsequent lethal arrhythmias may be assumed to be a dominant mechanism precipitating SCD during hiking. In contrast, in skiers especially non-occlusive plaques may precipitate ischemia leading to an imbalance between oxygen demand and supply and subsequent lethal arrhythmias. As preventive measures recommended to hikers at risk, adaptation to regular mountain sports activities by an adequate training program and pharmacological interventions, e.g. lipid lowering drugs, aspirin, and beta-blockers, should be considered.

Risks of non-lethal weapon use: case studies of three French victims of stinger grenades.

PubMed

Scolan, V; Herry, C; Carreta, M; Stahl, C; Barret, L; Romanet, J P; Paysant, F

2012-11-30

The development of non-lethal weapons started in the 1960s. In France, they have been used by the police for about 10 years. We relate the cases of three French women, victims of stinger grenades, non-lethal weapons recently adopted by the French law enforcement to distract and disperse crowds. The three victims presented serious injuries requiring emergency surgical care. One lost her eye. Based on these cases, we discuss the lethal character of these weapons and propose measures to be taken to prevent their dramatic consequences. Although the danger is obviously less than for firearms, stinger grenades are nonetheless potentially lethal and cause serious physical injuries. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

[Surgical treatment of anastomosis ulcers. 1. Short-term results].

PubMed

Lüders, K; Fellmann, E; März, E

1980-02-14

Records of 151 patients from the years 1964--1979 with anastomotic ulcers including relapses of ulcers after vagotomy reveal a total lethality of 3.3 per cent after reoperation. Re-gastrectomy with or without additional vagotomy shows a lethality of 5.7 per cent. If vagotomy alone is carried out there were no lethality and nearly no serious complications. Gastrectomy because of recurrent peptic ulcer after primary vagotomy has also no lethality. With regard to less serious postoperative complications including lethality after vagotomy instead of re-gastrectomy we should favour vagotomy for re-operation. Our further examinations will show whether this attitude is justified by long-term results after re-operation of the stomach in consequence of recurrent pepti ulcer.

Lethal and sublethal effects of cypermethrin to Hypsiboas pulchellus tadpoles.

PubMed

Agostini, M Gabriela; Natale, Guillermo S; Ronco, Alicia E

2010-11-01

The study of the effects of the insecticide cypermethrin (CY) technical grade and its Sherpa® commercial formulation on Hypsiboas pulchellus tadpoles assessing lethality, behavior, growth, and abnormalities under standardized laboratory conditions is reported. Observed behaviors were identified and categorized by means of a ranking system according to the loss of mobility. Results of acute lethal effects indicate higher potency for Sherpa® at this level of assessment. All effects on behavior showed an increasing degree of injury as insecticide concentration increased. Organisms exposed to technical grade CY showed lower body length with respect to controls from 3.44 µg CY/L to higher concentrations, whereas those exposed to Sherpa® exhibited lower growth from 0.83 µg CY/L. Both forms of the tested insecticide caused abnormalities between 0.34 and 4.18 µg CY/L, but 100% of malformed individuals was detected from 34.4 µg CY/L for those exposed to the technical grade CY, and from 8.36 µg CY/L for those exposed to Sherpa®. This study proposes the use of easily identifiable and distinguishable sublethal end-points. The high input loads of CY in natural environments, the detected concentrations in the field, in addition to the low levels of this insecticide required to induce sublethal effects (which could eventually lead to death), allow for the conclusion that the insecticide is a risk factor for amphibians inhabiting agroecosystems.

Modeling Powassan virus infection in Peromyscus leucopus, a natural host

PubMed Central

Meade-White, Kimberly; Saturday, Greg; Scott, Dana; Bloom, Marshall E.

2017-01-01

The tick-borne flavivirus, Powassan virus (POWV) causes life-threatening encephalitis in humans in North America and Europe. POWV is transmitted by ixodid tick vectors that feed on small to medium-sized mammals, such as Peromyscus leucopus mice, which may serve as either reservoir, bridge or amplification hosts. Intraperitoneal and intracranial inoculation of 4-week old Peromyscus leucopus mice with 103 PFU of POWV did not result in overt clinical signs of disease. However, following intracranial inoculation, infected mice seroconverted to POWV and histopathological examinations revealed that the mice uniformly developed mild lymphocytic perivascular cuffing and microgliosis in the brain and spinal cord from 5 to 15 days post infection (dpi), suggesting an early inflammatory response. In contrast, intracranial inoculation of 4-week old C57BL/6 and BALB/c mice was lethal by 5 dpi. Intraperitoneal inoculation was lethal in BALB/c mice, but 40% (2/5) of C57BL/6 mice survived. We concluded that Peromyscus leucopus mice infected i.c. with a lethal dose of POWV support a limited infection, restricted to the central nervous system and mount an antibody response to the virus. However, they fail to develop clinical signs of disease and are able to control the infection. These results suggest the involvement of restriction factors, and the mechanism by which Peromyscus leucopus mice restrict POWV infection remains under study. PMID:28141800

Modeling Powassan virus infection in Peromyscus leucopus, a natural host.

PubMed

Mlera, Luwanika; Meade-White, Kimberly; Saturday, Greg; Scott, Dana; Bloom, Marshall E

2017-01-01

The tick-borne flavivirus, Powassan virus (POWV) causes life-threatening encephalitis in humans in North America and Europe. POWV is transmitted by ixodid tick vectors that feed on small to medium-sized mammals, such as Peromyscus leucopus mice, which may serve as either reservoir, bridge or amplification hosts. Intraperitoneal and intracranial inoculation of 4-week old Peromyscus leucopus mice with 103 PFU of POWV did not result in overt clinical signs of disease. However, following intracranial inoculation, infected mice seroconverted to POWV and histopathological examinations revealed that the mice uniformly developed mild lymphocytic perivascular cuffing and microgliosis in the brain and spinal cord from 5 to 15 days post infection (dpi), suggesting an early inflammatory response. In contrast, intracranial inoculation of 4-week old C57BL/6 and BALB/c mice was lethal by 5 dpi. Intraperitoneal inoculation was lethal in BALB/c mice, but 40% (2/5) of C57BL/6 mice survived. We concluded that Peromyscus leucopus mice infected i.c. with a lethal dose of POWV support a limited infection, restricted to the central nervous system and mount an antibody response to the virus. However, they fail to develop clinical signs of disease and are able to control the infection. These results suggest the involvement of restriction factors, and the mechanism by which Peromyscus leucopus mice restrict POWV infection remains under study.

Biological responses of Habrobracon to spaceflight.

PubMed

von Borstel, R C; Smith, R H; Whiting, A R; Grosch, D S

1970-01-01

Since the interaction of the parasitic wasp Habrobracon with the space environment could not be prejudged, we decided to test approximately 30 different parameters of a genetic, mutational, biochemical, behavioral, and physiological character in the one spaceflight we had at our disposal. These parameters were examined at six different exposures of gamma-radiation (including 0 dose) in flight, resulting in about 180 different endpoints in all. The most profound effects of spaceflight in conjunction with radiation were decreased hatchability and enhanced fecundity of eggs exposed to spaceflight at different stages of oogenesis. The interpretation we favor is that these two endpoints are reflections of chromosomal non-disjunction in the former case and inhibition of cell division in the latter. Our most comprehensive study of mutagenesis was on sperm, where dominant lethality, recessive lethality, translocations, and visible mutations were assayed; the only effect found was a threefold enhancement of the recessive lethal mutation frequency in the non-irradiated sperm in the orbited Habrobracon males. Behavioral and biochemical differences were found. Mating activity of orbited males was severely disrupted and xanthine dehydrogenase activity was sharply decreased in the irradiated flight animals, an unexpected observation. Postflight experiments were like the ground-based control experiments in all aspects but one. Under conditions of vibration similar to those encountered during the launch and re-entry, the mutation frequency in the sperm increased by a factor of three over that of the non-vibrated control.

Role of natural killer cells in innate protection against lethal ebola virus infection.

PubMed

Warfield, Kelly L; Perkins, Jeremy G; Swenson, Dana L; Deal, Emily M; Bosio, Catharine M; Aman, M Javad; Yokoyama, Wayne M; Young, Howard A; Bavari, Sina

2004-07-19

Ebola virus is a highly lethal human pathogen and is rapidly driving many wild primate populations toward extinction. Several lines of evidence suggest that innate, nonspecific host factors are potentially critical for survival after Ebola virus infection. Here, we show that nonreplicating Ebola virus-like particles (VLPs), containing the glycoprotein (GP) and matrix protein virus protein (VP)40, administered 1-3 d before Ebola virus infection rapidly induced protective immunity. VLP injection enhanced the numbers of natural killer (NK) cells in lymphoid tissues. In contrast to live Ebola virus, VLP treatment of NK cells enhanced cytokine secretion and cytolytic activity against NK-sensitive targets. Unlike wild-type mice, treatment of NK-deficient or -depleted mice with VLPs had no protective effect against Ebola virus infection and NK cells treated with VLPs protected against Ebola virus infection when adoptively transferred to naive mice. The mechanism of NK cell-mediated protection clearly depended on perforin, but not interferon-gamma secretion. Particles containing only VP40 were sufficient to induce NK cell responses and provide protection from infection in the absence of the viral GP. These findings revealed a decisive role for NK cells during lethal Ebola virus infection. This work should open new doors for better understanding of Ebola virus pathogenesis and direct the development of immunotherapeutics, which target the innate immune system, for treatment of Ebola virus infection.

PARP inhibition as a prototype for synthetic lethal screens.

PubMed

Liu, Xuesong

2013-01-01

Although DNA damaging chemotherapy and radiation therapy remain the main stay of current treatments for cancer patient, these therapies usually have toxic side effect and narrow therapeutic window. One of the challenges in cancer drug discovery is how to identify drugs that selectively kill cancer cells while leaving the normal cell intact. Recently, synthetic lethality has been applied to cancer drug discovery in various settings, and has become a promising approach for identifying novel agents for the treatment of cancer. A prototypical example is the synthetic lethal interaction between PARP inhibition and BRCA deficiency. PARP inhibitors represent the most advanced clinical agents targeting specifically DNA repair mechanisms in cancer therapy. In this chapter, I will review the molecular mechanism for this synthetic lethality and the clinical applications for PARP inhibitors. I will also discuss the formats of synthetic lethal screens, current progress on the utilization of these screens, and some of the advantages and challenges of synthetic lethal screens in cancer drug discovery.

Terrorist Attacks Escalate in Frequency and Fatalities Preceding Highly Lethal Attacks

PubMed Central

Martens, Andy; Sainudiin, Raazesh; Sibley, Chris G.; Schimel, Jeff; Webber, David

2014-01-01

Highly lethal terrorist attacks, which we define as those killing 21 or more people, account for 50% of the total number of people killed in all terrorist attacks combined, yet comprise only 3.5% of terrorist attacks. Given the disproportionate influence of these incidents, uncovering systematic patterns in attacks that precede and anticipate these highly lethal attacks may be of value for understanding attacks that exact a heavy toll on life. Here we examined whether the activity of terrorist groups escalates–both in the number of people killed per attack and in the frequency of attacks–leading up to highly lethal attacks. Analyses of terrorist attacks drawn from a state-of-the-art international terrorism database (The Global Terrorism Database) showed evidence for both types of escalation leading up to highly lethal attacks, though complexities to the patterns emerged as well. These patterns of escalation do not emerge among terrorist groups that never commit a highly lethal attack. PMID:24755753

Lethality of firearms relative to other suicide methods: a population based study.

PubMed

Shenassa, E D; Catlin, S N; Buka, S L

2003-02-01

(1) To quantify lethality of firearms relative to other suicide methods, (2) to quantify the extent to which suicide mortality may be reduced by limiting access to firearms. Data on suicides and hospitalised para-suicides that occurred in the state of Illinois from 1990 to 1997 were combined. Total number of episodes for each suicide method was estimated as the sum of the number of suicides and the number of para-suicides for that method. Gender and suicide method were used as proxies for intention to die, and estimated lethality of suicide methods within method-gender groups (for example, male firearm users). Logistic regression was used to quantify the lethality of firearms relative to other suicide methods. Excess mortality associated with the use of firearms was estimated by conservatively assuming that in the absence of firearms the next most lethal suicide method would be used. From January 1990 to December 1997, among individuals 10 years or older in the state of Illinois, there were 37,352 hospital admissions for para-suicide and 10,287 completed suicides. Firearms are the most lethal suicide method. Episodes involving firearms are 2.6 times (95% CI 2.1 to 3.1) more lethal than those involving suffocation-the second most lethal suicide method. Preventing access to firearms can reduce the proportion of fatal firearms related suicides by 32% among minors, and 6.5% among adults. Limiting access to firearms is a potentially effective means of reducing suicide mortality.

A Bacterial Cocaine Esterase Protects Against Cocaine-Induced Epileptogenic Activity and Lethality

PubMed Central

Jutkiewicz, Emily M.; Baladi, Michelle G.; Cooper, Ziva D.; Narasimhan, Diwahar; Sunahara, Roger K.; Woods, James H.

2012-01-01

Study objective Cocaine toxicity results in cardiovascular complications, seizures, and death and accounts for approximately 20% of drug-related emergency department visits every year. Presently, there are no treatments to eliminate the toxic effects of cocaine. The present study hypothesizes that a bacterial cocaine esterase with high catalytic efficiency would provide rapid and robust protection from cocaine-induced convulsions, epileptogenic activity, and lethality. Methods Cocaine-induced paroxysmal activity and convulsions were evaluated in rats surgically implanted with radiotelemetry devices (N=6 per treatment group). Cocaine esterase was administered 1 minute after a lethal dose of cocaine or after cocaine-induced convulsions to determine the ability of the enzyme to prevent or reverse, respectively, the effects of cocaine. Results The cocaine esterase prevented all cocaine-induced electroencephalographic changes and lethality. This effect was specific for cocaine because the esterase did not prevent convulsions and death induced by a cocaine analog, (−)-2β-carbomethoxy-3β-phenyltropane. The esterase prevented lethality even after cocaine-induced convulsions occurred. In contrast, the short-acting benzodiazepine, midazolam, prevented cocaine-induced convulsions but not the lethal effects of cocaine. Conclusion The data showed that cocaine esterase successfully degraded circulating cocaine to prevent lethality and that cocaine-induced convulsions alone are not responsible for the lethal effects of cocaine in this model. Therefore, further investigation into the use of cocaine esterase for treating cocaine overdose and its toxic effects is warranted. PMID:19013687

Improved mutagen-testing systems in mice: Progress report, June 1, 1988--May 31, 1989

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

Roderick, T.H.

1989-01-01

In December we injected 20 mice with 250 mg/kg of ENU. Half of the mice were males of C57BL/6J and half were males of strains AEJ/GnRk. The strains were chosen to include a standard widely used strain (C57BL/6J) but also to include a strain (AEJ/GnRk) that has an unusually large litter size (mean = 10) to promote better survival of embryos with induced recessives. Sentinal females are in with the treated males to determine return to fertility of the injected males. All males will be mated with the new lethal test system. Lethal No. 1 has now been clearly determinedmore » to be just distal to the distal breakpoint of inversion In(1)1Rk. All other lethals, including the new lethal No. 8 are crossed with our specially constructed stocks for linkage analysis. Also, the lethals are being crossed with known recessive markers along the inverted segment to determine possible allelism. All lethals have been intercrossed to determine whether they complement each other. Wild type animals should not be recovered if the lethals are overlapping. In a new study we are examining the wild type animals from each of these crosses carefully for general phenotypic conformation, eye disorders, feet, body weight and gait. Although these lethals may be complementary, it is possible that some interactive effects could be produced in an animal doubly heterozygous for different deletions.« less

Fine Mapping and Transcriptome Analysis Reveal Candidate Genes Associated with Hybrid Lethality in Cabbage (Brassica Oleracea).

PubMed

Xiao, Zhiliang; Hu, Yang; Zhang, Xiaoli; Xue, Yuqian; Fang, Zhiyuan; Yang, Limei; Zhang, Yangyong; Liu, Yumei; Li, Zhansheng; Liu, Xing; Liu, Zezhou; Lv, Honghao; Zhuang, Mu

2017-06-05

Hybrid lethality is a deleterious phenotype that is vital to species evolution. We previously reported hybrid lethality in cabbage ( Brassica oleracea ) and performed preliminary mapping of related genes. In the present study, the fine mapping of hybrid lethal genes revealed that BoHL1 was located on chromosome C1 between BoHLTO124 and BoHLTO130, with an interval of 101 kb. BoHL2 was confirmed to be between insertion-deletion (InDels) markers HL234 and HL235 on C4, with a marker interval of 70 kb. Twenty-eight and nine annotated genes were found within the two intervals of BoHL1 and BoHL2 , respectively. We also applied RNA-Seq to analyze hybrid lethality in cabbage. In the region of BoHL1 , seven differentially expressed genes (DEGs) and five resistance (R)-related genes (two in common, i.e., Bo1g153320 and Bo1g153380 ) were found, whereas in the region of BoHL2 , two DEGs and four R-related genes (two in common, i.e., Bo4g173780 and Bo4g173810 ) were found. Along with studies in which R genes were frequently involved in hybrid lethality in other plants, these interesting R-DEGs may be good candidates associated with hybrid lethality. We also used SNP/InDel analyses and quantitative real-time PCR to confirm the results. This work provides new insight into the mechanisms of hybrid lethality in cabbage.

Command and Control for Distributed Lethality

DTIC Science & Technology

2017-06-01

based systems engineering (MBSE) approach to C2 within the distributed lethality environment requires development of methodologies to provide...lethality environment requires development of methodologies to provide definition and structure for existing operational concepts while providing...2  D.  SCOPE AND METHODOLOGY ............................................................2  E.  STAKEHOLDER ANALYSIS

Response of the Cottonwood Leaf Beetle (Coleoptera: Chrysomelidae) to Bacillus thuringiensis var. san diego

Treesearch

Leah S. Bauer

1990-01-01

A standardized laboratory bioassay was used to quantify the lethal and sub-lethal responses of larval and adult cottonwood leaf beetles, Chrysomela scripta F., to Bacillus thuringiensis var. san diego, formulated as M-One standard powder (Mycogen Corporation, San Diego). The median lethal concentration (LC

77 FR 6548 - Notice of Availability of Ballistic Survivability, Lethality and Vulnerability Analyses

Federal Register 2010, 2011, 2012, 2013, 2014

2012-02-08

..., Lethality and Vulnerability Analyses AGENCY: Department of the Army, DoD. ACTION: Notice of availability...) is a leader in ballistic survivability, lethality and vulnerability (SLV) analyses. ARL/SLAD conducts SLV analyses, using the MUVES-S2 vulnerability model, to quantify system, subsystem and/or component...

Improving on Army Field Gauze for Lethal Vascular Injuries: Challenges in Dressing Development

USDA-ARS?s Scientific Manuscript database

Accounting for half of all deaths, uncontrolled hemorrhage remains the leading cause of death on the battlefield. Gaining hemostatic control of lethal vascular injuries sustained in combat using topical agents remains a challenge. Recent animal testing using a lethal arterial injury model compared a...

Defense Management: DOD Needs to Improve Program Management, Policy, and Testing to Enhance Ability to Field Operationally Useful Non-lethal Weapons

DTIC Science & Technology

2009-04-01

through Fielding and Support 12 Figure 3: Active Denial System 2 25 Figure 4: FN-303 Less-Lethal Launching System 26 Figure 5: TASER ® X-26 27 Figure 6...System Grenades 5, 6, 8, 9, 11, 12 , 13, 14, 19, 21, 25, 26 Human Electro Muscular Incapacitation TASER ® X-26 5, 13, 14, 21 Improved Acoustic...modes Modular accessory shotgun system Provides the capability to fire lethal, non-lethal, and door- breaching 12 - gauge rounds. Future force

The influence of gender on the relationship between wildlife value orientations, beliefs, and the acceptability of lethal deer control in Cuyahoga Valley National Park

USGS Publications Warehouse

Dougherty, E.M.; Fulton, D.C.; Anderson, D.H.

2003-01-01

This study examines how wildlife value orientations, attitudes, and gender influence acceptance of lethal actions to control deer in Cuyahoga Valley National Park in Ohio. Data were collected from female and male residents (n = 659) in a nine-county area, the primary service area of the park. Females and males demonstrated significant differences in their wildlife value orientations, attitudes toward lethal deer control, beliefs about the outcome of lethal deer control, and perceived personal impacts of lethal deer control. Gender also acted as a moderator of the relationship between values, beliefs and attitudes. Results indicate that a focus on understanding differences between males and females is essential to public participation in decision making concerning this and similar issues.

Sex-Specific Sub-Lethal Effects and Immune Response in Ceratitis capitata Wied. (Diptera: Tephritidae) Challenged with Spinosad.

PubMed

Mura, Maria Elena; Ruiu, Luca

2018-06-21

The main objective of this study was to investigate the effects of the insecticidal compound spinosad on the survival, reproduction, and immune functions of the Mediterranean fruit fly. The lethal and sub-lethal effects were determined on Ceratitis capitata Wied. (Diptera: Tephritidae) challenged with different concentrations of spinosad. A median lethal concentration of 0.28 ppm was observed on flies feeding for 5 days on a treated diet. A significant and concentration-dependent decrease in fecundity, egg hatch rate, and lifespan was also detected in treated compared with control flies. Gene expression analyses conducted on treated insects by RT-qPCR revealed an immunomodulatory action of sub-lethal concentrations of spinosad. Target transcripts included several genes involved in medfly immunity and male or female reproductive functions. While a significant upregulation was detected in treated males a short time after spinosad ingestion, most target genes were downregulated in treated females. Our study confirmed the high toxicity of spinosad to C. capitata , highlighting an indirect effect on insect lifespan and reproductive performance at sub-lethal doses. In addition to defining the acute and sub-lethal toxicity of spinosad against the fly, this study provides new insights on the interaction of this compound with insect physiology.

Impacts of West Nile Virus on wildlife

USGS Publications Warehouse

Saito, E.K.; Wild, M.A.

2004-01-01

The recent epidemic of West Nile virus in the United States proved to be unexpectedly active and was the largest epidemic of the virus ever recorded. Much remains to be discovered about the ecology and epidemiology of West Nile virus in the United States, including which species are important in maintaining the virus in nature, why some species are more susceptible to lethal infection, and what environmental factors are important in predicting future epidemics. These factors will likely vary regionally, depending on local ecological characteristics. Until scientists better understand the virus and factors influencing its activity, predicting its effects for future seasons is impossible. However, experts are certain about one thing: West Nile virus is here to stay.

CTCF knockout reveals an essential role for this protein during the zebrafish development.

PubMed

Carmona-Aldana, Francisco; Zampedri, Cecilia; Suaste-Olmos, Fernando; Murillo-de-Ozores, Adrián; Guerrero, Georgina; Arzate-Mejía, Rodrigo; Maldonado, Ernesto; Navarro, Rosa; Chimal-Monroy, Jesús; Recillas-Targa, Félix

2018-05-01

Chromatin regulation and organization are essential processes that regulate gene activity. The CCCTC-binding factor (CTCF) is a protein with different and important molecular functions related with chromatin dynamics. It is conserved since invertebrates to vertebrates, posing it as a factor with an important role in the physiology. In this work, we aimed to understand the distribution and functional relevance of CTCF during the embryonic development of the zebrafish (Danio rerio). We generated a zebrafish specific anti-Ctcf antibody, and found this protein to be ubiquitous, through different stages and tissues. We used the CRISPR-Cas9 system to induce molecular alterations in the locus. This resulted in early lethality. We delayed the lethality performing knockdown morpholino experiments, and found an aberrant embryo morphology involving malformations in structures through all the length of the embryo. These phenotypes were rescued with human CTCF mRNA injections, showing the specificity of the morpholinos and a partial functional conservation between the fish and the human proteins. Lastly, we found that the pro-apoptotic genes p53 and bbc3/PUMA are deregulated in the ctcf morpholino-injected embryos. In conclusion, CTCF is a ubiquitous factor during the zebrafish development, which regulates the correct formation of different structures of the embryo, and its deregulation impacts on essential cell survival genes. Overall, this work provides a basis to look for the particular functions of CTCF in the different developing tissues and organs of the zebrafish. Copyright © 2018. Published by Elsevier B.V.

Allelic asymmetry of the Lethal hybrid rescue (Lhr) gene expression in the hybrid between Drosophila melanogaster and D. simulans: confirmation by using genetic variations of D. melanogaster.

PubMed

Shirata, Mika; Araye, Quenta; Maehara, Kazunori; Enya, Sora; Takano-Shimizu, Toshiyuki; Sawamura, Kyoichi

2014-02-01

In the cross between Drosophila melanogaster females and D. simulans males, hybrid males die at the late larval stage, and the sibling females also die at later stages at high temperatures. Removing the D. simulans allele of the Lethal hybrid rescue gene (Lhr (sim) ) improves the hybrid incompatibility phenotypes. However, the loss-of-function mutation of Lhr (sim) (Lhr (sim0) ) does not rescue the hybrid males in crosses with several D. melanogaster strains. We first describe the genetic factor possessed by the D. melanogaster strains. It has been suggested that removing the D. melanogaster allele of Lhr (Lhr (mel) ), that is Lhr (mel0) , does not have the hybrid male rescue effect, contrasting to Lhr (sim0) . Because the expression level of the Lhr gene is known to be Lhr (sim) > Lhr (mel) in the hybrid, Lhr (mel0) may not lead to enough of a reduction in total Lhr expression. Then, there is a possibility that the D. melanogaster factor changes the expression level to Lhr (sim) < Lhr (mel) . But in fact, the expression level was Lhr (sim) > Lhr (mel) in the hybrid irrespectively of the presence of the factor. At last, we showed that Lhr (mel0) slightly improves the viability of hybrid females, which was not realized previously. All of the present results are consistent with the allelic asymmetry model of the Lhr gene expression in the hybrid.

New insights into the biological effects of anthrax toxins: linking cellular to organismal responses

PubMed Central

Guichard, Annabel; Nizet, Victor; Bier, Ethan

2013-01-01

The anthrax toxins lethal toxin (LT) and edema toxin (ET), are essential virulence factors produced by B. anthracis. These toxins act during two distinct phases of anthrax infection. During the first, prodromal phase, which is often asymptomatic, anthrax toxins act on cells of the immune system to help the pathogen establish infection. Then, during the rapidly progressing (or fulminant) stage of the disease bacteria disseminate via a hematological route to various target tissues and organs, which are typically highly vascularized. As bacteria proliferate in the bloodstream LT and ET begin to accumulate rapidly reaching a critical threshold level that will cause death even when the bacterial proliferation is curtailed by antibiotics. During this final phase of infection the toxins cause an increase in vascular permeability and a decrease in function of target organs including the heart, spleen, kidney, adrenal gland, and brain. In this review, we examine the various biological effects of anthrax toxins, focusing on the fulminant stage of the disease and on mechanisms by which the two toxins may collaborate to cause cardiovascular collapse. We discuss normal mechanisms involved in maintaining vascular integrity and based on recent studies indicating that LT and ET cooperatively inhibit membrane trafficking to cell-cell junctions we explore several potential mechanisms by which the toxins may achieve their lethal effects. We also summarize the effects of other potential virulence factors secreted by B. anthracis and consider the role of toxic factors in the evolutionarily recent emergence of this devastating disease. PMID:21930233

Influence of forest and rangeland management on anadromous fish habitat in Western North America: processing mills and camps.

Treesearch

Donald C. Schmiege

1980-01-01

For nearly 50 years, effluents from pulp and paper mills have been known to be toxic to fish and other aquatic animals. Lethal concentrations have been determined for several species of fish and other organisms. Many factors- -such as water temperature, age of fish, and additional stresses—affect the ability of fish to withstand pollution. Kraft mill wastes...

Quantifying Factors Affecting Optical Turbulence Propagation Using a Controlled Towed Vehicle From an Aircraft

DTIC Science & Technology

2017-12-01

12a. DISTRIBUTION / AVAILABILITY STATEMENT Approved for public release. Distribution is unlimited. 12b. DISTRIBUTION CODE A 13. ABSTRACT...maximum 200 words) High Energy Laser (HEL) systems are advantageous for their precision against small surface targets, lethality, and ability to...illustrated using individual examples as well as all available data. 14. SUBJECT TERMS Scintillation, Cn2, Controlled Towed Vehicle (CTV), CASPER-East

Toward Finding Driving Communications Factors in the System of Systems Survivability Simulation Model

DTIC Science & Technology

2014-03-01

BLANK 53 LIST OF REFERENCES Bernstein Jr ., R., Flores , R., & Starks, M. (2006). Objectives and capabilities of the system of...Reader Robert Dell Chair, Department of Operations Research iv THIS PAGE INTENTIONALLY LEFT BLANK v ABSTRACT The System of Systems...larger system (Starks & Flores , 2004). One of the primary concerns for a new platform is its survivability, lethality, and vulnerability (SLV) as part

Proof of concept for a banding scheme to support risk assessments related to multi-product biologics manufacturing.

PubMed

Card, Jeffrey W; Fikree, Hana; Haighton, Lois A; Blackwell, James; Felice, Brian; Wright, Teresa L

2015-11-01

A banding scheme theory has been proposed to assess the potency/toxicity of biologics and assist with decisions regarding the introduction of new biologic products into existing manufacturing facilities. The current work was conducted to provide a practical example of how this scheme could be applied. Information was identified for representatives from the following four proposed bands: Band A (lethal toxins); Band B (toxins and apoptosis signals); Band C (cytokines and growth factors); and Band D (antibodies, antibody fragments, scaffold molecules, and insulins). The potency/toxicity of the representative substances was confirmed as follows: Band A, low nanogram quantities exert lethal effects; Band B, repeated administration of microgram quantities is tolerated in humans; Band C, endogenous substances and recombinant versions administered to patients in low (interferons), intermediate (growth factors), and high (interleukins) microgram doses, often on a chronic basis; and Band D, endogenous substances present or produced in the body in milligram quantities per day (insulin, collagen) or protein therapeutics administered in milligram quantities per dose (mAbs). This work confirms that substances in Bands A, B, C, and D represent very high, high, medium, and low concern with regard to risk of cross-contamination in manufacturing facilities, thus supporting the proposed banding scheme. Copyright © 2015 Elsevier Inc. All rights reserved.

Inactivation of MS2 bacteriophage by streamer corona discharge in water.

PubMed

Lee, Changha; Kim, Jaeeun; Yoon, Jeyong

2011-02-01

Electrical discharge processes are emerging as water treatment technologies applicable to both the degradation of organic contaminants as well as inactivation of pathogens. Particularly as a disinfection technology, electrical discharge processes do not produce toxic byproducts, and effectively inactivate a wide spectrum of microorganisms by multiple lethal actions generated by the formation of plasma channels. This study demonstrates the inactivation of a virus using the streamer corona discharge process (SCDP) with MS2 phage as a surrogate. A rapid inactivation of MS2 phage (i.e., approximately 4 log inactivation in 5 min) was observed in all experimental runs conducted. Discharge conditions such as applied voltage and storage capacitance significantly affected the inactivation efficiency of MS2 phage, whereas the influence of water quality parameters was minor. In order to elucidate the mechanism of MS2 phage inactivation, potentially lethal factors that can be generated by the SCDP were selected, and their roles in the inactivation of MS2 phage were examined. As a result, effects of UV radiation, chemical oxidants, and pulsed electric fields were found to be insignificant. The shockwave generated upon plasma channel formation appears to be the most important factor responsible for MS2 phage inactivation. Copyright © 2010 Elsevier Ltd. All rights reserved.

Development of antibodies to protective antigen and lethal factor components of anthrax toxin in humans and guinea pigs and their relevance to protective immunity.

PubMed Central

Turnbull, P C; Broster, M G; Carman, J A; Manchee, R J; Melling, J

1986-01-01

A competitive inhibition enzyme-linked immunosorbent assay (ELISA) was developed to detect antibodies in serum to the protective antigen (PA) and lethal factor (LF) components of anthrax toxin. Current human vaccination schedules with an acellular vaccine induce predictable and lasting antibody titers to PA and, when present in the vaccine, to LF. Live spore vaccine administered to guinea pigs in a single dose conferred significantly better protection than the human vaccines (P less than 0.001), although they elicited significantly lower (P less than 0.0005) anti-PA and anti-LF titers at time of challenge with virulent Bacillus anthracis. Substantial anti-PA and anti-LF titers may not, therefore, indicate solid protective immunity against anthrax infection. The ELISA system was also shown to be capable of detecting anti-PA and anti-LF antibodies in the sera of individuals with histories of clinical anthrax. The advantage of ELISA over the Ouchterlony gel diffusion test and indirect microhemagglutination assay are demonstrated. There was a highly significant degree of correlation between ELISA and the indirect microhemagglutination assay (P less than 0.0005); but ELISA was markedly superior in terms of reproducibility, reliability, specificity, and simplicity in performance and stability of the bound antigen. PMID:3084381

Intimate partner violence, depression, PTSD, and use of mental health resources among ethnically diverse black women.

PubMed

Sabri, Bushra; Bolyard, Richelle; McFadgion, Akosoa L; Stockman, Jamila K; Lucea, Marguerite B; Callwood, Gloria B; Coverston, Catherine R; Campbell, Jacquelyn C

2013-01-01

This study examined exposure to violence and risk for lethality in intimate partner relationships as factors related to co-occurring MH problems and use of mental health (MH) resources among women of African descent. Black women with intimate partner violence (IPV) experiences (n = 431) were recruited from primary care, prenatal or family planning clinics in the United States and the U.S. Virgin Islands. Severity of IPV was significantly associated with co-occurring MH problems, but was not associated with the use of MH resources among African-American women. Risk for lethality and co-occurring problems were also not significantly related to the use of resources. African Caribbean women with severe physical abuse experiences were significantly less likely to use resources. In contrast, severity of physical abuse was positively associated with the use of resources among Black women with mixed ethnicity. Severe IPV experiences are risk factors for co-occurring MH problems, which in turn, increases the need for MH services. However, Black women may not seek help for MH problems. Thus, social work practitioners in health care settings must thoroughly assess women for their IPV experiences and develop tailored treatment plans that address their abuse histories and MH needs.

Freeze and Thaw of CD4+CD25+Foxp3+ Regulatory T Cells Results in Loss of CD62L Expression and a Reduced Capacity to Protect against Graft-versus-Host Disease

PubMed Central

Pierini, Antonio; Baker, Jeanette; Armstrong, Randall; Pan, Yuqiong; Leveson-Gower, Dennis; Negrin, Robert; Meyer, Everett

2015-01-01

The adoptive transfer of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in murine models of allogeneic hematopoietic cell transplantation (HCT) has been shown to protect recipient mice from lethal acute graft-versus-host disease (GVHD) and this approach is being actively investigated in human clinical trials. Here, we examined the effects of cryopreservation on Tregs. We found that freeze and thaw of murine and human Tregs is associated with reduced expression of L-selectin (CD62L), which was previously established to be an important factor that contributes to the in vivo protective effects of Tregs. Frozen and thawed murine Tregs showed a reduced capacity to bind to the CD62L binding partner MADCAM1 in vitro as well as an impaired homing to secondary lymphoid organs in vivo. Upon adoptive transfer frozen and thawed Tregs failed to protect against lethal GVHD compared with fresh Tregs in a murine model of allogeneic HCT across major histocompatibility barriers. In summary, the direct administration of adoptively transferred frozen and thawed Tregs adversely affects their immunosuppressive potential which is an important factor to consider in the clinical implementation of Treg immunotherapies. PMID:26693907

NMR conformational properties of an Anthrax Lethal Factor domain studied by multiple amino acid-selective labeling

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

Vourtsis, Dionysios J.; Chasapis, Christos T.; Pairas, George

2014-07-18

Highlights: • A polypeptide, N-ALF{sub 233}, was overexpressed in E. coli and successfully isolated. • We produced {sup 2}H/{sup 15}N/{sup 13}C labeled protein samples. • Amino acid selective approaches were applied. • We acquired several heteronuclear NMR spectra, to complete the backbone assignment. • Prediction of the secondary structure was performed. - Abstract: NMR-based structural biology urgently needs cost- and time-effective methods to assist both in the process of acquiring high-resolution NMR spectra and their subsequent analysis. Especially for bigger proteins (>20 kDa) selective labeling is a frequently used means of sequence-specific assignment. In this work we present the successfulmore » overexpression of a polypeptide of 233 residues, corresponding to the structured part of the N-terminal domain of Anthrax Lethal Factor, using Escherichia coli expression system. The polypeptide was subsequently isolated in pure, soluble form and analyzed structurally by solution NMR spectroscopy. Due to the non-satisfying quality and resolution of the spectra of this 27 kDa protein, an almost complete backbone assignment became feasible only by the combination of uniform and novel amino acid-selective labeling schemes. Moreover, amino acid-type selective triple-resonance NMR experiments proved to be very helpful.« less

Soluble P-selectin rescues mice from anthrax lethal toxin-induced mortality through PSGL-1 pathway-mediated correction of hemostasis.

PubMed

Sun, Der-Shan; Chang, Yao-Wen; Kau, Jyh-Hwa; Huang, Hsin-Hsien; Ho, Pei-Hsun; Tzeng, Yin-Jeh; Chang, Hsin-Hou

2017-10-03

As one of the virulence factors of Bacillus anthracis, lethal toxin (LT) induces various pathogenic responses including the suppression of the coagulation system. In this study, we observed that LT markedly increased the circulating soluble P-selectin (sP-sel) levels and microparticle (MP) count in wild-type but not P-selectin (P-sel, Selp -/- ) or P-sel ligand-1 (PSGL-1, Selplg -/- ) knockout mice. Because sP-sel induces a hypercoagulable state through PSGL-1 pathway to generate tissue factor-positive MPs, we hypothesized that the increase in plasma sP-sel levels can be a self-rescue response in hosts against the LT-mediated suppression of the coagulation system. In agreement with our hypothesis, our results indicated that compared with wild-type mice, Selp -/- and Selplg -/- mice were more sensitive to LT. In addition, the recombinant sP-sel treatment markedly ameliorated LT-mediated pathogenesis and reduced mortality. As a result, elicitation of circulating sP-sel is potentially a self-rescue response, which is beneficial to host recovery from an LT-induced hypocoagulation state. These results suggest that the administration of sP-sel is likely to be useful in the development of a new strategy to treat anthrax.

Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABA{sub A} receptors

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

Shakarjian, Michael P., E-mail: michael_shakarjian@nymc.edu; Department of Medicine, Division of Pulmonary and Critical Care Medicine, UMDNJ–Robert Wood Johnson Medical School, Piscataway, NJ 08854; Velíšková, Jana, E-mail: jana_veliskova@nymc.edu

Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic–clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4 mg/kg was 100% lethal. The NMDA antagonist, ketamine (35 mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic–clonic seizures or lethality, but increased the numbermore » of clonic seizures. Doubling the ketamine dose decreased tonic–clonic seizures and eliminated lethality through a 60 min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1 mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15 min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABA{sub A} receptor allosteric enhancer diazepam (5 mg/kg) greatly reduced seizure manifestations and prevented lethality 60 min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists is more likely to be effective in treating TMDT poisoning. -- Highlights: ► TMDT produces convulsions and lethality at low doses in mice. ► Diazepam pre- or post-treatments inhibit TMDT-induced convulsions and death. ► Ketamine and MK-801 display biphasic actions on TMDT seizures. ► Diazepam stops convulsions, but ictal EEG events persist to cause lethality hrs later. ► Diazepam repeat dose or paired with ketamine/MK-801 may more effectively block TMDT.« less

Multi-locus phylogeny of lethal amanitas: Implications for species diversity and historical biogeography

PubMed Central

2014-01-01

Background Lethal amanitas (Amanita section Phalloideae) are a group of wild, fatal mushrooms causing many poisoning cases worldwide. However, the diversity and evolutionary history of these lethal mushrooms remain poorly known due to the limited sampling and insufficient gene fragments employed for phylogenetic analyses. In this study, five gene loci (nrLSU, ITS, rpb2, ef1-α and β-tubulin) with a widely geographic sampling from East and South Asia, Europe, North and Central America, South Africa and Australia were analysed with maximum-likelihood, maximum-parsimony and Bayesian inference methods. Biochemical analyses were also conducted with intention to detect amatoxins and phalloidin in 14 representative samples. Result Lethal amanitas were robustly supported to be a monophyletic group after excluding five species that were provisionally defined as lethal amanitas based on morphological studies. In lethal amanitas, 28 phylogenetic species were recognised by integrating molecular phylogenetic analyses with morphological studies, and 14 of them represented putatively new species. The biochemical analyses indicated a single origin of cyclic peptide toxins (amatoxins and phalloidin) within Amanita and suggested that this kind of toxins seemed to be a synapomorphy of lethal amanitas. Molecular dating through BEAST and biogeographic analyses with LAGRANGE and RASP indicated that lethal amanitas most likely originated in the Palaeotropics with the present crown group dated around 64.92 Mya in the early Paleocene, and the East Asia–eastern North America or Eurasia–North America–Central America disjunct distribution patterns were primarily established during the middle Oligocene to Miocene. Conclusion The cryptic diversity found in this study indicates that the species diversity of lethal amanitas is strongly underestimated under the current taxonomy. The intercontinental sister species or sister groups relationships among East Asia and eastern North America or Eurasia–North America–Central America within lethal amanitas are best explained by the diversification model of Palaeotropical origin, dispersal via the Bering Land Bridge, followed by regional vicariance speciation resulting from climate change during the middle Oligocene to the present. These findings indicate the importance of both dispersal and vicariance in shaping the intercontinental distributions of these ectomycorrhizal fungi. PMID:24950598

Lethal Forethought: Delayed Reward Discounting Differentiates High- and Low-Lethality Suicide Attempts in Old Age

PubMed Central

Dombrovski, Alexandre Y.; Szanto, Katalin; Siegle, Greg J.; Wallace, Meredith L.; Forman, Steven D.; Sahakian, Barbara; Reynolds, Charles F.; Clark, Luke

2011-01-01

Background The decision to commit suicide may be impulsive, but lethal suicidal acts often involve planning and forethought. People who attempt suicide make disadvantageous decisions in other contexts, but nothing is known about the way they decide about the future. Can the willingness to postpone future gratification differentiate between individuals prone to serious, premeditated and less serious, unplanned suicidal acts? Methods Four groups of depressed participants aged 60+ made choices between smaller immediate and larger delayed monetary rewards: 15 who made high-lethality suicide attempts, 14 who made low-lethality suicide attempts, 12 who seriously contemplated suicide, and 42 people with depression but no history of suicidal thoughts. The reference group was 31 psychiatrically healthy elders. Results Individuals who had made low-lethality attempts displayed an exaggerated preference for immediate rewards compared to non-suicidal depressed and healthy controls. Those who had carried out high-lethality suicide attempts were more willing to delay future rewards, compared to low-lethality attempters. Better planned suicide attempts were also associated with willingness to wait for larger rewards. These effects were unchanged after accounting for education, global cognitive function, substance use disorders, psychotropic medications, and possible brain injury from attempts. Discount rates were correlated with having debt but were not significantly associated with income, hopelessness, depressive severity, premorbid IQ, age at first attempt, or choice of violent means. Conclusions While clinicians often focus on impulsivity in patients at risk for suicide, these data suggest that identifying biological characteristics and treatments for non-impulsive suicidal older people may be even more important. PMID:21329911

[Dynamics of complement hemolytic activity in experimental Ebola infection].

PubMed

Zabavichene, N M; Chepurnov, A A

2004-01-01

The dynamic hemolytic activity of complements (HAC) was investigated in blood of guinea pigs in lethal and non-lethal Ebola infection. The increasing HAC dynamic activity in the animal blood was found to correlate with the infection lethal course. HAC as observed in animals with lethal infection was sweepingly increasing after they, were infected with Ebola virus, and yet after 15 hours from the infection time the complement activity parameters topped 2-fold the basic values in 100% of guinea pigs. They began to be dropping by the end of day 1, their decrease reached, when the incubation time was over (days 3-4 after infection) the basic value, after which they continued to go down to the zero value in 2-3 days before the lethal outcome. The described phenomenon, like the phenomenon of accelerated death, was even more pronounced, when the animals were infected after a single immunization by activated Ebola virus. In case, guinea pigs were infected by a non-lethal Ebola virus strain, the compliment synthesis was observed to be activated only at the end of the incubation period; the process was accompanied with a gradual raise and with a plateau-type or wave-type increase of the complement during the treatment time--it was equally accompanied with normalizing activity parameters during recovery. The detected specificity could be important in prognosticating a disease outcome. A reliable correlation was demonstrated between the complement hemolytic activity and the level of circulating immune complexes in blood of experimental animals, which can be traced both in lethal and non-lethal infection.

Maternal-Effect Lethal Mutations on Linkage Group II of Caenorhabditis Elegans

PubMed Central

Kemphues, K. J.; Kusch, M.; Wolf, N.

1988-01-01

We have analyzed a set of linkage group (LG) II maternal-effect lethal mutations in Caenorhabditis elegans isolated by a new screening procedure. Screens of 12,455 F(1) progeny from mutagenized adults resulted in the recovery of 54 maternal-effect lethal mutations identifying 29 genes. Of the 54 mutations, 39 are strict maternal-effect mutations defining 17 genes. These 17 genes fall into two classes distinguished by frequency of mutation to strict maternal-effect lethality. The smaller class, comprised of four genes, mutated to strict maternal-effect lethality at a frequency close to 5 X 10(-4), a rate typical of essential genes in C. elegans. Two of these genes are expressed during oogenesis and required exclusively for embryogenesis (pure maternal genes), one appears to be required specifically for meiosis, and the fourth has a more complex pattern of expression. The other 13 genes were represented by only one or two strict maternal alleles each. Two of these are identical genes previously identified by nonmaternal embryonic lethal mutations. We interpret our results to mean that although many C. elegans genes can mutate to strict maternal-effect lethality, most genes mutate to that phenotype rarely. Pure maternal genes, however, are among a smaller class of genes that mutate to maternal-effect lethality at typical rates. If our interpretation is correct, we are near saturation for pure maternal genes in the region of LG II balanced by mnC1. We conclude that the number of pure maternal genes in C. elegans is small, being probably not much higher than 12. PMID:3224814

Inherent envelope fluctuations in forward maskers: Effects of masker-probe delay for listeners with normal and impaired hearinga)

PubMed Central

Svec, Adam; Dubno, Judy R.; Nelson, Peggy B.

2016-01-01

Forward-masked thresholds increase as the magnitude of inherent masker envelope fluctuations increase for both normal-hearing (NH) and hearing-impaired (HI) adults for a short masker-probe delay (25 ms). The slope of the recovery from forward masking is shallower for HI than for NH listeners due to reduced cochlear nonlinearities. However, effects of hearing loss on additional masking due to inherent envelope fluctuations across masker-probe delays remain unknown. The current study assessed effects of hearing loss on the slope and amount of recovery from forward maskers that varied in inherent envelope fluctuations. Forward-masked thresholds were measured at 2000 and 4000 Hz, for masker-probe delays of 25, 50, and 75 ms, for NH and HI adults. Four maskers at each center frequency varied in inherent envelope fluctuations: Gaussian noise (GN) or low-fluctuation noise (LFN), with 1 or 1/3 equivalent rectangular bandwidths (ERBs). Results suggested that slopes of recovery from forward masking were shallower for HI than for NH listeners regardless of masker fluctuations. Additional masking due to inherent envelope fluctuations was greater for HI than for NH listeners at longer masker-probe delays, suggesting that inherent envelope fluctuations are more disruptive for HI than for NH listeners for a longer time course PMID:27036255

Immunity profile in breast cancer patients.

PubMed

Hrubisko, M; Sanislo, L; Zuzulova, M; Michalickova, J; Zeleznikova, T; Sedlak, J; Bella, V

2010-01-01

Despite the multifactorial pathogenesis of malignant transformation, it is assumed that deficiency in some immune mechanisms plays a considerable role in its development. Chronically activated immune cells exert tumour-promoting effects directly by influencing the proliferation and survival of neoplastic cells, as well as by indirect modulation of neoplastic microenvironments in favour of tumour progression. We refer to results of two separate investigations that aim to monitor the immune functions in patients with breast cancer. In the first investigation, we compare the picture of basic cellular immunity profile of patients in early stage of breast cancer with those suffering from advanced disease; in the second one, we compare the production of Th1-cytokines in patients in different stages of breast cancer and atopic healthy controls. We recognized that the totals of T-lymphocytes and T-helpers were lower and the expression of HLADR on T-lymphocytes were higher in patients with advanced disease; the expression of IL-2 and LFN-gamma by T-lymphocytes was decreased in metastatic breast cancer patients, however IL-2 production was increased in patients in early stage of disease. We conclude that the role of immune system in cancer development is ambivalent as it may be not only protective, but also harmful (Tab. 1, Fig. 3, Ref. 22). Full Text (Free, PDF) www.bmj.sk.

Securing the AliEn File Catalogue - Enforcing authorization with accountable file operations

NASA Astrophysics Data System (ADS)

Schreiner, Steffen; Bagnasco, Stefano; Sankar Banerjee, Subho; Betev, Latchezar; Carminati, Federico; Vladimirovna Datskova, Olga; Furano, Fabrizio; Grigoras, Alina; Grigoras, Costin; Mendez Lorenzo, Patricia; Peters, Andreas Joachim; Saiz, Pablo; Zhu, Jianlin

2011-12-01

The AliEn Grid Services, as operated by the ALICE Collaboration in its global physics analysis grid framework, is based on a central File Catalogue together with a distributed set of storage systems and the possibility to register links to external data resources. This paper describes several identified vulnerabilities in the AliEn File Catalogue access protocol regarding fraud and unauthorized file alteration and presents a more secure and revised design: a new mechanism, called LFN Booking Table, is introduced in order to keep track of access authorization in the transient state of files entering or leaving the File Catalogue. Due to a simplification of the original Access Envelope mechanism for xrootd-protocol-based storage systems, fundamental computational improvements of the mechanism were achieved as well as an up to 50% reduction of the credential's size. By extending the access protocol with signed status messages from the underlying storage system, the File Catalogue receives trusted information about a file's size and checksum and the protocol is no longer dependent on client trust. Altogether, the revised design complies with atomic and consistent transactions and allows for accountable, authentic, and traceable file operations. This paper describes these changes as part and beyond the development of AliEn version 2.19.

Evaluating the Predictive Validity of Suicidal Intent and Medical Lethality in Youth

ERIC Educational Resources Information Center

Sapyta, Jeffrey; Goldston, David B.; Erkanli, Alaattin; Daniel, Stephanie S.; Heilbron, Nicole; Mayfield, Andrew; Treadway, S. Lyn

2012-01-01

Objectives: To examine whether suicidal intent and medical lethality of past suicide attempts are predictive of future attempts, the association between intent and lethality, and the consistency of these characteristics across repeated attempts among youth. Method: Suicide attempts in a 15-year prospective study of 180 formerly psychiatrically…

Maternal vaccination with a fimbrial tip adhesin and passive protection of neonatal mice against lethal human enterotoxigenic Escherichia coli challenge.

PubMed

Luiz, Wilson B; Rodrigues, Juliana F; Crabb, Joseph H; Savarino, Stephen J; Ferreira, Luis C S

2015-12-01

Globally, enterotoxigenic Escherichia coli (ETEC) is a leading cause of childhood and travelers' diarrhea, for which an effective vaccine is needed. Prevalent intestinal colonization factors (CFs) such as CFA/I fimbriae and heat-labile enterotoxin (LT) are important virulence factors and protective antigens. We tested the hypothesis that donor strand-complemented CfaE (dscCfaE), a stabilized form of the CFA/I fimbrial tip adhesin, is a protective antigen, using a lethal neonatal mouse ETEC challenge model and passive dam vaccination. For CFA/I-ETEC strain H10407, which has been extensively studied in volunteers, an inoculum of 2 × 10(7) bacteria resulted in 50% lethal doses (LD50) in neonatal DBA/2 mice. Vaccination of female DBA/2 mice with CFA/I fimbriae or dscCfaE, each given with a genetically attenuated LT adjuvant (LTK63) by intranasal or orogastric delivery, induced high antigen-specific serum IgG and fecal IgA titers and detectable milk IgA responses. Neonates born to and suckled by dams antenatally vaccinated with each of these four regimens showed 78 to 93% survival after a 20× LD50 challenge with H10407, compared to 100% mortality in pups from dams vaccinated with sham vaccine or LTK63 only. Crossover experiments showed that high pup survival rates after ETEC challenge were associated with suckling but not birthing from vaccinated dams, suggesting that vaccine-specific milk antibodies are protective. In corroboration, preincubation of the ETEC inoculum with antiadhesin and antifimbrial bovine colostral antibodies conferred a dose-dependent increase in pup survival after challenge. These findings indicate that the dscCfaE fimbrial tip adhesin serves as a protective passive vaccine antigen in this small animal model and merits further evaluation. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

HOST-PARASITE FACTORS IN GROUP A STREPTOCOCCAL INFECTIONS

PubMed Central

Watson, Dennis W.

1960-01-01

The factors present in streptococcal lesion extracts (SLE) which enhanced the lethal and tissue-damaging properties of Gram-negative bacterial endotoxins and streptolysin O were identified with the scarlet fever group of toxins. Toxic manifestations attributed to this group of toxins included lethality, cardiotoxic and other tissue damage, enhancement of toxicity, and pyrogenicity. Of these, the measurement of febrile response in American Dutch rabbits was the most useful parameter of toxicity. In rabbits, repeated daily intravenous injections of 0.125 Lf of a purified erythrogenic toxin immunizes specifically against the pyrogenic activity; this technique was used to type the toxins and to distinguish them from exogenous and endogenous pyrogens; non-specific pyrogens, such as streptococcal endotoxin, were not found in SLE. All types of the Lancefield Group A streptococci tested produced one or or more immunologically distinct toxins in vivo in contrast to Groups B and C which did not produce them; toxins A and B, previously distinguished by neutralization of rash-inducing activity in the skin, were produced in vivo. The A toxin was the most common, as indicated by its presence in extracts prepared with Types 28, 12, 17, and 10 (NY-5); B toxin was found in 10 (NY-5) and 19. A new toxin, designated C, was obtained from a Type 18. In American Dutch rabbits, purified toxin at a concentration of 15 Lf (900,000 STD) neither gave a Dick test nor prepared the skin for the local Shwartzman reaction; by this route, however, in contrast to classical endotoxins, they enhance the lethal and tissue-damaging properties of sublethal doses of these and other toxins. These properties of the immunologic distinct exotoxins as demonstrated in American Dutch rabbits suggest by analogy their importance in the pathogenesis of streptococcal disease in man. Evidence that might implicate them in sequelae, in addition to scarlet fever, is discussed. PMID:13783427

Fos metamorphoses: Lessons from mutants in model organisms (Drosophila).

PubMed

Alfonso-Gonzalez, Carlos; Riesgo-Escovar, Juan Rafael

2018-05-10

The Fos oncogene gene family is evolutionarily conserved throughout Eukarya. Fos proteins characteristically have a leucine zipper and a basic region with a helix-turn-helix motif that binds DNA. In vertebrates, there are several Fos homologs. They can homo- or hetero-dimerize via the leucine zipper domain. Fos homologs coupled with other transcription factors, like Jun oncoproteins, constitute the Activator Protein 1 (AP-1) complex. From its original inception as an oncogene, the subsequent finding that they act as transcription factors binding DNA sequences known as TRE, to the realization that they are activated in many different scenarios, and to loss-of-function analysis, the Fos proteins have traversed a multifarious path in development and physiology. They are instrumental in 'immediate early genes' responses, and activated by a seemingly myriad assemblage of different stimuli. Yet, the majority of these studies were basically gain-of-function studies, since it was thought that Fos genes would be cell lethal. Loss-of-function mutations in vertebrates were recovered later, and were not cell lethal. In fact, c-fos null mutations are viable with developmental defects (osteopetrosis and myeloid lineage abnormalities). It was then hypothesized that vertebrate genomes exhibit partial redundancy, explaining the 'mild' phenotypes, and complicating assessment of complete loss-of-function phenotypes. Due to its promiscuous activation, fos genes (especially c-fos) are now commonly used as markers for cellular responses to stimuli. fos homologs high sequence conservation (including Drosophila) is advantageous as it allows critical assessment of fos genes functions in this genetic model. Drosophila melanogaster contains only one fos homolog, the gene kayak. kayak mutations are lethal, and allow study of all the processes where fos is required. The kayak locus encodes several different isoforms, and is a pleiotropic gene variously required for development involving cell shape changes. In general, fos genes seem to primarily activate programs involved in cellular architectural rearrangements and cell shape changes. Copyright © 2018. Published by Elsevier B.V.

Adenoviral Expression of a Bispecific VHH-Based Neutralizing Agent That Targets Protective Antigen Provides Prophylactic Protection from Anthrax in Mice.

PubMed

Moayeri, Mahtab; Tremblay, Jacqueline M; Debatis, Michelle; Dmitriev, Igor P; Kashentseva, Elena A; Yeh, Anthony J; Cheung, Gordon Y C; Curiel, David T; Leppla, Stephen; Shoemaker, Charles B

2016-01-06

Bacillus anthracis, the causative agent of anthrax, secretes three polypeptides, which form the bipartite lethal and edema toxins (LT and ET, respectively). The common component in these toxins, protective antigen (PA), is responsible for binding to cellular receptors and translocating the lethal factor (LF) and edema factor (EF) enzymatic moieties to the cytosol. Antibodies against PA protect against anthrax. We previously isolated toxin-neutralizing variable domains of camelid heavy-chain-only antibodies (VHHs) and demonstrated their in vivo efficacy. In this work, gene therapy with an adenoviral (Ad) vector (Ad/VNA2-PA) (VNA, VHH-based neutralizing agents) promoting the expression of a bispecific VHH-based neutralizing agent (VNA2-PA), consisting of two linked VHHs targeting different PA-neutralizing epitopes, was tested in two inbred mouse strains, BALB/cJ and C57BL/6J, and found to protect mice against anthrax toxin challenge and anthrax spore infection. Two weeks after a single treatment with Ad/VNA2-PA, serum VNA2-PA levels remained above 1 μg/ml, with some as high as 10 mg/ml. The levels were 10- to 100-fold higher and persisted longer in C57BL/6J than in BALB/cJ mice. Mice were challenged with a lethal dose of LT or spores at various times after Ad/VNA2-PA administration. The majority of BALB/cJ mice having serum VNA2-PA levels of >0.1 μg/ml survived LT challenge, and 9 of 10 C57BL/6J mice with serum levels of >1 μg/ml survived spore challenge. Our findings demonstrate the potential for genetic delivery of VNAs as an effective method for providing prophylactic protection from anthrax. We also extend prior findings of mouse strain-based differences in transgene expression and persistence by adenoviral vectors. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

High-sensitivity MALDI-TOF MS quantification of anthrax lethal toxin for diagnostics and evaluation of medical countermeasures.

PubMed

Boyer, Anne E; Gallegos-Candela, Maribel; Quinn, Conrad P; Woolfitt, Adrian R; Brumlow, Judith O; Isbell, Katherine; Hoffmaster, Alex R; Lins, Renato C; Barr, John R

2015-04-01

Inhalation anthrax has a rapid progression and high fatality rate. Pathology and death from inhalation of Bacillus anthracis spores are attributed to the actions of secreted protein toxins. Protective antigen (PA) binds and imports the catalytic component lethal factor (LF), a zinc endoprotease, and edema factor (EF), an adenylyl cyclase, into susceptible cells. PA-LF is termed lethal toxin (LTx) and PA-EF, edema toxin. As the universal transporter for both toxins, PA is an important target for vaccination and immunotherapeutic intervention. However, its quantification has been limited to methods of relatively low analytic sensitivity. Quantification of LTx may be more clinically relevant than LF or PA alone because LTx is the toxic form that acts on cells. A method was developed for LTx-specific quantification in plasma using anti-PA IgG magnetic immunoprecipitation of PA and quantification of LF activity that co-purified with PA. The method was fast (<4 h total time to detection), sensitive at 0.033 ng/mL LTx in plasma for the fast analysis (0.0075 ng/mL LTx in plasma for an 18 h reaction), precise (6.3-9.9% coefficient of variation), and accurate (0.1-12.7%error; n ≥ 25). Diagnostic sensitivity was 100% (n = 27 animal/clinical cases). Diagnostic specificity was 100% (n = 141). LTx was detected post-antibiotic treatment in 6/6 treated rhesus macaques and 3/3 clinical cases of inhalation anthrax and as long as 8 days post-treatment. Over the course of infection in two rhesus macaques, LTx was first detected at 0.101 and 0.237 ng/mL at 36 h post-exposure and increased to 1147 and 12,107 ng/mL in late-stage anthrax. This demonstrated the importance of LTx as a diagnostic and therapeutic target. This method provides a sensitive, accurate tool for anthrax toxin detection and evaluation of PA-directed therapeutics.

Public acceptance of management methods under different human-wildlife conflict scenarios.

PubMed

Liordos, Vasilios; Kontsiotis, Vasileios J; Georgari, Marina; Baltzi, Kerasia; Baltzi, Ioanna

2017-02-01

Wildlife management seeks to minimise public controversy for successful application of wildlife control methods. Human dimensions research in wildlife seeks a better understanding of public preferences for effective human-wildlife conflict resolution. In face to face interviews, 630 adults in Greece were asked to rate on a 5-point Likert-like scale their acceptance of 3 management methods, i.e., do nothing, non-lethal control, and lethal control, in the context of 5 human-wildlife conflict scenarios: 1) corvids damage crops; 2) starlings damage crops; 3) starlings foul urban structures; 4) coypus damage crops; and 5) coypus transfer disease. Univariate GLMs determined occupation, hunting membership and their interaction as the stronger predictors of public acceptance, generating 4 stakeholder groups: the general public, farmers, hunters, and farmers-hunters. Differences in acceptance and consensus among stakeholder groups were assessed using the Potential for Conflict Index 2 (PCI 2 ). All 4 stakeholder groups agreed that doing nothing was unacceptable and non-lethal control acceptable in all 5 scenarios, with generally high consensus within and between groups. The lethal control method was more controversial and became increasingly more acceptable as the severity of scenarios was increased and between non-native and native species. Lethal control was unacceptable for the general public in all scenarios. Farmers accepted lethal methods in the corvids and starlings scenarios, were neutral in the coypus damage crops scenario, whereas they accepted lethal control when coypus transfer disease. Hunters' opinion was neutral in the corvids, starlings and coypus damage crops and starlings foul urban structures scenarios, but they accepted lethal methods in the coypus transfer disease scenario. Farmers-hunters considered lethal control acceptable in all 5 scenarios. Implications from this study could be used for designing a socio-ecological approach which incorporates wildlife management with public interests. The studied species have a wide distribution, therefore present findings might also prove useful elsewhere. Copyright © 2016 Elsevier B.V. All rights reserved.

Influence UHF radiation on the process of self-assembly and lethal effect of bacterial lipopolysaccharide

NASA Astrophysics Data System (ADS)

Brill, G. E.; Egorova, A. V.; Bugaeva, I. O.; Postnov, D. E.; Melnikov, A. G.; Ushakova, O. V.

2018-04-01

The influence of low-intensity electromagnetic radiation on the process of self-assembly, spectral-fluorescent characteristics and lethal effect of bacterial lipopolysaccharide (endotoxin) was performed. A solution of bacterial lipopolysaccharide exposed to electromagnetic waves with a frequency of 1 GHz, the power density of 0.1 μW/cm2 for 10 min. In experiments on a large group of control and irradiated mice, a comparative analysis of the estimated lethal dose of endotoxin was performed. It was proved that UHF radiation of certain parameters reduces the lethal effects of bacterial lipopolysaccharide on 26%.

Distinctive emotional responses of clinicians to suicide-attempting patients - a comparative study

PubMed Central

2013-01-01

Background Clinician responses to patients have been recognized as an important factor in treatment outcome. Clinician responses to suicidal patients have received little attention in the literature however, and no quantitative studies have been published. Further, although patients with high versus low lethality suicidal behaviors have been speculated to represent two distinct populations, clinicians’ emotional responses to them have not been examined. Methods Clinicians’ responses to their patients when last seeing them prior to patients’ suicide attempt or death were assessed retrospectively with the Therapist Response/Countertransference Questionnaire, administered anonymously via an Internet survey service. Scores on individual items and subscale scores were compared between groups, and linear discriminant analysis was applied to determine the combination of items that best discriminated between groups. Results Clinicians reported on patients who completed suicide, made high-lethality attempts, low-lethality attempts, or died unexpected non-suicidal deaths in a total of 82 cases. We found that clinicians treating imminently suicidal patients had less positive feelings towards these patients than for non-suicidal patients, but had higher hopes for their treatment, while finding themselves notably more overwhelmed, distressed by, and to some degree avoidant of them. Further, we found that the specific paradoxical combination of hopefulness and distress/avoidance was a significant discriminator between suicidal patients and those who died unexpected non-suicidal deaths with 90% sensitivity and 56% specificity. In addition, we identified one questionnaire item that discriminated significantly between high- and low-lethality suicide patients. Conclusions Clinicians’ emotional responses to patients at risk versus not at risk for imminent suicide attempt may be distinct in ways consistent with responses theorized by Maltsberger and Buie in 1974. Prospective replication is needed to confirm these results, however. Our findings demonstrate the feasibility of using quantitative self-report methodologies for investigation of the relationship between clinicians’ emotional responses to suicidal patients and suicide risk. PMID:24053664

A simple electroelution method for rapid protein purification: isolation and antibody production of alpha toxin from Clostridium septicum.

PubMed

Vázquez-Iglesias, Lorena; Estefanell-Ucha, Borja; Barcia-Castro, Leticia; Páez de la Cadena, María; Álvarez-Chaver, Paula; Ayude-Vázquez, Daniel; Rodríguez-Berrocal, Francisco Javier

2017-01-01

Clostridium septicum produces a number of diseases in human and farm animals which, in most of the cases, are fatal without clinical intervention. Alpha toxin is an important agent and the unique lethal virulent factor produced by Clostridium septicum. This toxin is haemolytic, highly lethal and necrotizing activities but is being used as an antigen to develop animal vaccines. The aim of this study was to isolate the alpha toxin of Clostridium septicum and produce highly specific antibodies against it. In this work, we have developed a simple and efficient method for alpha toxin purification, based on electroelution that can be used as a time-saving method for purifying proteins. This technique avoids contamination by other proteins that could appear during other protein purification techniques such chromatography. The highly purified toxin was used to produce polyclonal antibodies. The specificity of the antibodies was tested by western blot and these antibodies can be applied to the quantitative determination of alpha toxin by slot blot.

A simple electroelution method for rapid protein purification: isolation and antibody production of alpha toxin from Clostridium septicum

PubMed Central

Estefanell-Ucha, Borja; Barcia-Castro, Leticia; Páez de la Cadena, María; Álvarez-Chaver, Paula; Ayude-Vázquez, Daniel; Rodríguez-Berrocal, Francisco Javier

2017-01-01

Clostridium septicum produces a number of diseases in human and farm animals which, in most of the cases, are fatal without clinical intervention. Alpha toxin is an important agent and the unique lethal virulent factor produced by Clostridium septicum. This toxin is haemolytic, highly lethal and necrotizing activities but is being used as an antigen to develop animal vaccines. The aim of this study was to isolate the alpha toxin of Clostridium septicum and produce highly specific antibodies against it. In this work, we have developed a simple and efficient method for alpha toxin purification, based on electroelution that can be used as a time-saving method for purifying proteins. This technique avoids contamination by other proteins that could appear during other protein purification techniques such chromatography. The highly purified toxin was used to produce polyclonal antibodies. The specificity of the antibodies was tested by western blot and these antibodies can be applied to the quantitative determination of alpha toxin by slot blot. PMID:28652930

Killing Range

PubMed Central

Asal, Victor; Rethemeyer, R. Karl; Horgan, John

2015-01-01

This paper presents an analysis of the Provisional Irish Republican Army's (PIRA) brigade level behavior during the Northern Ireland Conflict (1970-1998) and identifies the organizational factors that impact a brigade's lethality as measured via terrorist attacks. Key independent variables include levels of technical expertise, cadre age, counter-terrorism policies experienced, brigade size, and IED components and delivery methods. We find that technical expertise within a brigade allows for careful IED usage, which significantly minimizes civilian casualties (a specific strategic goal of PIRA) while increasing the ability to kill more high value targets with IEDs. Lethal counter-terrorism events also significantly affect a brigade's likelihood of killing both civilians and high-value targets but in different ways. Killing PIRA members significantly decreases IED fatalities but also significantly decreases the possibility of zero civilian IED-related deaths in a given year. Killing innocent Catholics in a Brigade's county significantly increases total and civilian IED fatalities. Together the results suggest the necessity to analyze dynamic situational variables that impact terrorist group behavior at the sub-unit level. PMID:25838603

Non-lethal Clostridium sordellii bacteraemia in an immunocompromised patient with pleomorphic sarcoma.

PubMed

Bonnecaze, Alex K; Stephens, Sarah Ellen Elza; Miller, Peter John

2016-08-03

Clostridium sordellii is a spore-forming anaerobic Gram-positive rod that has rarely been reported to cause disease in humans. Resultant mortality from infection is estimated at nearly 70% and is most often correlated with gynaecological procedures, intravenous drug abuse or trauma. C. sordellii infection often presents similarly to toxic shock syndrome (TSS); notable features of infection include refractory hypotension, haemoconcentration and marked leucocytosis. Although clinically similar to TSS, a notable difference is C. sordellii infections rarely involve fever. The organism's major toxins include haemorrhagic (TcsH) and lethal factor (TcsL), which function to disrupt cytoskeletal integrity. Current literature suggests treating C. sordelli infection with a broad-spectrum penicillin, metronidazole and clindamycin. We present a case of C. sordellii bacteraemia and septic shock in an immunocompromised patient who was recently diagnosed with pleomorphic gluteal sarcoma. Despite presenting in critical condition, the patient improved after aggressive hemodynamic resuscitation, source control and intravenous antibiotic therapy. 2016 BMJ Publishing Group Ltd.

Implementation of a non-lethal biopsy punch monitoring program for mercury in smallmouth bass, Micropterus dolomieu Lacepède, from the Eleven Point River, Missouri

USGS Publications Warehouse

Ackerson, J.R.; Schmitt, C.J.; McKee, M.J.; Brumbaugh, W.G.

2013-01-01

A non-lethal biopsy method for monitoring mercury (Hg) concentrations in smallmouth bass (Micropterus dolomieu; smallmouth) from the Eleven Point River in southern Missouri USA was evaluated. A biopsy punch was used to remove a muscle tissue plug from the area immediately below the anterior dorsal fin of 31 smallmouth. An additional 35 smallmouth (controls) were held identically except that no tissue plug was removed. After sampling, all fish were held in a concrete hatchery raceway for 6 weeks. Mean survival at the end of the holding period was 97 % for both groups. Smallmouth length, weight and Fulton’s condition factor at the end of the holding period were also similar between plugged and non-plugged controls, indicating that the biopsy procedure had minimal impact on growth under these conditions. Tissue plug Hg concentrations were similar to smallmouth Hg data obtained in previous years by removing the entire fillet for analysis.

Implementation of a non-lethal biopsy punch monitoring program for mercury in smallmouth bass, Micropterus dolomieu Lacepede, from the Eleven Point River, Missouri

USGS Publications Warehouse

Ackerson, R.J.; McKee, J.M.; Schmitt, C.J.; Brumbaugh, William G.

2014-01-01

A non-lethal biopsy method for monitoring mercury (Hg) concentrations in smallmouth bass (Micropterus dolomieu; smallmouth) from the Eleven Point River in southern Missouri USA was evaluated. A biopsy punch was used to remove a muscle tissue plug from the area immediately below the anterior dorsal fin of 31 smallmouth. An additional 35 smallmouth (controls) were held identically except that no tissue plug was removed. After sampling, all fish were held in a concrete hatchery raceway for 6 weeks. Mean survival at the end of the holding period was 97 % for both groups. Smallmouth length, weight and Fulton’s condition factor at the end of the holding period were also similar between plugged and non-plugged controls, indicating that the biopsy procedure had minimal impact on growth under these conditions. Tissue plug Hg concentrations were similar to smallmouth Hg data obtained in previous years by removing the entire fillet for analysis.

Optimized P2A for reporter gene insertion into Nipah virus results in efficient ribosomal skipping and wild-type lethality.

PubMed

Park, Arnold; Yun, Tatyana; Hill, Terence E; Ikegami, Tetsuro; Juelich, Terry L; Smith, Jennifer K; Zhang, Lihong; Freiberg, Alexander N; Lee, Benhur

2016-04-01

Incorporation of reporter genes within virus genomes is an indispensable tool for interrogation of virus biology and pathogenesis. In previous work, we incorporated a fluorophore into a viral ORF by attaching it to the viral gene via a P2A ribosomal skipping sequence. This recombinant Nipah virus, however, was attenuated in vitro relative to WT virus. In this work, we determined that inefficient ribosomal skipping was a major contributing factor to this attenuation. Inserting a GSG linker before the P2A sequence resulted in essentially complete skipping, significantly improved growth in vitro, and WT lethality in vivo. To the best of our knowledge, this represents the first time a recombinant virus of Mononegavirales with integration of a reporter into a viral ORF has been compared with the WT virus in vivo. Incorporating the GSG linker for improved skipping efficiency whenever functionally important is a critical consideration for recombinant virus design.

Assessment of the lethal and sublethal effects of 20 environmental chemicals in zebrafish embryos and larvae by using OECD TG 212.

PubMed

Horie, Yoshifumi; Yamagishi, Takahiro; Takahashi, Hiroko; Shintaku, Youko; Iguchi, Taisen; Tatarazako, Norihisa

2017-10-01

Fish embryo toxicity tests are used to assess the lethal and sublethal effects of environmental chemicals in aquatic organisms. Previously, we used a short-term toxicity test published by the Organization for Economic Co-operation and Development (test no. 212: Fish, Short-term Toxicity Test on Embryo and Sac-Fry Stages [OECD TG 212]) to assess the lethal and sublethal effects of aniline and several chlorinated anilines in zebrafish embryos and larvae. To expand upon this previous study, we used OECD TG 212 in zebrafish embryos and larvae to assess the lethal and sublethal effects of 20 additional environmental chemicals that included active pharmaceutical ingredients, pesticides, metals, aromatic compounds or chlorinated anilines. Zebrafish embryos (Danio rerio) were exposed to the test chemicals until 8 days post-fertilization. A delayed lethal effect was induced by 16 of the 20 test chemicals, and a positive correlation was found between heart rate turbulence and mortality. We also found that exposure to the test chemicals at concentrations lower than the lethal concentration induced the sublethal effects of edema, body curvature and absence of swim-bladder inflation. In conclusion, the environmental chemicals assessed in the present study induced both lethal and sublethal effects in zebrafish embryos and larvae, as assessed by using OECD TG 212. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

77 FR 38585 - Fisheries of the Caribbean, Gulf of Mexico, and South Atlantic; Reef Fish Fishery of the Gulf of...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-06-28

... to temporarily possess goliath grouper for non-lethal sampling during the course of their normal fishing activities. This non-lethal sampling would include measuring, tagging, and removing a portion of... temporarily possess goliath grouper for non-lethal sampling during the course of their normal fishing...

Examining the Impact of Psychiatric Diagnosis and Comorbidity on the Medical Lethality of Adolescent "Suicide Attempts"

ERIC Educational Resources Information Center

Mc Manama O'Brien, Kimberly H.; Berzin, Stephanie C.

2012-01-01

Specific psychiatric diagnoses and comorbidity patterns were examined to determine if they were related to the medical lethality of "suicide attempts" among adolescents presenting to an urban general hospital (N = 375). Bivariate analysis showed that attempters with substance abuse disorders had higher levels of lethality than attempters without…

Effects of Training with Lethal Chemicals on Job Proficiency and Job Confidence.

ERIC Educational Resources Information Center

Smith, Paula; And Others

A study was designed to determine if soldiers trained to use chemical agents are more proficient in performing their jobs in an environment where lethal chemical agents are used and more confident of their ability to survive. A treatment group, composed of 150 soldiers, knew that their training would involve lethal agents in the Chemical…

Non-lethal effects of an invasive species in the marine environment: the importance of early life-history stages.

PubMed

Rius, Marc; Turon, Xavier; Marshall, Dustin J

2009-04-01

Studies examining the effects of invasive species have focussed traditionally on the direct/lethal effects of the invasive on the native community but there is a growing recognition that invasive species may also have non-lethal effects. In terrestrial systems, non-lethal effects of invasive species can disrupt early life-history phases (such as fertilisation, dispersal and subsequent establishment) of native species, but in the marine environment most studies focus on adult rather than early life-history stages. Here, we examine the potential for an introduced sessile marine invertebrate (Styela plicata) to exert both lethal and non-lethal effects on a native species (Microcosmus squamiger) across multiple early life-history stages. We determined whether sperm from the invasive species interfered with the fertilisation of eggs from the native species and found no effect. However, we did find strong effects of the invasive species on the post-fertilisation performance of the native species. The invasive species inhibited the settlement of native larvae and, in the field, the presence of the invasive species was associated with a ten-fold increase in the post-settlement mortality of the native species, as well as an initial reduction of growth in the native. Our results suggest that larvae of the native species avoid settling near the invasive species due to reduced post-settlement survival in its presence. Overall, we found that invasive species can have complex and pervasive effects (both lethal and non-lethal) across the early life-history stages of the native species, which are likely to result in its displacement and to facilitate further invasion.

Differential antagonism of tetramethylenedisulfotetramine-induced seizures by agents acting at NMDA and GABAA receptors

PubMed Central

Shakarjian, Michael P.; Velíšková, Jana; Stanton, Patric K.; Velíšek, Libor

2012-01-01

Tetramethylenedisulfotetramine (TMDT) is a highly lethal neuroactive rodenticide responsible for many accidental and intentional poisonings in mainland China. Ease of synthesis, water solubility, potency, and difficulty to treat make TMDT a potential weapon for terrorist activity. We characterized TMDT-induced convulsions and mortality in male C57BL/6 mice. TMDT (ip) produced a continuum of twitches, clonic, and tonic-clonic seizures decreasing in onset latency and increasing in severity with increasing dose; 0.4 mg/kg was 100% lethal. The NMDA antagonist, ketamine (35 mg/kg) injected ip immediately after the first TMDT-induced seizure, did not change number of tonic-clonic seizures or lethality, but increased the number of clonic seizures. Doubling the ketamine dose decreased tonic-clonic seizures and eliminated lethality through a 60 min observation period. Treating mice with another NMDA antagonist, MK-801, 0.5 or 1 mg/kg ip, showed similar effects as low and high doses of ketamine, respectively, and prevented lethality, converting status epilepticus EEG activity to isolated interictal discharges. Treatment with these agents 15 min prior to TMDT administration did not increase their effectiveness. Post-treatment with the GABAA receptor allosteric enhancer diazepam (5 mg/kg) greatly reduced seizure manifestations and prevented lethality 60 min post-TMDT, but ictal events were evident in EEG recordings and, hours post-treatment, mice experienced status epilepticus and died. Thus, TMDT is a highly potent and lethal convulsant for which single-dose benzodiazepine treatment is inadequate in managing electrographic seizures or lethality. Repeated benzodiazepine dosing or combined application of benzodiazepines and NMDA receptor antagonists are more likely to be effective in treating TMDT poisoning. PMID:23022509

Functional genomics reveals the induction of inflammatory response and metalloproteinase gene expression during lethal Ebola virus infection.

PubMed

Cilloniz, Cristian; Ebihara, Hideki; Ni, Chester; Neumann, Gabriele; Korth, Marcus J; Kelly, Sara M; Kawaoka, Yoshihiro; Feldmann, Heinz; Katze, Michael G

2011-09-01

Ebola virus is the etiologic agent of a lethal hemorrhagic fever in humans and nonhuman primates with mortality rates of up to 90%. Previous studies with Zaire Ebola virus (ZEBOV), mouse-adapted virus (MA-ZEBOV), and mutant viruses (ZEBOV-NP(ma), ZEBOV-VP24(ma), and ZEBOV-NP/VP24(ma)) allowed us to identify the mutations in viral protein 24 (VP24) and nucleoprotein (NP) responsible for acquisition of high virulence in mice. To elucidate specific molecular signatures associated with lethality, we compared global gene expression profiles in spleen samples from mice infected with these viruses and performed an extensive functional analysis. Our analysis showed that the lethal viruses (MA-ZEBOV and ZEBOV-NP/VP24(ma)) elicited a strong expression of genes 72 h after infection. In addition, we found that although the host transcriptional response to ZEBOV-VP24(ma) was nearly the same as that to ZEBOV-NP/VP24(ma), the contribution of a mutation in the NP gene was required for a lethal phenotype. Further analysis indicated that one of the most relevant biological functions differentially regulated by the lethal viruses was the inflammatory response, as was the induction of specific metalloproteinases, which were present in our newly identify functional network that was associated with Ebola virus lethality. Our results suggest that this dysregulated proinflammatory response increased the severity of disease. Consequently, the newly discovered molecular signature could be used as the starting point for the development of new drugs and therapeutics. To our knowledge, this is the first study that clearly defines unique molecular signatures associated with Ebola virus lethality.

Non-lethal genotyping of Tribolium castaneum adults using genomic DNA extracted from wing tissue.

PubMed

Strobl, Frederic; Ross, J Alexander; Stelzer, Ernst H K

2017-01-01

The red flour beetle Tribolium castaneum has become the second most important insect model organism and is frequently used in developmental biology, genetics and pest-associated research. Consequently, the methodological arsenal increases continuously, but many routinely applied techniques for Drosophila melanogaster and other insect species are still unavailable. For example, a protocol for non-lethal genotyping has not yet been adapted but is particularly useful when individuals with known genotypes are required for downstream experiments. In this study, we present a workflow for non-lethal genotyping of T. castaneum adults based on extracting genomic DNA from wing tissue. In detail, we describe a convenient procedure for wing dissection and a custom method for wing digestion that allows PCR-based genotyping of up to fifty adults in less than an afternoon with a success rate of about 86%. The amount of template is sufficient for up to ten reactions while viability and fertility of the beetles are preserved. We prove the applicability of our protocol by genotyping the white / scarlet gene pair alleles from the black-eyed San Bernadino wild-type and white-eyed Pearl recessive mutant strains spanning four generations. Non-lethal genotyping has the potential to improve and accelerate many workflows: Firstly, during the establishment process of homozygous cultures or during stock keeping of cultures that carry recessively lethal alleles, laborious test crossing is replaced by non-lethal genotyping. Secondly, in genome engineering assays, non-lethal genotyping allows the identification of appropriate founders before they are crossed against wild-types, narrowing the efforts down to only the relevant individuals. Thirdly, non-lethal genotyping simplifies experimental strategies, in which genotype and behavior should be correlated, since the genetic configuration of potential individuals can be determined before the actual behavior assays is performed.

Decision-making competence and attempted suicide

PubMed Central

Szanto, Katalin; Bruine de Bruin, Wändi; Parker, Andrew M; Hallquist, Michael N; Vanyukov, Polina M; Dombrovski, Alexandre Y

2015-01-01

Objective The propensity of people vulnerable to suicide to make poor life decisions is increasingly well documented. Do they display an extreme degree of decision biases? The present study used a behavioral decision approach to examine the susceptibility of low-lethality and high-lethality suicide attempters to common decision biases, which may ultimately obscure alternative solutions and deterrents to suicide in a crisis. Method We assessed older and middle-aged individuals who made high-lethality (medically serious; N=31) and low-lethality suicide attempts (N=29). Comparison groups included suicide ideators (N=30), non-suicidal depressed (N=53), and psychiatrically healthy participants (N=28). Attempters, ideators, and non-suicidal depressed participants had unipolar non-psychotic major depression. Decision biases included sunk cost (inability to abort an action for which costs are irrecoverable), framing (responding to superficial features of how a problem is presented), under/overconfidence (appropriateness of confidence in knowledge), and inconsistent risk perception. Data were collected between June of 2010 and February of 2014. Results Both high- and low-lethality attempters were more susceptible to framing effects, as compared to the other groups included in this study (p≤ 0.05, ηp2 =.06). In contrast, low-lethality attempters were more susceptible to sunk costs than both the comparison groups and high-lethality attempters (p≤ 0.01, ηp2 =.09). These group differences remained after accounting for age, global cognitive performance, and impulsive traits. Premorbid IQ partially explained group differences in framing effects. Conclusion Suicide attempters’ failure to resist framing may reflect their inability to consider a decision from an objective standpoint in a crisis. Low-lethality attempters’ failure to resist sunk-cost may reflect their tendency to confuse past and future costs of their behavior, lowering their threshold for acting on suicidal thoughts. PMID:26717535

Decision-making competence and attempted suicide.

PubMed

Szanto, Katalin; Bruine de Bruin, Wändi; Parker, Andrew M; Hallquist, Michael N; Vanyukov, Polina M; Dombrovski, Alexandre Y

2015-12-01

The propensity of people vulnerable to suicide to make poor life decisions is increasingly well documented. Do they display an extreme degree of decision biases? The present study used a behavioral-decision approach to examine the susceptibility of low-lethality and high-lethality suicide attempters to common decision biases that may ultimately obscure alternative solutions and deterrents to suicide in a crisis. We assessed older and middle-aged (42-97 years) individuals who made high-lethality (medically serious) (n = 31) and low-lethality suicide attempts (n = 29). Comparison groups included suicide ideators (n = 30), nonsuicidal depressed participants (n = 53), and psychiatrically healthy participants (n = 28). Attempters, ideators, and nonsuicidal depressed participants had nonpsychotic major depression (DSM-IV criteria). Decision biases included sunk cost (inability to abort an action for which costs are irrecoverable), framing (responding to superficial features of how a problem is presented), underconfidence/overconfidence (appropriateness of confidence in knowledge), and inconsistent risk perception. Data were collected between June 2010 and February 2014. Both high- and low-lethality attempters were more susceptible to framing effects as compared to the other groups included in this study (P ≤ .05, ηp2 = 0.06). In contrast, low-lethality attempters were more susceptible to sunk costs than both the comparison groups and high-lethality attempters (P ≤ .01, ηp2 = 0.09). These group differences remained after accounting for age, global cognitive performance, and impulsive traits. Premorbid IQ partially explained group differences in framing effects. Suicide attempters' failure to resist framing may reflect their inability to consider a decision from an objective standpoint in a crisis. Failure of low-lethality attempters to resist sunk cost may reflect their tendency to confuse past and future costs of their behavior, lowering their threshold for acting on suicidal thoughts. © Copyright 2015 Physicians Postgraduate Press, Inc.

Structure-Based Systematic Isolation of Conditional-Lethal Mutations in the Single Yeast Calmodulin Gene

PubMed Central

Ohya, Y.; Botstein, D.

1994-01-01

Conditional-lethal mutations of the single calmodulin gene in Saccharomyces cerevisiae have been very difficult to isolate by random and systematic methods, despite the fact that deletions cause recessive lethality. We report here the isolation of numerous conditional-lethal mutants that were recovered by systematically altering phenylalanine residues. The phenylalanine residues of calmodulin were implicated in function both by structural studies of calmodulin bound to target peptides and by their extraordinary conservation in evolution. Seven single and 26 multiple Phe -> Ala mutations were constructed. Mutant phenotypes were examined in a haploid cmd1 disrupted strain under three conditions: single copy, low copy, and overexpressed. Whereas all but one of the single mutations caused no obvious phenotype, most of the multiple mutations caused obvious growth phenotypes. Five were lethal, 6 were lethal only in synthetic medium, 13 were temperature-sensitive lethal and 2 had no discernible phenotypic consequences. Overexpression of some of the mutant genes restored the phenotype to nearly wild type. Several temperature-sensitive calmodulin mutations were suppressed by elevated concentration of CaCl(2) in the medium. Mutant calmodulin protein was detected at normal levels in extracts of most of the lethal mutant cells, suggesting that the deleterious phenotypes were due to loss of the calmodulin function and not protein instability. Analysis of diploid strains heterozygous for all combinations of cmd1-ts alleles revealed four intragenic complementation groups. The contributions of individual phe->ala changes to mutant phenotypes support the idea of internal functional redundancy in the symmetrical calmodulin protein molecule. These results suggest that the several phenylalanine residues in calmodulin are required to different extents in different combinations in order to carry out each of the several essential tasks. PMID:7896089

Risk factors of suicide mortality among multiple attempters: A national registry study in Taiwan.

PubMed

Chen, I-Ming; Liao, Shih-Cheng; Lee, Ming-Been; Wu, Chia-Yi; Lin, Po-Hsien; Chen, Wei J

2016-05-01

Little is known about the risk factors of suicide mortality among multiple attempters. This study aims to investigate the predictors of suicidal mortality in a prospective cohort of attempters in Taiwan, focusing on the time interval and suicide method change between the last two nonfatal attempts. The representative data retrieved from the National Suicide Surveillance System (NSSS) was linked with National Mortality Database to identify the causes of death in multiple attempters during 2006-2008. Cox-proportional hazard models were applied to calculate the hazard ratios for the predictors of suicide. Among the 55,560 attempters, 6485 (11.7%) had survived attempts ranging from one to 11 times; 861 (1.5%) eventually died by suicide. Multiple attempters were characterized by female (OR = 1.56, p < 0.0001), nonrecipient of national aftercare service (OR = 1.62, p < 0.0001), and current contact with mental health services (OR = 3.17, p < 0.0001). Most multiple attempters who survived from hanging (68.1%) and gas poisoning (61.9%) chose the same method in the following fatal episode. Predictors of suicidal death were identified as male, older age (≥ 45 years), shorter interval and not maintaining methods of low lethality in the last two nonfatal attempts. Receipt of nationwide aftercare was associated with lower risk of suicide but the effect was insignificant. The time interval of the last two nonfatal attempts and alteration in the lethality of suicide method were significant factors for completed suicide. Risk assessment involving these two factors may be necessary for multiple attempters in different clinical settings. Effective strategies for suicide prevention emphasizing this high risk population should be developed in the future. Copyright © 2015. Published by Elsevier B.V.

Obstructive Lymphangitis Precedes Colitis in Murine Norovirus-Infected Stat1-Deficient Mice.

PubMed

Seamons, Audrey; Treuting, Piper M; Meeker, Stacey; Hsu, Charlie; Paik, Jisun; Brabb, Thea; Escobar, Sabine S; Alexander, Jonathan S; Ericsson, Aaron; Smith, Jason G; Maggio-Price, Lillian

2018-05-17

Murine norovirus (MNV) is an RNA virus that can prove lethal in mice with impaired innate immunity. We found that MNV-4 infection of Stat1 -/- mice was not lethal, but produced a 100% penetrant, previously undescribed lymphatic phenotype characterized by chronic-active lymphangitis with hepatitis, splenitis, and chronic cecal and colonic inflammation. Lesion pathogenesis progressed from early ileal enteritis and regional dilated lymphatics to lymphangitis, granulomatous changes in the liver and spleen, and, ultimately, typhlocolitis. Lesion development was neither affected by antibiotics nor reproduced by infection with another enteric RNA virus, rotavirus. MNV-4 infection in Stat1 -/- mice decreased expression of vascular endothelial growth factor (Vegf) receptor 3, Vegf-c, and Vegf-d and increased interferon (Ifn)-γ, tumor necrosis factor-α, and inducible nitric oxide synthase. However, anti-IFN-γ and anti-tumor necrosis factor-α antibody treatment did not attenuate the histologic lesions. Studies in Ifnαβγr -/- mice suggested that canonical signaling via interferon receptors did not cause MNV-4-induced disease. Infected Stat1 -/- mice had increased STAT3 phosphorylation and expressed many STAT3-regulated genes, consistent with our findings of increased myeloid cell subsets and serum granulocyte-specific colony-stimulating factor, which are also associated with increased STAT3 activity. In conclusion, in Stat1 -/- mice, MNV-4 induces lymphatic lesions similar to those seen in Crohn disease as well as hepatitis, splenitis, and typhlocolitis. MNV-4-infected Stat1 -/- mice may be a useful model to study mechanistic associations between viral infections, lymphatic dysfunction, and intestinal inflammation in a genetically susceptible host. Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Factors associated with law enforcement-related use-of-force injury.

PubMed

Castillo, Edward M; Prabhakar, Nitin; Luu, Bethi

2012-05-01

Use-of-force (UOF) techniques are used by law enforcement to gain control of noncompliant subjects. The purpose of this study was to assess factors associated with subject and deputy injuries during law enforcement UOF. This is a retrospective study of nonlethal UOF events from January to June 2009 by a single law enforcement agency serving a population of 3 million. A standard data collection tool, which included basic demographic data, the type of force used, subject response, and if there were any injuries to the subject or deputies involved, was used by deputies for each UOF event. Descriptive statistics were used to describe the specific subject and incident details. Univariate and multivariate analysis was used to identify factors potentially associated with subject and deputy injuries. There were 1174 UOF incidents recorded during the study period. A total of 282 incidents (24%) involved no physical force, 135 (11.5%) involved less lethal methods, 620 (52.8%) involved other physical restraint methods, and 137 (11.7%) involved both less lethal and other physical methods. Factors with the largest independent associations with subject injury were physical resistance by the subject (odds ratio [OR], 2.65; 95% confidence interval [CI], 1.49-4.74) and force used to prevent a violent felony (OR, 2.15; 95% CI, 1.24-3.71). When the subject had a weapon (OR, 4.15; 95% CI, 1.53-11.23) and physical resistance by the subject (OR, 4.15; 95% CI, 1.24-13.94) had the largest associations with deputy injury. This study identifies situational characteristics potentially associated with subject and deputy injuries during UOF events. Copyright © 2012 Elsevier Inc. All rights reserved.

Role of CD14 in responses to clinical isolates of Escherichia coli: effects of K1 capsule expression.

PubMed

Metkar, Shalaka; Awasthi, Shanjana; Denamur, Erick; Kim, Kwang Sik; Gangloff, Sophie C; Teichberg, Saul; Haziot, Alain; Silver, Jack; Goyert, Sanna M

2007-11-01

Severe bacterial infections leading to sepsis or septic shock can be induced by bacteria that utilize different factors to drive pathogenicity and/or virulence, leading to disease in the host. One major factor expressed by all clinical isolates of gram-negative bacteria is lipopolysaccharide (LPS); a second factor expressed by some Escherichia coli strains is a K1 polysaccharide capsule. To determine the role of the CD14 LPS receptor in the pathogenic effects of naturally occurring E. coli, the responses of CD14-/- and CD14+/+ mice to three different isolates of E. coli obtained from sepsis patients were compared; two isolates express both smooth LPS and the K1 antigen, while the third isolate expresses only LPS and is negative for K1. An additional K1-positive isolate obtained from a newborn with meningitis and a K1-negative isogenic mutant of this strain were also used for these studies. CD14-/- mice were resistant to the lethal effects of the K1-negative isolates. This resistance was accompanied by significantly lower levels of systemic tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) in these mice than in CD14+/+ mice, enhanced clearance of the bacteria, and significantly fewer additional gross symptoms. In contrast, CD14-/- mice were as sensitive as CD14+/+ mice to the lethal effects of the K1-positive isolates, even though they had significantly lower levels of TNF-alpha and IL-6 than CD14+/+ mice. These studies show that different bacterial isolates can use distinctly different mechanisms to cause disease and suggest that new, nonantibiotic therapeutics need to be directed against multiple targets.

O-chromosome lethal frequencies in Serbian and Montenegrin Drosophila subobscura populations.

PubMed

Zivanovic, G; Arenas, C; Mestres, F

2011-10-01

Lethal chromosomal frequencies were obtained from three Drosophila subobscura samples from the Mt. Avala (Serbia) population in September 2003 (0.218), June 2004 (0.204) and September 2004 (0.250). These values and those from other Balkan populations studied previously (Petnica, Kamariste, Zanjic and Djerdap) were used to analyze the possible effect of population, year, month and altitude above sea level on lethal chromosomal frequencies. According to ANOVAS no effect were observed. Furthermore, the lethal frequencies of the Balkan populations did not vary according to latitude. This is probably due to the relative proximity and high gene flow between these populations. From a joint study of all the Palearctic D. subobscura populations so far analyzed, it can be deduced that the Balkan populations are located in the central area of the species distribution. Finally, it seems that lethal chromosomal frequencies are a consequence of the genetic structure of the populations.

Back to the future: revisiting HIV-1 lethal mutagenesis

PubMed Central

Dapp, Michael J.; Patterson, Steven E.; Mansky, Louis M.

2012-01-01

The concept of eliminating HIV-1 infectivity by elevating the viral mutation rate was first proposed over a decade ago, even though the general concept had been conceived earlier for RNA viruses. Lethal mutagenesis was originally viewed as a novel chemotherapeutic approach for treating HIV-1 infection in which use of a viral mutagen would over multiple rounds of replication lead to the lethal accumulation of mutations, rendering the virus population non infectious – known as the slow mutation accumulation model. There have been limitations in obtaining good efficacy data with drug leads, leaving some doubt into clinical translation. More recent studies of the APOBEC3 proteins as well as new progress in the use of nucleoside analogs for inducing lethal mutagenesis have helped to refocus attention on rapid induction of HIV-1 lethal mutagenesis in a single or limited number of replication cycles leading to a rapid mutation accumulation model. PMID:23195922

Induction of high tolerance to artemisinin by sub-lethal administration: A new in vitro model of P. falciparum.

PubMed

De Lucia, Serena; Tsamesidis, Ioannis; Pau, Maria Carmina; Kesely, Kristina R; Pantaleo, Antonella; Turrini, Francesco

2018-01-01

Artemisinin resistance is a major threat to malaria control efforts. Resistance is characterized by an increase in the Plasmodium falciparum parasite clearance half-life following treatment with artemisinin-based combination therapies (ACTs) and an increase in the percentage of surviving parasites. The remarkably short blood half-life of artemisinin derivatives may contribute to drug-resistance, possibly through factors including sub-lethal plasma concentrations and inadequate exposure. Here we selected for a new strain of artemisinin resistant parasites, termed the artemisinin resistant strain 1 (ARS1), by treating P. falciparum Palo Alto (PA) cultures with sub-lethal concentrations of dihydroartemisinin (DHA). The resistance phenotype was maintained for over 1 year through monthly maintenance treatments with low doses of 2.5 nM DHA. There was a moderate increase in the DHA IC50 in ARS1 when compared with parental strain PA after 72 h of drug exposure (from 0.68 nM to 2 nM DHA). In addition, ARS1 survived treatment physiologically relevant DHA concentrations (700 nM) observed in patients. Furthermore, we confirmed a lack of cross-resistance against a panel of antimalarials commonly used as partner drugs in ACTs. Finally, ARS1 did not contain Pfk13 propeller domain mutations associated with ART resistance in the Greater Mekong Region. With a stable growth rate, ARS1 represents a valuable tool for the development of new antimalarial compounds and studies to further elucidate the mechanisms of ART resistance.

An oral Hemokine™, α-methylhydrocinnamate, enhances myeloid and neutrophil recovery following irradiation in vivo

PubMed Central

Faller, Douglas V.; Castaneda, Serguei A.; Zhou, Daohong; Vedamony, Merriline; Newburger, Peter E.; White, Gary L.; Kosanke, Stanley; Plett, P. Artur; Orschell, Christie M.; Boosalis, Michael S.; Perrine, Susan P.

2017-01-01

An oral therapeutic which reduces duration of cytopenias and is active following accidental radiation exposures is an unmet need in radiation countermeasures. Alpha methylhydrocinnamate (ST7) prolongs STAT-5 phosphorylation, reduces growth-factor dependency of multi-lineage cell lines, and stimulates erythropoiesis. Here, ST7 and its isomers were studied for their effects on myeloid progenitors and hematopoietic stem cells (HSCs) following radiation, in nonhuman primates, and murine irradiation models. Addition of ST7 or ST7-S increased CFU-GM production by 1.7-fold (p<0.001), reduced neutrophil apoptosis comparable to G-CSF, and enhanced HSC survival post-radiation by 2-fold, (p=0.028). ST7 and ST7-S administered in normal baboons increased ANC and platelet counts by 50–400%. In sub-lethally-irradiated mice, ANC nadir remained >200/mm3 and neutropenia recovered in 6 days with ST7 treatment and 18 days in controls (p<0.05). In lethally-irradiated mice, marrow pathology at 15 days was hypocellular (10% cellularity) in controls, but normal (55–75% cellularity) with complete neutrophil maturation with ST7-S treatment. Following lethal irradiation, ST7, given orally for 4 days, reduced mortality, with 30% survival in ST7-animals vs 8% in controls, (p<0.05). Collectively, the studies indicate that ST7 and ST7-S enhance myeloid recovery post-radiation and merit further evaluation to accelerate hematologic recovery in conditions of radiation-related and other marrow hypoplasias. PMID:27888688

Experimental Investigations of the Effects of Underwater Explosions on Swimbladder Fish. I. 1973 Chesapeake Bay Tests

DTIC Science & Technology

1975-06-20

H1101600 Underwater Explosions Explosion Effects on Fish Fish Lethal Ranges " Environmental Effects of Explosions 𔃺. A*STRACT reverse side It nooosemy and...effects of its research operations. When such operations involve the detonation of underwater explosions, one of the environmental factors to be evaluated...04o APPENDIX A: EXPERIMENTS WITH CRABS AND OYSTERS ......... .. A-I APPENDIX B: FINAL REPORT: ENVIRONMENTAL EFFECTS OF EXPLOSIVE TESTING

Suicide Intent and Accurate Expectations of Lethality: Predictors of Medical Lethality of Suicide Attempts

ERIC Educational Resources Information Center

Brown, Gregory K.; Henriques, Gregg R.; Sosdjan, Daniella; Beck, Aaron T.

2004-01-01

The degree of intent to commit suicide and the severity of self-injury were examined in individuals (N = 180) who had recently attempted suicide. Although a minimal association was found between the degree of suicide intent and the degree of lethality of the attempt, the accuracy of expectations about the likelihood of dying was found to moderate…

Effect of temperature and heating rate on apparent lethal concentrations of pyrolysis products

NASA Technical Reports Server (NTRS)

Hilado, C. J.; Solis, A. N.; Marcussen, W. H.; Furst, A.

1976-01-01

The apparent lethal concentrations for 50 percent of the test animals of the pyrolysis products from twelve polymeric materials were studied as a function of temperature and heating rate. The materials were polyethylene, nylon 6, ABS, polycarbonate, polyether sulfone, polyaryl sulfone, wool fabric, aromatic polyamide fabric, polychloroprene foam, polyvinyl fluoride film, Douglas fir, and red oak. The apparent lethal concentration values of most materials vary significantly with temperature and heating rate. The apparent lethal concentration values, based on weight of sample charged, appears to effectively integrate the thermophysical, thermochemical, and physiological responses from a known quantity of material under specified imposed conditions.

Microwave and Man—The Direct and Indirect Hazards, and the Precautions

PubMed Central

Merckel, Charles

1972-01-01

Microwave-radar is a form of electromagnetic energy with potential hazards to human health and safety. Its lethal and non-lethal harmful effects have been demonstrated in experimental animals. Lethal effects upon humans from exposure to microwave have not been proved. Alleged non-lethal effects have been limited primarily to cataractogenesis. Increasing use of microwave commercially in communications and domestically, as in micro-ovens, increases the hazard of exposure to microwave. Increasing use of devices which are at risk from microwave, such as implanted cardiac pacemakers and metal surgical appliances and electronic monitoring devices in operating rooms and clinics, present increasing environmental hazards. PMID:5039801

Non-lethal sampling of walleye for stable isotope analysis: a comparison of three tissues

USGS Publications Warehouse

Chipps, Steven R.; VanDeHey, J.A.; Fincel, M.J.

2012-01-01

Stable isotope analysis of fishes is often performed using muscle or organ tissues that require sacrificing animals. Non-lethal sampling provides an alternative for evaluating isotopic composition for species of concern or individuals of exceptional value. Stable isotope values of white muscle (lethal) were compared with those from fins and scales (non-lethal) in walleye, Sander vitreus (Mitchill), from multiple systems, size classes and across a range of isotopic values. Isotopic variability was also compared among populations to determine the potential of non-lethal tissues for diet-variability analyses. Muscle-derived isotope values were enriched compared with fins and depleted relative to scales. A split-sample validation technique and linear regression found that isotopic composition of walleye fins and scales was significantly related to that in muscle tissue for both δ13C and δ15N (r2 = 0.79–0.93). However, isotopic variability was significantly different between tissue types in two of six populations for δ15N and three of six populations for δ13C. Although species and population specific, these findings indicate that isotopic measures obtained from non-lethal tissues are indicative of those obtained from muscle.

An analysis of lethal and sublethal interactions among type I and type II pyrethroid pesticide mixtures using standard Hyalella azteca water column toxicity tests.

PubMed

Hoffmann, Krista Callinan; Deanovic, Linda; Werner, Inge; Stillway, Marie; Fong, Stephanie; Teh, Swee

2016-10-01

A novel 2-tiered analytical approach was used to characterize and quantify interactions between type I and type II pyrethroids in Hyalella azteca using standardized water column toxicity tests. Bifenthrin, permethrin, cyfluthrin, and lambda-cyhalothrin were tested in all possible binary combinations across 6 experiments. All mixtures were analyzed for 4-d lethality, and 2 of the 6 mixtures (permethrin-bifenthrin and permethrin-cyfluthrin) were tested for subchronic 10-d lethality and sublethal effects on swimming motility and growth. Mixtures were initially analyzed for interactions using regression analyses, and subsequently compared with the additive models of concentration addition and independent action to further characterize mixture responses. Negative interactions (antagonistic) were significant in 2 of the 6 mixtures tested, including cyfluthrin-bifenthrin and cyfluthrin-permethrin, but only on the acute 4-d lethality endpoint. In both cases mixture responses fell between the additive models of concentration addition and independent action. All other mixtures were additive across 4-d lethality, and bifenthrin-permethrin and cyfluthrin-permethrin were also additive in terms of subchronic 10-d lethality and sublethal responses. Environ Toxicol Chem 2016;35:2542-2549. © 2016 SETAC. © 2016 SETAC.

Killing wolves to prevent predation on livestock may protect one farm but harm neighbors.

PubMed

Santiago-Avila, Francisco J; Cornman, Ari M; Treves, Adrian

2018-01-01

Large carnivores, such as gray wolves, Canis lupus, are difficult to protect in mixed-use landscapes because some people perceive them as dangerous and because they sometimes threaten human property and safety. Governments may respond by killing carnivores in an effort to prevent repeated conflicts or threats, although the functional effectiveness of lethal methods has long been questioned. We evaluated two methods of government intervention following independent events of verified wolf predation on domestic animals (depredation) in the Upper Peninsula of Michigan, USA between 1998-2014, at three spatial scales. We evaluated two intervention methods using log-rank tests and conditional Cox recurrent event, gap time models based on retrospective analyses of the following quasi-experimental treatments: (1) selective killing of wolves by trapping near sites of verified depredation, and (2) advice to owners and haphazard use of non-lethal methods without wolf-killing. The government did not randomly assign treatments and used a pseudo-control (no removal of wolves was not a true control), but the federal permission to intervene lethally was granted and rescinded independent of events on the ground. Hazard ratios suggest lethal intervention was associated with an insignificant 27% lower risk of recurrence of events at trapping sites, but offset by an insignificant 22% increase in risk of recurrence at sites up to 5.42 km distant in the same year, compared to the non-lethal treatment. Our results do not support the hypothesis that Michigan's use of lethal intervention after wolf depredations was effective for reducing the future risk of recurrence in the vicinities of trapping sites. Examining only the sites of intervention is incomplete because neighbors near trapping sites may suffer the recurrence of depredations. We propose two new hypotheses for perceived effectiveness of lethal methods: (a) killing predators may be perceived as effective because of the benefits to a small minority of farmers, and (b) if neighbors experience side-effects of lethal intervention such as displaced depredations, they may perceive the problem growing and then demand more lethal intervention rather than detecting problems spreading from the first trapping site. Ethical wildlife management guided by the "best scientific and commercial data available" would suggest suspending the standard method of trapping wolves in favor of non-lethal methods (livestock guarding dogs or fladry) that have been proven effective in preventing livestock losses in Michigan and elsewhere.

Lymphopenia associated with highly virulent H5N1 virus infection due to plasmacytoid dendritic cell mediated apoptosis of T cells

PubMed Central

Boonnak, Kobporn; Vogel, Leatrice; Feldmann, Friederike; Feldmann, Heinz; Legge, Kevin L.; Subbarao, Kanta

2014-01-01

Although lymphopenia is a hallmark of severe infection with highly pathogenic H5N1 and the newly emerged H7N9 influenza viruses in humans, the mechanism(s) by which lethal H5N1 viruses cause lymphopenia in mammalian hosts remains poorly understood. Because influenza-specific T cell responses are initiated in the lung draining lymph nodes, and lymphocytes subsequently traffic to the lungs or peripheral circulation, we compared the immune responses in the lung draining lymph nodes following infection with a lethal A/HK/483/97 or non-lethal A/HK/486/97 (H5N1) virus in a mouse model. We found that lethal H5N1, but not non-lethal H5N1 virus infection in mice enhances Fas ligand (FasL) expression on plasmacytoid dendritic cells (pDCs), resulting in apoptosis of influenza-specific CD8+ T cells via a Fas-FasL mediated pathway. We also found that pDCs, but not other DC subsets, preferentially accumulate in the lung draining lymph nodes of lethal H5N1 virus-infected mice and that the induction of FasL expression on pDCs correlates with high levels of IL-12p40 monomer/homodimer in the lung draining lymph nodes. Our data suggest that one of the mechanisms of lymphopenia associated with lethal H5N1 virus infection involves a deleterious role for pDCs. PMID:24829418

Sub-lethal glyphosate exposure alters flowering phenology and causes transient male-sterility in Brassica spp

PubMed Central

2014-01-01

Background Herbicide resistance in weedy plant populations can develop through different mechanisms such as gene flow of herbicide resistance transgenes from crop species into compatible weedy species or by natural evolution of herbicide resistance or tolerance following selection pressure. Results from our previous studies suggest that sub-lethal levels of the herbicide glyphosate can alter the pattern of gene flow between glyphosate resistant Canola®, Brassica napus, and glyphosate sensitive varieties of B. napus and B. rapa. The objectives of this study were to examine the phenological and developmental changes that occur in Brassica crop and weed species following sub-lethal doses of the herbicides glyphosate and glufosinate. We examined several vegetative and reproductive traits of potted plants under greenhouse conditions, treated with sub-lethal herbicide sprays. Results Our results indicate that exposure of Brassica spp. to a sub-lethal dose of glyphosate results in altering flowering phenology and reproductive function. Flowering of all sensitive species was significantly delayed and reproductive function, specifically male fertility, was suppressed. Higher dosage levels typically contributed to an increase in the magnitude of phenotypic changes. Conclusions These results demonstrate that Brassica spp. plants that are exposed to sub-lethal doses of glyphosate could be subject to very different pollination patterns and an altered pattern of gene flow that would result from changes in the overlap of flowering phenology between species. Implications include the potential for increased glyphosate resistance evolution and spread in weedy communities exposed to sub-lethal glyphosate. PMID:24655547

Sub-lethal glyphosate exposure alters flowering phenology and causes transient male-sterility in Brassica spp.

PubMed

Londo, Jason Paul; McKinney, John; Schwartz, Matthew; Bollman, Mike; Sagers, Cynthia; Watrud, Lidia

2014-03-21

Herbicide resistance in weedy plant populations can develop through different mechanisms such as gene flow of herbicide resistance transgenes from crop species into compatible weedy species or by natural evolution of herbicide resistance or tolerance following selection pressure. Results from our previous studies suggest that sub-lethal levels of the herbicide glyphosate can alter the pattern of gene flow between glyphosate resistant Canola®, Brassica napus, and glyphosate sensitive varieties of B. napus and B. rapa. The objectives of this study were to examine the phenological and developmental changes that occur in Brassica crop and weed species following sub-lethal doses of the herbicides glyphosate and glufosinate. We examined several vegetative and reproductive traits of potted plants under greenhouse conditions, treated with sub-lethal herbicide sprays. Our results indicate that exposure of Brassica spp. to a sub-lethal dose of glyphosate results in altering flowering phenology and reproductive function. Flowering of all sensitive species was significantly delayed and reproductive function, specifically male fertility, was suppressed. Higher dosage levels typically contributed to an increase in the magnitude of phenotypic changes. These results demonstrate that Brassica spp. plants that are exposed to sub-lethal doses of glyphosate could be subject to very different pollination patterns and an altered pattern of gene flow that would result from changes in the overlap of flowering phenology between species. Implications include the potential for increased glyphosate resistance evolution and spread in weedy communities exposed to sub-lethal glyphosate.

Suppression of the lethal effect of acidic-phospholipid deficiency by defective formation of the major outer membrane lipoprotein in Escherichia coli.

PubMed Central

Asai, Y; Katayose, Y; Hikita, C; Ohta, A; Shibuya, I

1989-01-01

The Escherichia coli pgsA3 allele encoding a defective phosphatidylglycerophosphate synthase is lethal for all but certain strains. Genetic analysis of such strains has revealed that the lethal effect is fully suppressed by the lack of the major outer membrane lipoprotein that consumes phosphatidylglycerol for its maturation. Images PMID:2556377

Ribosomal elongation factor 4 promotes cell death associated with lethal stress.

PubMed

Li, Liping; Hong, Yuzhi; Luan, Gan; Mosel, Michael; Malik, Muhammad; Drlica, Karl; Zhao, Xilin

2014-12-09

Ribosomal elongation factor 4 (EF4) is highly conserved among bacteria, mitochondria, and chloroplasts. However, the EF4-encoding gene, lepA, is nonessential and its deficiency shows no growth or fitness defect. In purified systems, EF4 back-translocates stalled, posttranslational ribosomes for efficient protein synthesis; consequently, EF4 has a protective role during moderate stress. We were surprised to find that EF4 also has a detrimental role during severe stress: deletion of lepA increased Escherichia coli survival following treatment with several antimicrobials. EF4 contributed to stress-mediated lethality through reactive oxygen species (ROS) because (i) the protective effect of a ΔlepA mutation against lethal antimicrobials was eliminated by anaerobic growth or by agents that block hydroxyl radical accumulation and (ii) the ΔlepA mutation decreased ROS levels stimulated by antimicrobial stress. Epistasis experiments showed that EF4 functions in the same genetic pathway as the MazF toxin, a stress response factor implicated in ROS-mediated cell death. The detrimental action of EF4 required transfer-messenger RNA (tmRNA, which tags truncated proteins for degradation and is known to be inhibited by EF4) and the ClpP protease. Inhibition of a protective, tmRNA/ClpP-mediated degradative activity would allow truncated proteins to indirectly perturb the respiratory chain and thereby provide a potential link between EF4 and ROS. The connection among EF4, MazF, tmRNA, and ROS expands a pathway leading from harsh stress to bacterial self-destruction. The destructive aspect of EF4 plus the protective properties described previously make EF4 a bifunctional factor in a stress response that promotes survival or death, depending on the severity of stress. Translation elongation factor 4 (EF4) is one of the most conserved proteins in nature, but it is dispensable. Lack of strong phenotypes for its genetic knockout has made EF4 an enigma. Recent biochemical work has demonstrated that mild stress may stall ribosomes and that EF4 can reposition stalled ribosomes to resume proper translation. Thus, EF4 protects cells from moderate stress. Here we report that EF4 is paradoxically harmful during severe stress, such as that caused by antimicrobial treatment. EF4 acts in a pathway that leads to excessive accumulation of reactive oxygen species (ROS), thereby participating in a bacterial self-destruction that occurs when cells cannot effectively repair stress-mediated damage. Thus, EF4 has two opposing functions-at low-to-moderate levels of stress, the protein is protective by allowing stress-paused translation to resume; at high-levels of stress, EF4 helps bacteria self-destruct. These data support the existence of a bacterial live-or-die response to stress. Copyright © 2014 Li et al.

The lethal injection quandary: how medicine has dismantled the death penalty.

PubMed

Denno, Deborah W

2007-10-01

On February 20, 2006, Michael Morales was hours away from execution in California when two anesthesiologists declined to participate in his lethal injection procedure, thereby halting all state executions. The events brought to the surface the long-running schism between law and medicine, raising the question of whether any beneficial connection between the professions ever existed in the execution context. History shows it seldom did. Decades of botched executions prove it. This Article examines how states ended up with such constitutionally vulnerable lethal injection procedures, suggesting that physician participation in executions, though looked upon with disdain, is more prevalent--and perhaps more necessary--than many would like to believe. The Article also reports the results of this author's unique nationwide study of lethal injection protocols and medical participation. The study demonstrates that states have continued to produce grossly inadequate protocols that severely restrict sufficient understanding of how executions are performed and heighten the likelihood of unconstitutionality. The analysis emphasizes in particular the utter lack of medical or scientific testing of lethal injection despite the early and continuous involvement of doctors but ongoing detachment of medical societies. Lastly, the Article discusses the legal developments that led up to the current rush of lethal injection lawsuits as well as the strong and rapid reverberations that followed, particularly with respect to medical involvement. This Article concludes with two recommendations. First, much like what occurred in this country when the first state switched to electrocution, there should be a nationwide study of proper lethal injection protocols. An independent commission consisting of a diverse group of qualified individuals, including medical personnel, should conduct a thorough assessment of lethal injection, especially the extent of physician participation. Second, this Article recommends that states take their execution procedures out of hiding. Such visibility would increase public scrutiny, thereby enhancing the likelihood of constitutional executions. By clarifying the standards used for determining what is constitutional in Baze v. Rees, the U.S. Supreme Court can then provide the kind of Eighth Amendment guidance states need to conduct humane lethal injections.

Cellular and Physiological Effects of Anthrax Exotoxin and Its Relevance to Disease

PubMed Central

Lowe, David E.; Glomski, Ian J.

2012-01-01

Bacillus anthracis, the causative agent of anthrax, secretes a tri-partite exotoxin that exerts pleiotropic effects on the host. The purification of the exotoxin components, protective antigen, lethal factor, and edema factor allowed the rapid characterization of their physiologic effects on the host. As molecular biology matured, interest focused on the molecular mechanisms and cellular alterations induced by intoxication. Only recently have researchers begun to connect molecular and cellular knowledge back to the broader physiological effects of the exotoxin. This review focuses on the progress that has been made bridging molecular knowledge back to the exotoxin’s physiological effects on the host. PMID:22919667

Epigenetic control of skull morphogenesis by histone deacetylase 8

PubMed Central

Haberland, Michael; Mokalled, Mayssa H.; Montgomery, Rusty L.; Olson, Eric N.

2009-01-01

Histone deacetylases (Hdacs) are transcriptional repressors with crucial roles in mammalian development. Here we provide evidence that Hdac8 specifically controls patterning of the skull by repressing a subset of transcription factors in cranial neural crest cells. Global deletion of Hdac8 in mice leads to perinatal lethality due to skull instability, and this is phenocopied by conditional deletion of Hdac8 in cranial neural crest cells. Hdac8 specifically represses the aberrant expression of homeobox transcription factors such as Otx2 and Lhx1. These findings reveal how the identity and patterning of vertebrate-specific portions of the skull are epigenetically controlled by a histone deacetylase. PMID:19605684

Natural killer cells promote tissue injury and systemic inflammatory responses during fatal Ehrlichia-induced toxic shock-like syndrome.

PubMed

Stevenson, Heather L; Estes, Mark D; Thirumalapura, Nagaraja R; Walker, David H; Ismail, Nahed

2010-08-01

Human monocytotropic ehrlichiosis is caused by Ehrlichia chaffeensis, a Gram-negative bacterium lacking lipopolysaccharide. We have shown that fatal murine ehrlichiosis is associated with CD8(+)T cell-mediated tissue damage, tumor necrosis factor-alpha, and interleukin (IL)-10 overproduction, and CD4(+)Th1 hyporesponsiveness. In this study, we examined the relative contributions of natural killer (NK) and NKT cells in Ehrlichia-induced toxic shock. Lethal ehrlichial infection in wild-type mice induced a decline in NKT cell numbers, and late expansion and migration of activated NK cells to the liver, a main infection site that coincided with development of hepatic injury. The spatial and temporal changes in NK and NKT cells in lethally infected mice correlated with higher NK cell cytotoxic activity, higher expression of cytotoxic molecules such as granzyme B, higher production of interferon-gamma and tumor necrosis factor-alpha, increased hepatic infiltration with CD8alphaCD11c(+) dendritic cells and CD8(+)T cells, decreased splenic CD4(+)T cells, increased serum concentrations of IL-12p40, IL-18, RANTES, and monocyte chemotactic protein-1, and elevated production of IL-18 by liver mononuclear cells compared with nonlethally infected mice. Depletion of NK cells prevented development of severe liver injury, decreased serum levels of interferon-gamma, tumor necrosis factor-alpha, and IL-10, and enhanced bacterial elimination. These data indicate that NK cells promote immunopathology and defective anti-ehrlichial immunity, possibly via decreasing the protective immune response mediated by interferon-gamma producing CD4(+)Th1 and NKT cells.

Gallbladder cancer: review of a rare orphan gastrointestinal cancer with a focus on populations of New Mexico.

PubMed

Nemunaitis, Jacklyn M; Brown-Glabeman, Ursa; Soares, Heloisa; Belmonte, Jessica; Liem, Ben; Nir, Itzhak; Phuoc, Victor; Gullapalli, Rama R

2018-06-18

Gallbladder cancer is a rare malignancy of the biliary tract with a poor prognosis, frequently presenting at an advanced stage. While rare in the United States overall, gallbladder cancer has an elevated incidence in geographically distinct locations of the globe including Chile, North India, Korea, Japan and the state of New Mexico in the United States. People with Native American ancestry have a much elevated incidence of gallbladder cancer compared to Hispanic and non-Hispanic white populations of New Mexico. Gallbladder cancer is also one of the few bi-gendered cancers with an elevated female incidence compared to men. Similar to other gastrointestinal cancers, gallbladder cancer etiology is likely multi-factorial involving a combination of genomic, immunological, and environmental factors. Understanding the interplay of these unique epidemiological factors is crucial in improving the prevention, early detection, and treatment of this lethal disease. Previous studies have failed to identify a distinct genomic mutational profile in gallbladder cancers, however, work to identify promising clinically actionable targets is this form of cancer is ongoing. Examples include, interest in the HER2/Neu signaling pathway and the recognition that chronic inflammation plays a crucial role in gallbladder cancer pathogenesis. In this review, we provide a comprehensive overview of gallbladder cancer epidemiology, risk factors, pathogenesis, and treatment with a specific focus on the rural and Native American populations of New Mexico. We conclude this review by discussing future research directions with the goal of improving clinical outcomes for patients of this lethal malignancy.

The Protective Antigen Component of Anthrax Toxin Forms Functional Octameric Complexes

PubMed Central

Kintzer, Alexander F.; Thoren, Katie L.; Sterling, Harry J.; Dong, Ken C.; Feld, Geoffrey K.; Tang, Iok I.; Zhang, Teri T.; Williams, Evan R.; Berger, James M.; Krantz, Bryan A.

2009-01-01

The assembly of bacterial toxins and virulence factors is critical to their function, but the regulation of assembly during infection has not been studied. We begin to address this question using anthrax toxin as a model. The protective antigen (PA) component of the toxin assembles into ring-shaped homooligomers that bind the two other enzyme components of the toxin, lethal factor (LF) and edema factor (EF), to form toxic complexes. To disrupt the host, these toxic complexes are endocytosed, such that the PA oligomer forms a membrane-spanning channel that LF and EF translocate through to enter the cytosol. We show using single-channel electrophysiology that PA channels contain two populations of conductance states, which correspond with two different PA pre-channel oligomers observed by electron microscopy—the well-described heptamer and a novel octamer. Mass spectrometry demonstrates that the PA octamer binds four LFs, and assembly routes leading to the octamer are populated with even-numbered, dimeric and tetrameric, PA intermediates. Both heptameric and octameric PA complexes can translocate LF and EF with similar rates and efficiencies. Here we also report a 3.2-Å crystal structure of the PA octamer. The octamer comprises ∼20−30% of the oligomers on cells, but outside of the cell, the octamer is more stable than the heptamer under physiological pH. Thus the PA octamer is a physiological, stable, and active assembly state capable of forming lethal toxins that may withstand the hostile conditions encountered in the bloodstream. This assembly mechanism may provide a novel means to control cytotoxicity. PMID:19627991

Subchronic chloroform priming protects mice from a subsequently administered lethal dose of chloroform

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

Philip, Binu K.; Anand, Sathanandam S.; Palkar, Prajakta S.

2006-10-01

Protection offered by pre-exposure priming with a small dose of a toxicant against the toxic and lethal effects of a subsequently administered high dose of the same toxicant is autoprotection. Although autoprotection has been extensively studied with diverse toxicants in acute exposure regimen, not much is known about autoprotection after priming with repeated exposure. The objective of this study was to investigate this concept following repeated exposure to a common water contaminant, chloroform. Swiss Webster (SW) mice, exposed continuously to either vehicle (5% Emulphor, unprimed) or chloroform (150 mg/kg/day po, primed) for 30 days, were challenged with a normally lethalmore » dose of chloroform (750 mg chloroform/kg po) 24 h after the last exposure. As expected, 90% of the unprimed mice died between 48 and 96 h after administration of the lethal dose in contrast to 100% survival of mice primed with chloroform. Time course studies indicated lower hepato- and nephrotoxicity in primed mice as compared to unprimed mice. Hepatic CYP2E1, glutathione levels (GSH), and covalent binding of {sup 14}C-chloroform-derived radiolabel did not differ between livers of unprimed and primed mice after lethal dose exposure, indicating that protection in liver is neither due to decreased bioactivation nor increased detoxification. Kidney GSH and glutathione reductase activity were upregulated, with a concomitant reduction in oxidized glutathione in the primed mice following lethal dose challenge, leading to decreased renal covalent binding of {sup 14}C-chloroform-derived radiolabel, in the absence of any change in CYP2E1 levels. Buthionine sulfoximine (BSO) intervention led to 70% mortality in primed mice challenged with lethal dose. These data suggest that higher detoxification may play a role in the lower initiation of kidney injury observed in primed mice. Exposure of primed mice to a lethal dose of chloroform led to 40% lower chloroform levels (AUC{sub 15-360min}) in the systemic circulation. Exhalation of {sup 14}C-chloroform was unchanged in primed as compared to unprimed mice (AUC{sub 1-6h}). Urinary excretion of {sup 14}C-chloroform was higher in primed mice after administration of the lethal dose. However, neither slightly higher urinary elimination nor unchanged expiration can account for the difference in systemic levels of chloroform. Liver and kidney regeneration was inhibited by the lethal dose in unprimed mice leading to progressive injury, organ failure, and 90% mortality. In contrast, sustained and highly stimulated compensatory hepato- and nephrogenic repair prevented the progression of injury resulting in 100% survival of primed mice challenged with the lethal dose. These findings affirm the critical role of tissue regeneration and favorable detoxification (only in kidney) of the lethal dose of chloroform in subchronic chloroform priming-induced autoprotection.« less

Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet

PubMed Central

Krebs, Philippe; Fan, Weiwei; Chen, Yen-Hui; Tobita, Kimimasa; Downes, Michael R.; Wood, Malcolm R.; Sun, Lei; Xia, Yu; Ding, Ning; Spaeth, Jason M.; Moresco, Eva Marie Y.; Boyer, Thomas G.; Lo, Cecilia Wen Ya; Yen, Jeffrey; Evans, Ronald M.; Beutler, Bruce

2011-01-01

Deficiencies of subunits of the transcriptional regulatory complex Mediator generally result in embryonic lethality, precluding study of its physiological function. Here we describe a missense mutation in Med30 causing progressive cardiomyopathy in homozygous mice that, although viable during lactation, show precipitous lethality 2–3 wk after weaning. Expression profiling reveals pleiotropic changes in transcription of cardiac genes required for oxidative phosphorylation and mitochondrial integrity. Weaning mice to a ketogenic diet extends viability to 8.5 wk. Thus, we establish a mechanistic connection between Mediator and induction of a metabolic program for oxidative phosphorylation and fatty acid oxidation, in which lethal cardiomyopathy is mitigated by dietary intervention. PMID:22106289

Systematic discovery of mutation-specific synthetic lethals by mining pan-cancer human primary tumor data

NASA Astrophysics Data System (ADS)

Sinha, Subarna; Thomas, Daniel; Chan, Steven; Gao, Yang; Brunen, Diede; Torabi, Damoun; Reinisch, Andreas; Hernandez, David; Chan, Andy; Rankin, Erinn B.; Bernards, Rene; Majeti, Ravindra; Dill, David L.

2017-05-01

Two genes are synthetically lethal (SL) when defects in both are lethal to a cell but a single defect is non-lethal. SL partners of cancer mutations are of great interest as pharmacological targets; however, identifying them by cell line-based methods is challenging. Here we develop MiSL (Mining Synthetic Lethals), an algorithm that mines pan-cancer human primary tumour data to identify mutation-specific SL partners for specific cancers. We apply MiSL to 12 different cancers and predict 145,891 SL partners for 3,120 mutations, including known mutation-specific SL partners. Comparisons with functional screens show that MiSL predictions are enriched for SLs in multiple cancers. We extensively validate a SL interaction identified by MiSL between the IDH1 mutation and ACACA in leukaemia using gene targeting and patient-derived xenografts. Furthermore, we apply MiSL to pinpoint genetic biomarkers for drug sensitivity. These results demonstrate that MiSL can accelerate precision oncology by identifying mutation-specific targets and biomarkers.

[Lethal effect after transmutation of 33P incorporated into bacteriophage S 13 and mechanisms of DNA double helix rupture].

PubMed

Apelgot, S

1980-04-01

The experiments show the lethal effect of the beta decay of 33P incorporated in DNA of bacteriophage S 13. The lethal efficiency is high, 0.72 at 0 degrees C and 0.55 at--197 degrees C. The presence of a radical scavenger like AET has no influence. It was found previously that for such phages with single-stranded DNA, the lethal efficiency of 32P decay is unity, and that the lethal event is a DNA single-strand break, owing to the high energy of the nucleogenic 32S atom. As the recoil energy of the 33S atom is too low to account for such a break, it is suggested that the reorganization of the phosphate molecule into sulphate is able to bring about a DNA single-strand break with an efficiency as high as 0.7, at 0 degrees C. A model for the DNA double-strand-break produced by a transmutation processes is suggested.

Variability in mutational fitness effects prevents full lethal transitions in large quasispecies populations

NASA Astrophysics Data System (ADS)

Sardanyés, Josep; Simó, Carles; Martínez, Regina; Solé, Ricard V.; Elena, Santiago F.

2014-04-01

The distribution of mutational fitness effects (DMFE) is crucial to the evolutionary fate of quasispecies. In this article we analyze the effect of the DMFE on the dynamics of a large quasispecies by means of a phenotypic version of the classic Eigen's model that incorporates beneficial, neutral, deleterious, and lethal mutations. By parameterizing the model with available experimental data on the DMFE of Vesicular stomatitis virus (VSV) and Tobacco etch virus (TEV), we found that increasing mutation does not totally push the entire viral quasispecies towards deleterious or lethal regions of the phenotypic sequence space. The probability of finding regions in the parameter space of the general model that results in a quasispecies only composed by lethal phenotypes is extremely small at equilibrium and in transient times. The implications of our findings can be extended to other scenarios, such as lethal mutagenesis or genomically unstable cancer, where increased mutagenesis has been suggested as a potential therapy.

Prediction of Protein-Peptide Interactions: Application of the XPairIT to Anthrax Lethal Factor and Substrates

DTIC Science & Technology

2013-09-01

hydrogen bonds in Tyrosine-containing peptides. Dalkas et al[7] used docking and molecular dynamics simulations to study a variety of MAPKK-based... simulated using NAMD molecular dynamics and the CHARMM[20] forcefield at 300K and employing the Generalized Born Implicit Solvent (GBIS[21]) with the...which were reported in Section 2. Specifically, after a ~10ns molecular dynamics simulation in TIP3 explicit water, significant motion of domains III

A coagulase-negative and non-haemolytic strain of Staphylococcus aureus for investigating the roles of SrtA in a murine model of bloodstream infection.

PubMed

Wang, Lin; Bi, Chongwei; Wang, Tiedong; Xiang, Hua; Chen, Fuguang; Hu, Jinping; Liu, Bingrun; Cai, Hongjun; Zhong, Xiaobo; Deng, Xuming; Wang, Dacheng

2015-08-01

Sortase A (SrtA) is a cysteine transpeptidase and virulence factor from Staphylococcus aureus (S. aureus) that catalyses the attachment and display of surface proteins on the cell wall, thereby mediating bacterial adhesion to host tissues, host-cell entry and evasion of the immune response. As a result, SrtA has become an important target in the development of therapies for S. aureus infections. In this study, we used the new reference strain S. aureus Newman D2C to investigate the role of SrtA in a murine model of bloodstream infection, when the impact of coagulase and haemolysin is excluded. The results suggested that deletion of SrtA reduced the bacterial burden on the heart, liver and kidneys by blunting the host proinflammatory cytokine response at an early point in infection. Kidneys, but not heart or liver, formed abscesses on the sixth day following non-lethal infection, and this effect was diminished by SrtA mutation. These findings indicate that SrtA is a determining virulence factor in lethality and formation of renal abscesses in mice followed by S. aureus bloodstream infection. We have thus established a convenient in vitro and mouse model for developing SrtA-targeted therapeutic strategies. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

From dynamic ocean management to climate-ready management: a case study using blue whales in the northeast Pacific.

NASA Astrophysics Data System (ADS)

Hazen, E. L.

2016-02-01

Highly migratory species regularly traverse human-imposed boundaries including exclusive economic zones and marine protected areas, thus are difficult to manage using traditional spatial approaches. Blue whales (Balaenoptera musculus) are seasonal visitors to the California Current System that target a single prey resource, krill (Euphausia pacifica, Thysanoessa spinifera), and migrate large distances to find and exploit ephemeral prey patches. Successful management of blue whales requires improved understanding of how fine-scale foraging ecology translates to population abundances. Specifically, sub-lethal factors such as anthropogenic noise and climate change, and lethal factors such as ship strikes may be limiting recovery and can be difficult to account for in current management strategies. Here we use an extensive dataset of fine-scale accelerometers (55) and broad-scale satellite tags (104) deployed on Northeast Pacific blue whales to examine the energetics of foraging, overlap with human risk, and projections of future habitat with climate change. We quantify the importance of dense prey patches (> 100 krill per cubic meter) for blue whale energetics and fitness. Distribution models can be used in concert with industry and regional offices to produce dynamic rules to reduce vessel interactions. We propose telemetry data are ripe for use in establishing dynamic management approaches that account for daily to seasonal management areas to minimize anthropogenic risks, and are also adaptable to long-term climate-driven changes in habitat.

From dynamic ocean management to climate-ready management: a case study using blue whales in the northeast Pacific.

NASA Astrophysics Data System (ADS)

Hazen, E. L.

2016-12-01

Highly migratory species regularly traverse human-imposed boundaries including exclusive economic zones and marine protected areas, thus are difficult to manage using traditional spatial approaches. Blue whales (Balaenoptera musculus) are seasonal visitors to the California Current System that target a single prey resource, krill (Euphausia pacifica, Thysanoessa spinifera), and migrate large distances to find and exploit ephemeral prey patches. Successful management of blue whales requires improved understanding of how fine-scale foraging ecology translates to population abundances. Specifically, sub-lethal factors such as anthropogenic noise and climate change, and lethal factors such as ship strikes may be limiting recovery and can be difficult to account for in current management strategies. Here we use an extensive dataset of fine-scale accelerometers (55) and broad-scale satellite tags (104) deployed on Northeast Pacific blue whales to examine the energetics of foraging, overlap with human risk, and projections of future habitat with climate change. We quantify the importance of dense prey patches (> 100 krill per cubic meter) for blue whale energetics and fitness. Distribution models can be used in concert with industry and regional offices to produce dynamic rules to reduce vessel interactions. We propose telemetry data are ripe for use in establishing dynamic management approaches that account for daily to seasonal management areas to minimize anthropogenic risks, and are also adaptable to long-term climate-driven changes in habitat.

Non-lethal control of the cariogenic potential of an agent-based model for dental plaque.

PubMed

Head, David A; Marsh, Phil D; Devine, Deirdre A

2014-01-01

Dental caries or tooth decay is a prevalent global disease whose causative agent is the oral biofilm known as plaque. According to the ecological plaque hypothesis, this biofilm becomes pathogenic when external challenges drive it towards a state with a high proportion of acid-producing bacteria. Determining which factors control biofilm composition is therefore desirable when developing novel clinical treatments to combat caries, but is also challenging due to the system complexity and the existence of multiple bacterial species performing similar functions. Here we employ agent-based mathematical modelling to simulate a biofilm consisting of two competing, distinct types of bacterial populations, each parameterised by their nutrient uptake and aciduricity, periodically subjected to an acid challenge resulting from the metabolism of dietary carbohydrates. It was found that one population was progressively eliminated from the system to give either a benign or a pathogenic biofilm, with a tipping point between these two fates depending on a multiplicity of factors relating to microbial physiology and biofilm geometry. Parameter sensitivity was quantified by individually varying the model parameters against putative experimental measures, suggesting non-lethal interventions that can favourably modulate biofilm composition. We discuss how the same parameter sensitivity data can be used to guide the design of validation experiments, and argue for the benefits of in silico modelling in providing an additional predictive capability upstream from in vitro experiments.

Pathogenesis of listeria-infected Drosophila wntD mutants is associated with elevated levels of the novel immunity gene edin.

PubMed

Gordon, Michael D; Ayres, Janelle S; Schneider, David S; Nusse, Roel

2008-07-25

Drosophila melanogaster mount an effective innate immune response against invading microorganisms, but can eventually succumb to persistent pathogenic infections. Understanding of this pathogenesis is limited, but it appears that host factors, induced by microbes, can have a direct cost to the host organism. Mutations in wntD cause susceptibility to Listeria monocytogenes infection, apparently through the derepression of Toll-Dorsal target genes, some of which are deleterious to survival. Here, we use gene expression profiling to identify genes that may mediate the observed susceptibility of wntD mutants to lethal infection. These genes include the TNF family member eiger and the novel immunity gene edin (elevated during infection; synonym CG32185), both of which are more strongly induced by infection of wntD mutants compared to controls. edin is also expressed more highly during infection of wild-type flies with wild-type Salmonella typhimurium than with a less pathogenic mutant strain, and its expression is regulated in part by the Imd pathway. Furthermore, overexpression of edin can induce age-dependent lethality, while loss of function in edin renders flies more susceptible to Listeria infection. These results are consistent with a model in which the regulation of host factors, including edin, must be tightly controlled to avoid the detrimental consequences of having too much or too little activity.

Introduction of moribund category to OECD fish acute test and its effect on suffering and LC50 values.

PubMed

Rufli, Hans

2012-05-01

It has become common practice in many laboratories in Europe to introduce the criterion "moribund" to reduce the suffering in fish acute lethality tests. Fish with severe sublethal symptoms might be declared moribund and are removed from the test as soon as this occurs (premature discontinuation of experiment). Moribund fish affect main study outcomes as the median lethal concentration (LC50) derived on fish declared as moribund may be lower than the conventional LC50. This was evaluated by a retrospective analysis of 328 fish acute toxicity tests of an industry laboratory based on five different definitions of moribund, and of 111 tests from 10 other laboratories from Europe and the United States. Using the criterion of moribund 10 to 23% of the fish were being declared as moribund in 49 to 79% of the studies. In 36 to 52% of the studies, the LC50(moribund) was lower than the conventional LC50 depending on the definitions of moribund. An inclusion of the moribund criterion in an updated Organisation for Economic Cooperation and Development guideline for the acute fish toxicity test would reduce the period of suffering by up to 92 h, lowering the value of the main toxicity endpoint by a factor of approximately 2, and maximal by a factor of approximately 16. Copyright © 2012 SETAC.

Testicular trauma secondary to less-lethal kinetic energy munitions.

PubMed

Kavoussi, Parviz K; Hermans, Michael R

2006-06-01

Many cases of testicular trauma secondary to munitions have been reported. We report a case of a 37-year-old man who suffered testicular trauma as a result of a less-lethal munition projectile. With the advent, and increased use, of less-lethal munitions by the military and law enforcement agencies, more of these new subsets of genitourinary trauma patients who will require care are sure to result.

Beliefs and attitudes toward lethal management of deer in Cuyahoga Valley National Park

USGS Publications Warehouse

Fulton, D.C.; Skerl, K.; Shank, E.M.; Lime, D.W.

2004-01-01

We used the theory of reasoned action to help understand attitudes and beliefs about lethal management of deer (Odocoileus virginianus) in Cuyahoga Valley National Park (CVNP), Ohio. We used a mail-back survey to collect data from Ohio residents in the surrounding 9-county area. Two strata were defined: residents <10 km from CVNP (near n = 369) and residents =10 km from CVNP (far n = 312). Respondents indicated that lethal control of deer was acceptable (near 71%??4.7%, far 62%??5.5%) and taking no action to reduce deer populations was unacceptable (near 75%??4.5%, far 72%??5.1%). Beliefs about outcomes of lethal control and evaluation of those outcomes proved to be strong predictors of the acceptability of lethal control of deer in CVNP. Lethal control was more acceptable if it was done to prevent severe consequences for humans (e.g., spread of disease, car collisions) or the natural environment (e.g., maintain a healthy deer herd) than to prevent negative aesthetic impacts or personal property damage. Results from the study can be used to assist managers at CVNP as they make decisions regarding alternatives for deer management in the park and to inform others managing abundant deer populations of socially relevant impacts of management actions.

Sub-lethal effects of Vip3A toxin on survival, development and fecundity of Heliothis virescens and Plutella xylostella.

PubMed

Gulzar, Asim; Wright, Denis J

2015-11-01

The assessment of sub-lethal effects is important to interpret the overall insecticide efficacy in controlling insect pest populations. In addition to the lethal effect, sub-lethal effects may also occur in exposed insects. Vegetative insecticidal proteins (Vips) have shown a broad spectrum of insecticidal activity against many insect pest species. In this study the sub-lethal effects of the Bacillus thuringiensis vegetative insecticidal toxin Vip3A on the development and reproduction of Heliothis virescens F. and Plutella xylostella L. were evaluated in the laboratory. The results indicated that the sub-lethal concentration of Vip3A increased the duration of the larval and pupal stages as compared with the control treatment for both species. The percent pupation and percent adult emergence were significantly lower for Vip3A-treated insects. The proportion of pairs that produced eggs and the longevity of adults were not significantly different between treatments. H. virescens and P. xylostella treated with Vip3A showed an 11 and 17 % decrease in their intrinsic rate of increase (rm) respectively compared with untreated insects. The results from this study will be helpful to develop the strategy to incorporate Vip 3A containing crops in an integrated pest management programme.

FOXF1 transcription factor is required for formation of embryonic vasculature by regulating VEGF signaling in endothelial cells.

PubMed

Ren, Xiaomeng; Ustiyan, Vladimir; Pradhan, Arun; Cai, Yuqi; Havrilak, Jamie A; Bolte, Craig S; Shannon, John M; Kalin, Tanya V; Kalinichenko, Vladimir V

2014-09-26

Inactivating mutations in the Forkhead Box transcription factor F1 (FOXF1) gene locus are frequently found in patients with alveolar capillary dysplasia with misalignment of pulmonary veins, a lethal congenital disorder, which is characterized by severe abnormalities in the respiratory, cardiovascular, and gastrointestinal systems. In mice, haploinsufficiency of the Foxf1 gene causes alveolar capillary dysplasia and developmental defects in lung, intestinal, and gall bladder morphogenesis. Although FOXF1 is expressed in multiple mesenchyme-derived cell types, cellular origins and molecular mechanisms of developmental abnormalities in FOXF1-deficient mice and patients with alveolar capillary dysplasia with misalignment of pulmonary veins remain uncharacterized because of lack of mouse models with cell-restricted inactivation of the Foxf1 gene. In the present study, the role of FOXF1 in endothelial cells was examined using a conditional knockout approach. A novel mouse line harboring Foxf1-floxed alleles was generated by homologous recombination. Tie2-Cre and Pdgfb-CreER transgenes were used to delete Foxf1 from endothelial cells. FOXF1-deficient embryos exhibited embryonic lethality, growth retardation, polyhydramnios, cardiac ventricular hypoplasia, and vascular abnormalities in the lung, placenta, yolk sac, and retina. Deletion of FOXF1 from endothelial cells reduced endothelial proliferation, increased apoptosis, inhibited vascular endothelial growth factor signaling, and decreased expression of endothelial genes critical for vascular development, including vascular endothelial growth factor receptors Flt1 and Flk1, Pdgfb, Pecam1, CD34, integrin β3, ephrin B2, Tie2, and the noncoding RNA Fendrr. Chromatin immunoprecipitation assay demonstrated that Flt1, Flk1, Pdgfb, Pecam1, and Tie2 genes are direct transcriptional targets of FOXF1. FOXF1 is required for the formation of embryonic vasculature by regulating endothelial genes critical for vascular development and vascular endothelial growth factor signaling. © 2014 American Heart Association, Inc.

Toll-like receptor 4 knockout protects against anthrax lethal toxin-induced cardiac contractile dysfunction: role of autophagy.

PubMed

Kandadi, Machender R; Frankel, Arthur E; Ren, Jun

2012-10-01

Anthrax lethal toxin (LeTx) is known to induce circulatory shock and death, although the underlying mechanisms have not been elucidated. This study was designed to evaluate the role of toll-like receptor 4 (TLR4) in anthrax lethal toxin-induced cardiac contractile dysfunction. Wild-type (WT) and TLR4 knockout (TLR⁻/⁻) mice were challenged with lethal toxin (2 µg·g⁻¹, i.p.), and cardiac function was assessed 18 h later using echocardiography and edge detection. Small interfering RNA (siRNA) was employed to knockdown TLR4 receptor or class III PI3K in H9C2 myoblasts. GFP-LC3 puncta was used to assess autophagosome formation. Western blot analysis was performed to evaluate autophagy (LC3, Becline-1, Agt5 and Agt7) and endoplasmic reticulum (ER) stress (BiP, eIF2α and calreticulin). In WT mice, lethal toxin exposure induced cardiac contractile dysfunction, as evidenced by reduced fractional shortening, peak shortening, maximal velocity of shortening/re-lengthening, prolonged re-lengthening duration and intracellular Ca²⁺ derangement. These effects were significantly attenuated or absent in the TLR4 knockout mice. In addition, lethal toxin elicited autophagy in the absence of change in ER stress. Knockdown of TLR4 or class III PI3 kinase using siRNA but not the autophagy inhibitor 3-methyladenine significantly attenuated or inhibited lethal toxin-induced autophagy in H9C2 cells. Our results suggest that TLR4 may be pivotal in mediating the lethal cardiac toxicity induced by anthrax possibly through induction of autophagy. These findings suggest that compounds that negatively modulate TLR4 signalling and autophagy could be used to treat anthrax infection-induced cardiovascular complications. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Sub-lethal and lethal toxicities of elevated CO2 on embryonic, juvenile, and adult stages of marine medaka Oryzias melastigma.

PubMed

Lee, Changkeun; Kwon, Bong-Oh; Hong, Seongjin; Noh, Junsung; Lee, Junghyun; Ryu, Jongseong; Kang, Seong-Gil; Khim, Jong Seong

2018-06-06

The potential leakage from marine CO 2 storage sites is of increasing concern, but few studies have evaluated the probable adverse effects on marine organisms. Fish, one of the top predators in marine environments, should be an essential representative species used for water column toxicity testing in response to waterborne CO 2 exposure. In the present study, we conducted fish life cycle toxicity tests to fully elucidate CO 2 toxicity mechanism effects. We tested sub-lethal and lethal toxicities of elevated CO 2 concentrations on marine medaka (Oryzias melastigma) at different developmental stages. At each developmental stage, the test species was exposed to varying concentrations of gaseous CO 2 (control air, 5%, 10%, 20%, and 30%), with 96 h of exposure at 0-4 d (early stage), 4-8 d (middle stage), and 8-12 d (late stage). Sub-lethal and lethal effects, including early developmental delays, cardiac edema, tail abnormalities, abnormal pigmentation, and mortality were monitored daily during the 14 d exposure period. At the embryonic stage, significant sub-lethal and lethal effects were observed at pH < 6.30. Hypercapnia can cause long-term and/or delayed developmental embryonic problems, even after transfer back to clean seawater. At fish juvenile and adult stages, significant mortality was observed at pH < 5.70, indicating elevated CO 2 exposure might cause various adverse effects, even during short-term exposure periods. It should be noted the early embryonic stage was found more sensitive to CO 2 exposure than other developmental stages of the fish life cycle. Overall, the present study provided baseline information for potential adverse effects of high CO 2 concentration exposure on fish developmental processes at different life cycle stages in marine ecosystems. Copyright © 2018 Elsevier Ltd. All rights reserved.

Toll-like receptor 4 knockout protects against anthrax lethal toxin-induced cardiac contractile dysfunction: role of autophagy

PubMed Central

Kandadi, Machender R; Frankel, Arthur E; Ren, Jun

2012-01-01

BACKGROUND AND PURPOSE Anthrax lethal toxin (LeTx) is known to induce circulatory shock and death, although the underlying mechanisms have not been elucidated. This study was designed to evaluate the role of toll-like receptor 4 (TLR4) in anthrax lethal toxin-induced cardiac contractile dysfunction. EXPERIMENTAL APPROACH Wild-type (WT) and TLR4 knockout (TLR−/−) mice were challenged with lethal toxin (2 µg·g−1, i.p.), and cardiac function was assessed 18 h later using echocardiography and edge detection. Small interfering RNA (siRNA) was employed to knockdown TLR4 receptor or class III PI3K in H9C2 myoblasts. GFP–LC3 puncta was used to assess autophagosome formation. Western blot analysis was performed to evaluate autophagy (LC3, Becline-1, Agt5 and Agt7) and endoplasmic reticulum (ER) stress (BiP, eIF2α and calreticulin). KEY RESULTS In WT mice, lethal toxin exposure induced cardiac contractile dysfunction, as evidenced by reduced fractional shortening, peak shortening, maximal velocity of shortening/re-lengthening, prolonged re-lengthening duration and intracellular Ca2+ derangement. These effects were significantly attenuated or absent in the TLR4 knockout mice. In addition, lethal toxin elicited autophagy in the absence of change in ER stress. Knockdown of TLR4 or class III PI3 kinase using siRNA but not the autophagy inhibitor 3-methyladenine significantly attenuated or inhibited lethal toxin-induced autophagy in H9C2 cells. CONCLUSION AND IMPLICATIONS Our results suggest that TLR4 may be pivotal in mediating the lethal cardiac toxicity induced by anthrax possibly through induction of autophagy. These findings suggest that compounds that negatively modulate TLR4 signalling and autophagy could be used to treat anthrax infection-induced cardiovascular complications. PMID:22612289

Theories of Lethal Mutagenesis: From Error Catastrophe to Lethal Defection.

PubMed

Tejero, Héctor; Montero, Francisco; Nuño, Juan Carlos

2016-01-01

RNA viruses get extinct in a process called lethal mutagenesis when subjected to an increase in their mutation rate, for instance, by the action of mutagenic drugs. Several approaches have been proposed to understand this phenomenon. The extinction of RNA viruses by increased mutational pressure was inspired by the concept of the error threshold. The now classic quasispecies model predicts the existence of a limit to the mutation rate beyond which the genetic information of the wild type could not be efficiently transmitted to the next generation. This limit was called the error threshold, and for mutation rates larger than this threshold, the quasispecies was said to enter into error catastrophe. This transition has been assumed to foster the extinction of the whole population. Alternative explanations of lethal mutagenesis have been proposed recently. In the first place, a distinction is made between the error threshold and the extinction threshold, the mutation rate beyond which a population gets extinct. Extinction is explained from the effect the mutation rate has, throughout the mutational load, on the reproductive ability of the whole population. Secondly, lethal defection takes also into account the effect of interactions within mutant spectra, which have been shown to be determinant for the understanding the extinction of RNA virus due to an augmented mutational pressure. Nonetheless, some relevant issues concerning lethal mutagenesis are not completely understood yet, as so survival of the flattest, i.e. the development of resistance to lethal mutagenesis by evolving towards mutationally more robust regions of sequence space, or sublethal mutagenesis, i.e., the increase of the mutation rate below the extinction threshold which may boost the adaptability of RNA virus, increasing their ability to develop resistance to drugs (including mutagens). A better design of antiviral therapies will still require an improvement of our knowledge about lethal mutagenesis.

Killing wolves to prevent predation on livestock may protect one farm but harm neighbors

PubMed Central

Cornman, Ari M.; Treves, Adrian

2018-01-01

Large carnivores, such as gray wolves, Canis lupus, are difficult to protect in mixed-use landscapes because some people perceive them as dangerous and because they sometimes threaten human property and safety. Governments may respond by killing carnivores in an effort to prevent repeated conflicts or threats, although the functional effectiveness of lethal methods has long been questioned. We evaluated two methods of government intervention following independent events of verified wolf predation on domestic animals (depredation) in the Upper Peninsula of Michigan, USA between 1998–2014, at three spatial scales. We evaluated two intervention methods using log-rank tests and conditional Cox recurrent event, gap time models based on retrospective analyses of the following quasi-experimental treatments: (1) selective killing of wolves by trapping near sites of verified depredation, and (2) advice to owners and haphazard use of non-lethal methods without wolf-killing. The government did not randomly assign treatments and used a pseudo-control (no removal of wolves was not a true control), but the federal permission to intervene lethally was granted and rescinded independent of events on the ground. Hazard ratios suggest lethal intervention was associated with an insignificant 27% lower risk of recurrence of events at trapping sites, but offset by an insignificant 22% increase in risk of recurrence at sites up to 5.42 km distant in the same year, compared to the non-lethal treatment. Our results do not support the hypothesis that Michigan’s use of lethal intervention after wolf depredations was effective for reducing the future risk of recurrence in the vicinities of trapping sites. Examining only the sites of intervention is incomplete because neighbors near trapping sites may suffer the recurrence of depredations. We propose two new hypotheses for perceived effectiveness of lethal methods: (a) killing predators may be perceived as effective because of the benefits to a small minority of farmers, and (b) if neighbors experience side-effects of lethal intervention such as displaced depredations, they may perceive the problem growing and then demand more lethal intervention rather than detecting problems spreading from the first trapping site. Ethical wildlife management guided by the “best scientific and commercial data available” would suggest suspending the standard method of trapping wolves in favor of non-lethal methods (livestock guarding dogs or fladry) that have been proven effective in preventing livestock losses in Michigan and elsewhere. PMID:29320512

Conflict Without Casualties: Non-Lethal Weapons in Irregular Warfare

DTIC Science & Technology

2007-09-01

the body,” and the Geneva Protocol of 1925, bans the use of chemical and biological weapons .11 On 8 April 1975, President Ford issued Executive...E Funding – PE 63851M) (accessed 15 December 2006). The American Journal of Bioethics . “Medical Ethics and Non-Lethal Weapons .” Bioethics.net...CASUALTIES: NON-LETHAL WEAPONS IN IRREGULAR WARFARE by Richard L. Scott September 2007 Thesis Advisor: Robert McNab Second Reader

[Comparative results of surgical treatment for perforating and bleeding pyloroduodenal ulcers].

PubMed

Gorbunov, V N; Sytnik, A P; Korenev, N N; Gordeev, S A; Stoliarchuk, E V; Urzhumtseva, G A

1998-01-01

Results of treatment of 1309 patients with perforated and bleeding pyloroduodenal ulcers for 20-years period have been analysed. Resection of the stomach performed in 85 cases resulted in high postoperative lethality which made up in bleeding ulcers 14.8%. Drainage operations of the stomach with excision or suturing of ulcer combined with bilateral truncal vagotomy was performed in 60 patients, postoperative lethality rate being 8.4%. 128 patients underwent selective proximal vagotomy together with pyloro- and duodenoplasty, lethality rate being 1.6%. Combined vagotomy (posterior truncal and anterior sero-muscular) with excision of ulcer, transversal pyloroplasty and duodenoplasty was carried out in 1036 patients (postoperative lethality--2.4%). Excellent and good functional results were achieved in 79.6% of the patients.

Health Risk Evaluations for Ingestion Exposure of Humans to Polonium-210

PubMed Central

Scott, Bobby R.

2007-01-01

The incident in London during November 2006 involving a lethal intake by Mr. Alexander Litvinenko of the highly-radioactive, alpha-particles-emitting polonium-210 (Po-210) isotope, presumably via ingestion, sparked renewed interest in the area of Po-210 toxicity to humans. This paper is the result of assembling and interpreting existing Po-210 data within the context of what is considered a reliable risk model (hazard-function [HF] model) for characterizing the risk of death from deterministic effects of high alpha radiation doses and dose rates to body organs. The HF model was developed to address radiation exposure scenarios involving combined exposures to alpha, beta, and gamma radiations and can be used in circumstances where only one type of radiation is involved. Under a plausible but not yet validated set of assumptions and using available megabecquerel (Po-210) to gray dose-conversion factors, acute lethality risk vs. dose curves were developed for circumstances of ingestion exposure to Po-210 by humans. Initial risk calculations were carried out for a reference adult male human (a hypothetical 70-kg person). Results were then modified for application to all ages (except the in utero child) via the use of systemic Po-210 burden. Because of the unavailability of acute lethality data derived from human ingestions of high levels of Po-210, plausibility of risk calculations were evaluated based on data from studies of Po-210 injections in animals. The animal data, although limited, were found to be consistent with the theoretical risk calculations. Key findings are as follows: (1) ingestion (or inhalation) of a few tents of a milligram of Po-210 will likely be fatal to all exposed persons. (2) Lethal intakes are expected to involve fatal damage to the bone marrow which is likely to be compounded by damage caused by higher doses to other organs including the kidneys and liver. (3) Lethal intakes are expected to cause severe damage to the kidney, spleen, stomach, small and large intestines, lymph nodes, skin, and testes (males) in addition to the fatal damage to bone marrow. (4) The time distribution of deaths is expected to depend on the level of radioactivity ingested or inhaled, with deaths occurring within about a month after very high levels of radioactivity intake (e.g., systemic burdens > 1 MBq/kg-body-mass) and occurring over longer periods, possibly up to or exceeding a year for lower but lethal intakes (systemic burdens from 0.1 to 1.0 MBq/kg-body-mass). Below a systemic burden estimate of 0.02 MBq/kg-body-mass, deaths from deterministic effects are not expected to occur but the risk of cancer and for life shortening could be significant. New, funded experimental and modeling/theoretical research is needed to improve on these estimates. PMID:18648599

Novel Tissue Level Effects of the Staphylococcus aureus Enterotoxin Gene Cluster Are Essential for Infective Endocarditis.

PubMed

Stach, Christopher S; Vu, Bao G; Merriman, Joseph A; Herrera, Alfa; Cahill, Michael P; Schlievert, Patrick M; Salgado-Pabón, Wilmara

2016-01-01

Superantigens are indispensable virulence factors for Staphylococcus aureus in disease causation. Superantigens stimulate massive immune cell activation, leading to toxic shock syndrome (TSS) and contributing to other illnesses. However, superantigens differ in their capacities to induce body-wide effects. For many, their production, at least as tested in vitro, is not high enough to reach the circulation, or the proteins are not efficient in crossing epithelial and endothelial barriers, thus remaining within tissues or localized on mucosal surfaces where they exert only local effects. In this study, we address the role of TSS toxin-1 (TSST-1) and most importantly the enterotoxin gene cluster (egc) in infective endocarditis and sepsis, gaining insights into the body-wide versus local effects of superantigens. We examined S. aureus TSST-1 gene (tstH) and egc deletion strains in the rabbit model of infective endocarditis and sepsis. Importantly, we also assessed the ability of commercial human intravenous immunoglobulin (IVIG) plus vancomycin to alter the course of infective endocarditis and sepsis. TSST-1 contributed to infective endocarditis vegetations and lethal sepsis, while superantigens of the egc, a cluster with uncharacterized functions in S. aureus infections, promoted vegetation formation in infective endocarditis. IVIG plus vancomycin prevented lethality and stroke development in infective endocarditis and sepsis. Our studies support the local tissue effects of egc superantigens for establishment and progression of infective endocarditis providing evidence for their role in life-threatening illnesses. In contrast, TSST-1 contributes to both infective endocarditis and lethal sepsis. IVIG may be a useful adjunct therapy for infective endocarditis and sepsis.

Cardiac fibrillation risk of Taser weapons.

PubMed

Leitgeb, Norbert

2014-06-01

The debate on potential health hazards associated with delivering electric discharges to incapacitated subjects, in particular on whether electric discharge weapons are lethal, less lethal or non-lethal, is still controversial. The cardiac fibrillation risks of Taser weapons X26 and X3 have been investigated by measuring the delivered high-tension pulses in dependence on load impedance. Excitation thresholds and sinus-to-Taser conversion factors have been determined by numerical modeling of endocardial, myocardial, and epicardial cells. Detailed quantitative assessment of cardiac electric exposure has been performed by numerical simulation at the normal-weighted anatomical model NORMAN. The impact of anatomical variation has been quantified at an overweight model (Visible Man), both with a spatial resolution of 2 × 2 × 2 mm voxels. Spacing and location of dart electrodes were systematically varied and the worst-case position determined. Based on volume-weighted cardiac exposure assessment, the fibrillation probability of the worst-case hit was determined to 30% (Taser X26) and 9% (Taser X3). The overall risk assessment of Taser application accounting for realistic spatial hit distributions was derived from training sessions of police officers under realistic scenarios and by accounting for the influence of body (over-)weight as well as gender. The analysis of the results showed that the overall fibrillation risk of Taser use is not negligible. It is higher at Taser X26 than at Taser X3 and amounts to about 1% for Europeans with an about 20% higher risk for Asians. Results demonstrate that enhancement as well as further reduction of fibrillation risk depends on responsible use or abuse of Taser weapons.

A soil bioassay using the nematode Caenorhabditis elegans

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

Freeman, M.N.; Peredney, C.L.; Williams, P.L.

1999-07-01

Caenorhabditis elegans is a free-livings soil nematode that is commonly used as a biological model. Recently, much work has been done using the nematode as a toxicological model as well. Much of the work involving C. elegans has been performed in aquatic media, since it lives in the interstitial water of soil. However, testing in soil would be expected to more accurately reproduce the organism's normal environment and may take into consideration other factors not available in an aquatic test, i.e., toxicant availability effects due to sorption, various chemical interactions, etc. This study used a modification of a previous experimentalmore » protocol to determine 24h LC{sub 50} values for Cu in a Cecil series soil mixture, and examined the use of CuCl{sub 2} as a reference toxicant for soil toxicity testing with C. elegans. Three different methods of determining percent lethality were used, each dependent on how the number of worms missing after the recovery process was used in the lethality calculations. Only tests having {ge}80% worm recovery and {ge}90% control survival were used in determining the LC{sub 50}s, by Probit analysis. The replicate LC{sub 50} values generated a control chart for each method of calculating percent lethality. The coefficient of variation (CV) for each of the three methods was {le}14%. The control charts and the protocol outlined in this study are intended to be used to assess test organism health and monitor precision of future soil toxicity tests with C. elegans.« less

Activated protein C ameliorates Bacillus anthracis lethal toxin-induced lethal pathogenesis in rats

PubMed Central

2012-01-01

Background Lethal toxin (LT) is a major virulence factor of Bacillus anthracis. Sprague Dawley rats manifest pronounced lung edema and shock after LT treatments, resulting in high mortality. The heart failure that is induced by LT has been suggested to be a principal mechanism of lung edema and mortality in rodents. Since LT-induced death occurs more rapidly in rats than in mice, suggesting that other mechanisms in addition to the heart dysfunction may be contributed to the fast progression of LT-induced pathogenesis in rats. Coagulopathy may contribute to circulatory failure and lung injury. However, the effect of LT on coagulation-induced lung dysfunction is unclear. Methods To investigate the involvement of coagulopathy in LT-mediated pathogenesis, the mortality, lung histology and coagulant levels of LT-treated rats were examined. The effects of activated protein C (aPC) on LT-mediated pathogenesis were also evaluated. Results Fibrin depositions were detected in the lungs of LT-treated rats, indicating that coagulation was activated. Increased levels of plasma D-dimer and thrombomodulin, and the ameliorative effect of aPC further suggested that the activation of coagulation-fibrinolysis pathways plays a role in LT-mediated pathogenesis in rats. Reduced mortality was associated with decreased plasma levels of D-dimer and thrombomodulin following aPC treatments in rats with LT-mediated pathogenesis. Conclusions These findings suggest that the activation of coagulation in lung tissue contributes to mortality in LT-mediated pathogenesis in rats. In addition, anticoagulant aPC may help to develop a feasible therapeutic strategy. PMID:23170801

Antibiotics induce redox-related physiological alterations as part of their lethality

PubMed Central

Dwyer, Daniel J.; Belenky, Peter A.; Yang, Jason H.; MacDonald, I. Cody; Martell, Jeffrey D.; Takahashi, Noriko; Chan, Clement T. Y.; Lobritz, Michael A.; Braff, Dana; Schwarz, Eric G.; Ye, Jonathan D.; Pati, Mekhala; Vercruysse, Maarten; Ralifo, Paul S.; Allison, Kyle R.; Khalil, Ahmad S.; Ting, Alice Y.; Walker, Graham C.; Collins, James J.

2014-01-01

Deeper understanding of antibiotic-induced physiological responses is critical to identifying means for enhancing our current antibiotic arsenal. Bactericidal antibiotics with diverse targets have been hypothesized to kill bacteria, in part by inducing production of damaging reactive species. This notion has been supported by many groups but has been challenged recently. Here we robustly test the hypothesis using biochemical, enzymatic, and biophysical assays along with genetic and phenotypic experiments. We first used a novel intracellular H2O2 sensor, together with a chemically diverse panel of fluorescent dyes sensitive to an array of reactive species to demonstrate that antibiotics broadly induce redox stress. Subsequent gene-expression analyses reveal that complex antibiotic-induced oxidative stress responses are distinct from canonical responses generated by supraphysiological levels of H2O2. We next developed a method to quantify cellular respiration dynamically and found that bactericidal antibiotics elevate oxygen consumption, indicating significant alterations to bacterial redox physiology. We further show that overexpression of catalase or DNA mismatch repair enzyme, MutS, and antioxidant pretreatment limit antibiotic lethality, indicating that reactive oxygen species causatively contribute to antibiotic killing. Critically, the killing efficacy of antibiotics was diminished under strict anaerobic conditions but could be enhanced by exposure to molecular oxygen or by the addition of alternative electron acceptors, indicating that environmental factors play a role in killing cells physiologically primed for death. This work provides direct evidence that, downstream of their target-specific interactions, bactericidal antibiotics induce complex redox alterations that contribute to cellular damage and death, thus supporting an evolving, expanded model of antibiotic lethality. PMID:24803433

A Bioprocessed Polysaccharide from Lentinus edodes Mycelia Cultures with Turmeric Protects Chicks from a Lethal Challenge of Salmonella Gallinarum.

PubMed

Han, Dalmuri; Lee, Hyung Tae; Lee, June Bong; Kim, Yongbaek; Lee, Sang Jong; Yoon, Jang Won

2017-02-01

Our previous studies demonstrated that a bioprocessed polysaccharide (BPP) isolated from Lentinus edodes mushroom mycelia cultures supplemented with black rice bran can protect mice against Salmonella lipopolysaccharide-induced endotoxemia and reduce the mortality from Salmonella Typhimurium infection through upregulated T-helper 1 immunity. Here, we report that a BPP from L. edodes mushroom mycelia liquid cultures supplemented with turmeric (referred to as BPP-turmeric) alters chicken macrophage responses against avian-adapted Salmonella Gallinarum and protects chicks against a lethal challenge from Salmonella Gallinarum. In vitro analyses revealed that the water extract of BPP-turmeric (i) changed the protein expression or secretion profile of Salmonella Gallinarum, although it was not bactericidal, (ii) reduced the phagocytic activity of the chicken-derived macrophage cell line HD-11 when infected with Salmonella Gallinarum, and (iii) significantly activated the transcription expression of interleukin (IL)-1β, IL-10, tumor necrosis factor α, and inducible nitric oxide synthase in response to various Salmonella infections, whereas it repressed that of IL-4, IL-6, interferon-β, and interferon-γ. We also found that BPP-turmeric (0.1 g/kg of feed) as a feed additive provided significant protection to 1-day-old chicks infected with a lethal dose of Salmonella Gallinarum. Collectively, these results imply that BPP-turmeric contains biologically active component(s) that protect chicks against Salmonella Gallinarum infection, possibly by regulating macrophage immune responses. Further studies are needed to evaluate the potential efficacy of BPP-turmeric as a livestock feed additive for the preharvest control of fowl typhoid or foodborne salmonellosis.

APOBEC3G-Induced Hypermutation of Human Immunodeficiency Virus Type-1 Is Typically a Discrete “All or Nothing” Phenomenon

PubMed Central

Armitage, Andrew E.; Deforche, Koen; Chang, Chih-hao; Wee, Edmund; Kramer, Beatrice; Welch, John J.; Gerstoft, Jan; Fugger, Lars; McMichael, Andrew; Rambaut, Andrew; Iversen, Astrid K. N.

2012-01-01

The rapid evolution of Human Immunodeficiency Virus (HIV-1) allows studies of ongoing host–pathogen interactions. One key selective host factor is APOBEC3G (hA3G) that can cause extensive and inactivating Guanosine-to-Adenosine (G-to-A) mutation on HIV plus-strand DNA (termed hypermutation). HIV can inhibit this innate anti-viral defense through binding of the viral protein Vif to hA3G, but binding efficiency varies and hypermutation frequencies fluctuate in patients. A pivotal question is whether hA3G-induced G-to-A mutation is always lethal to the virus or if it may occur at sub-lethal frequencies that could increase viral diversification. We show in vitro that limiting-levels of hA3G-activity (i.e. when only a single hA3G-unit is likely to act on HIV) produce hypermutation frequencies similar to those in patients and demonstrate in silico that potentially non-lethal G-to-A mutation rates are ∼10-fold lower than the lowest observed hypermutation levels in vitro and in vivo. Our results suggest that even a single incorporated hA3G-unit is likely to cause extensive and inactivating levels of HIV hypermutation and that hypermutation therefore is typically a discrete “all or nothing” phenomenon. Thus, therapeutic measures that inhibit the interaction between Vif and hA3G will likely not increase virus diversification but expand the fraction of hypermutated proviruses within the infected host. PMID:22457633

An oral HemokineTM, α-methylhydrocinnamate, enhances myeloid and neutrophil recovery following irradiation in vivo.

PubMed

Faller, Douglas V; Castaneda, Serguei A; Zhou, Daohong; Vedamony, Merriline; Newburger, Peter E; White, Gary L; Kosanke, Stanley; Plett, P Artur; Orschell, Christie M; Boosalis, Michael S; Perrine, Susan P

2017-03-01

An oral therapeutic which reduces duration of cytopenias and is active following accidental radiation exposures is an unmet need in radiation countermeasures. Alpha methylhydrocinnamate (ST7) prolongs STAT-5 phosphorylation, reduces growth-factor dependency of multi-lineage cell lines, and stimulates erythropoiesis. Here, ST7 and its isomers were studied for their effects on myeloid progenitors and hematopoietic stem cells (HSCs) following radiation, in nonhuman primates, and murine irradiation models. Addition of ST7 or ST7-S increased CFU-GM production by 1.7-fold (p<0.001), reduced neutrophil apoptosis comparable to G-CSF, and enhanced HSC survival post-radiation by 2-fold, (p=0.028). ST7 and ST7-S administered in normal baboons increased ANC and platelet counts by 50-400%. In sub-lethally-irradiated mice, ANC nadir remained >200/mm 3 and neutropenia recovered in 6days with ST7 treatment and 18days in controls (p<0.05). In lethally-irradiated mice, marrow pathology at 15days was hypocellular (10% cellularity) in controls, but normal (55-75% cellularity) with complete neutrophil maturation with ST7-S treatment. Following lethal irradiation, ST7, given orally for 4days, reduced mortality, with 30% survival in ST7-animals vs 8% in controls, (p<0.05). Collectively, the studies indicate that ST7 and ST7-S enhance myeloid recovery post-radiation and merit further evaluation to accelerate hematologic recovery in conditions of radiation-related and other marrow hypoplasias. Copyright © 2016 Elsevier Inc. All rights reserved.

Beneficial effects of interleukin-6 in neonatal mouse models of group B streptococcal disease.

PubMed Central

Mancuso, G; Tomasello, F; Migliardo, M; Delfino, D; Cochran, J; Cook, J A; Teti, G

1994-01-01

Previous studies have shown that tumor necrosis factor alpha (TNF-alpha) plays a pathophysiologic role in sepsis induced in rat pups by group B streptococci (GBS). In this model, TNF-alpha is also partially responsible for the induction of interleukin-6 (IL-6). The present study was undertaken to investigate the role of IL-6 in neonatal BALB/c mice infected with type III GBS. The effect of anti-IL-6 monoclonal antibodies and recombinant IL-6 on lethality and TNF-alpha production was investigated. In mouse pups infected with GBS strain COH1, plasma IL-6 reached levels of 3,067 +/- 955 and 1,923 +/- 891 U/ml when measured at 22 and 48 h, respectively (P < 0.05 compared with uninfected controls). Pretreatment with 25 micrograms of anti-IL-6 antibodies totally prevented the increase in circulating IL-6 bioactivity at both 22 and 48 h after infection (P < 0.05). Treatment with anti-IL-6 also induced a moderate decrease in survival time of mice infected with lethal doses of strains COH1 and COH31, as evidenced by increased lethality (P < 0.05) at 24 to 48 h but not at 96 h. Mouse recombinant IL-6 (12,500 U) given 6 h before challenge with strains COH1 and COH31 consistently increased survival time, as evidenced by decreased (P < 0.05) lethality at 48 to 72 h but not at 96 h. The effects of IL-6 pretreatment were dose dependent, since no protection was observed with doses lower than 12,500 U. In addition, no effects on lethality were noted when IL-6 was given at the time of challenge or at later times. TNF-alpha elevations (P < 0.05 compared with uninfected controls) were measured at 12, 22, and 48 h after challenge with strain COH1 (68 +/- 28, 233 +/- 98, and 98 +/- 34 U, respectively). Pretreatment with IL-6 significantly (P < 0.05) decreased plasma TNF-alpha levels at 12 and 22 h, with 55 and 69% inhibitions, respectively. Anti-IL-6 had an opposite effect, as evidenced by a 145% increase (P < 0.05) in TNF-alpha levels at 48 h after challenge. Collectively, our data are compatible with the hypothesis that IL-6 is involved in negative feedback regulation of plasma TNF-alpha levels in experimental GBS sepsis. In this model, IL-6 pretreatment can increase survival time. Future studies will be needed to investigate the mechanisms underlying this effect. PMID:7927780

Uncoupling thermotolerance from the induction of heat shock proteins.

PubMed Central

Smith, B J; Yaffe, M P

1991-01-01

Exposure of cells to elevated temperatures causes a rapid increase in the synthesis of heat shock proteins (hsps) and induces thermotolerance, the increased ability of cells to survive exposure to lethal temperatures; however, the connection between hsp induction and the acquisition of thermotolerance is unclear. hsp induction in the yeast Saccharomyces cerevisiae is mediated by the activation of heat-shock transcription factor, and recently we have described a mutation, hsf1-m3, in heat-shock transcription factor that prevents the factor's activation. We now demonstrate that this mutation results in a general block in heat-shock induction but does not affect the acquisition of thermotolerance. Our results indicate that high-level induction of the major hsps is not required for cells to acquire thermotolerance. Images PMID:1763024

Tumor therapy with a urokinase plasminogen activator-activated anthrax lethal toxin alone and in combination with paclitaxel.

PubMed

Wein, Alexander N; Liu, Shihui; Zhang, Yi; McKenzie, Andrew T; Leppla, Stephen H

2013-02-01

PA-U2, an engineered anthrax protective antigen that is activated by urokinase was combined with wildtype lethal factor in the treatment of Colo205 colon adenocarcinoma in vitro and B16-BL6 mouse melanoma in vitro and in vivo. This therapy was also tested in combination with the small molecule paclitaxel, based on prior reports suggesting synergy between ERK1/2 inhibition and chemotherapeutics. Colo205 was sensitive to PA-U2/LF while B16-BL6 was not. For the combination treatment of B16-BL6, paclitaxel showed a dose response in vitro, but cells remained resistant to PA-U2/LF even in the presence of paclitaxel. In vivo, each therapy slowed tumor progression, and an additive effect between the two was observed. Since LF targets tumor vasculature while paclitaxel is an antimitotic, it is possible the agents were acting against different cells in the stroma, precluding a synergistic effect. The engineered anthrax toxin PA-U2/LF warrants further development and testing, possibly in combination with an antiangiogenesis therapy such as sunitinib or sorafinib.

Stage-Dependent Expression of Deltamethrin Toxicity and Resistance in Triatoma infestans (Hemiptera: Reduviidae) From Argentina.

PubMed

Germano, Mónica D; Picollo, María I

2018-02-20

Triatoma infestans Klug (Hemiptera: Reduviidae) is the main vector of Chagas disease in Latin America. This insect has been controlled with pyrethroids since the 1980s, although the emergence of resistance to deltamethrin has decreased control success in some areas of the Gran Chaco ecoregion. The response of T. infestans to deltamethrin was evaluated per developmental stage. In addition, we evaluated the possible stage-dependent expression of deltamethrin resistance. The bioassays were conducted by topical application of the insecticide in acetone. The drop size, age at the time of exposure, and mortality measuring time were standardized per stage. The lethal dose of deltamethrin moderately increased with the developmental stage. The resistance to deltamethrin was expressed in every instar, and was the highest in the fourth- and fifth-instar nymphs. While increasing, weight plays a relevant role in lethal dose stage dependency, a number of contributing factors such as degradative metabolism are probably involved in the variability of insecticide effect and resistance described for different T. infestans developmental stages. Possible explanations for these differences and their implications on resistance management and chemical control are discussed.

Multichannel waveguides for the simultaneous detection of disease biomarkers

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

Mukundan, Harshini; Price, Dominique Z; Grace, Wynne K

2009-01-01

The sensor team at the Los Alamos National Laboratory has developed a waveguide-based optical biosensor that has previously been used for the detection of biomarkers associated with diseases such as tuberculosis, breast cancer, anthrax and influenza in complex biological samples (e.g., serum and urine). However, no single biomarker can accurately predict disease. To address this issue, we developed a multiplex assay for the detection of components of the Bacillus anthracis lethal toxin on single mode planar optical waveguides with tunable quantum dots as the fluorescence reporter. This limited ability to multiplex is still insufficient for accurate detection of disease ormore » for monitoring prognosis. In this manuscript, we demonstrate for the first time, the design, fabrication and successful evaluation of a multichannel planar optical waveguide for the simultaneous detection of at least three unknown samples in quadruplicate. We demonstrate the simultaneous, rapid (30 min), quantitative (with internal standard) and sensitive (limit of detection of 1 pM) detection of protective antigen and lethal factor of Bacillus anthracis in complex biological samples (serum) using specific monoclonal antibodies labeled with quantum dots as the fluorescence reporter.« less

A morphological study of the changes in the ultrastructure of a bacterial biofilm disrupted by an ac corona discharge in air

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

Stepanova, Olga, E-mail: o.m.stepanova@spbu.ru; Astafiev, Alexander; Kudryavtsev, Anatoly

The morphology of bacterial cells and biofilms subjected to a low frequency (∼10{sup 5} Hz) ac (∼10{sup −1} A) corona discharge was investigated using electron microscopy. A low-frequency ac corona discharge in air is shown to have a bactericidal and bacteriostatic effect on Escherichia coli M17 culture at both the cellular and population levels. Corona exposure inhibits the formation of a microbial community and results in the destruction of formed biofilms. This paper presents data on changes in the ultrastructure of cells and biofilms after corona treatment. Our results suggest that the E. coli M17 cells inside biofilms are affectedmore » with results similar to sub-lethal and lethal thermal exposure. Some of the biological aspects of colony and biofilm cells death are evaluated. Morphological changes in the ultrastructure of the biofilms under corona treatment are described. Our results indicate that the heating effect is the main factor responsible for the corona-induced inactivation of bacteria.« less

PDE5 inhibitors enhance the lethality of [pemetrexed + sorafenib

PubMed Central

Booth, Laurence; Roberts, Jane L.; Poklepovic, Andrew; Dent, Paul

2017-01-01

The combination of pemetrexed and sorafenib has significant clinical activity against a wide variety of tumor types in patients and the present studies were performed to determine whether sildenafil enhances the killing potential of [pemetrexed + sorafenib]. In multiple genetically diverse lung cancer cell lines, sildenafil enhanced the lethality of [pemetrexed + sorafenib]. The three-drug combination reduced the activities of AKT, mTOR and STAT transcription factors; increased the activities of eIF2α and ULK-1; lowered the expression of MCL-1, BCL-XL, thioredoxin and SOD2; and increased the expression of Beclin1. Enhanced cell killing by sildenafil was blocked by inhibition of death receptor signaling and autophagosome formation. Enforced activation of STAT3 and AKT or inhibition of JNK significantly reduced cell killing. The enhanced cell killing caused by sildenafil was more reliant on increased PKG signaling than on the generation of nitric oxide. In vivo sildenafil enhanced the anti-tumor properties of [pemetrexed + sorafenib]. Based on our data we argue that additional clinical studies combining pemetrexed, sorafenib and sildenafil are warranted. PMID:28088782

E2F function in muscle growth is necessary and sufficient for viability in Drosophila

PubMed Central

Zappia, Maria Paula; Frolov, Maxim V.

2016-01-01

The E2F transcription factor is a key cell cycle regulator. However, the inactivation of the entire E2F family in Drosophila is permissive throughout most of animal development until pupation when lethality occurs. Here we show that E2F function in the adult skeletal muscle is essential for animal viability since providing E2F function in muscles rescues the lethality of the whole-body E2F-deficient animals. Muscle-specific loss of E2F results in a significant reduction in muscle mass and thinner myofibrils. We demonstrate that E2F is dispensable for proliferation of muscle progenitor cells, but is required during late myogenesis to directly control the expression of a set of muscle-specific genes. Interestingly, E2f1 provides a major contribution to the regulation of myogenic function, while E2f2 appears to be less important. These findings identify a key function of E2F in skeletal muscle required for animal viability, and illustrate how the cell cycle regulator is repurposed in post-mitotic cells. PMID:26823289

Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies

PubMed Central

Steckel, Michael; Molina-Arcas, Miriam; Weigelt, Britta; Marani, Michaela; Warne, Patricia H; Kuznetsov, Hanna; Kelly, Gavin; Saunders, Becky; Howell, Michael; Downward, Julian; Hancock, David C

2012-01-01

Oncogenic mutations in RAS genes are very common in human cancer, resulting in cells with well-characterized selective advantages, but also less well-understood vulnerabilities. We have carried out a large-scale loss-of-function screen to identify genes that are required by KRAS-transformed colon cancer cells, but not by derivatives lacking this oncogene. Top-scoring genes were then tested in a larger panel of KRAS mutant and wild-type cancer cells. Cancer cells expressing oncogenic KRAS were found to be highly dependent on the transcription factor GATA2 and the DNA replication initiation regulator CDC6. Extending this analysis using a collection of drugs with known targets, we found that cancer cells with mutant KRAS showed selective addiction to proteasome function, as well as synthetic lethality with topoisomerase inhibition. Combination targeting of these functions caused improved killing of KRAS mutant cells relative to wild-type cells. These observations suggest novel targets and new ways of combining existing therapies for optimal effect in RAS mutant cancers, which are traditionally seen as being highly refractory to therapy. PMID:22613949

TGF-β Tumor Suppression through a Lethal EMT.

PubMed

David, Charles J; Huang, Yun-Han; Chen, Mo; Su, Jie; Zou, Yilong; Bardeesy, Nabeel; Iacobuzio-Donahue, Christine A; Massagué, Joan

2016-02-25

TGF-β signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-β mediator Smad4. We show that TGF-β induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-β-sensitive PDA cells, EMT becomes lethal by converting TGF-β-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-β. TGF-β-induced Sox4 is thus geared to bolster progenitor identity, whereas simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-β tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network. Copyright © 2016 Elsevier Inc. All rights reserved.

TGF-β Tumor Suppression Through A Lethal EMT

PubMed Central

David, Charles J.; Huang, Yun-Han; Chen, Mo; Su, Jie; Zou, Yilong; Bardeesy, Nabeel; Iacobuzio-Donahue, Christine A.; Massagué, Joan

2016-01-01

TGF-β signaling can be pro-tumorigenic or tumor suppressive. We investigated this duality in pancreatic ductal adenocarcinoma (PDA), which, with other gastrointestinal cancers, exhibits frequent inactivation of the TGF-β mediator Smad4. We show that TGF-β induces an epithelial-mesenchymal transition (EMT), generally considered a pro-tumorigenic event. However, in TGF-β sensitive PDA cells, EMT becomes lethal by converting TGF-β-induced Sox4 from an enforcer of tumorigenesis into a promoter of apoptosis. This is the result of an EMT-linked remodeling of the cellular transcription factor landscape, including the repression of the gastrointestinal lineage-master regulator Klf5. Klf5 cooperates with Sox4 in oncogenesis and prevents Sox4-induced apoptosis. Smad4 is required for EMT but dispensable for Sox4 induction by TGF-β. TGF-β-induced Sox4 is thus geared to bolster progenitor identity, while simultaneous Smad4-dependent EMT strips Sox4 of an essential partner in oncogenesis. Our work demonstrates that TGF-β tumor suppression functions through an EMT-mediated disruption of a lineage-specific transcriptional network. PMID:26898331

Anthrax Toxin-Expressing Bacillus cereus Isolated from an Anthrax-Like Eschar.

PubMed

Marston, Chung K; Ibrahim, Hisham; Lee, Philip; Churchwell, George; Gumke, Megan; Stanek, Danielle; Gee, Jay E; Boyer, Anne E; Gallegos-Candela, Maribel; Barr, John R; Li, Han; Boulay, Darbi; Cronin, Li; Quinn, Conrad P; Hoffmaster, Alex R

2016-01-01

Bacillus cereus isolates have been described harboring Bacillus anthracis toxin genes, most notably B. cereus G9241, and capable of causing severe and fatal pneumonias. This report describes the characterization of a B. cereus isolate, BcFL2013, associated with a naturally occurring cutaneous lesion resembling an anthrax eschar. Similar to G9241, BcFL2013 is positive for the B. anthracis pXO1 toxin genes, has a multi-locus sequence type of 78, and a pagA sequence type of 9. Whole genome sequencing confirms the similarity to G9241. In addition to the chromosome having an average nucleotide identity of 99.98% when compared to G9241, BcFL2013 harbors three plasmids with varying homology to the G9241 plasmids (pBCXO1, pBC210 and pBFH_1). This is also the first report to include serologic testing of patient specimens associated with this type of B. cereus infection which resulted in the detection of anthrax lethal factor toxemia, a quantifiable serum antibody response to protective antigen (PA), and lethal toxin neutralization activity.

Effects of a long-acting mutant bacterial cocaine esterase on acute cocaine toxicity in rats

PubMed Central

Collins, Gregory T.; Zaks, Matthew E.; Cunningham, Alyssa R.; St. Clair, Carley; Nichols, Joseph; Narasimhan, Diwahar; Ko, Mei-Chuan; Sunahara, Roger K.; Woods, James H.

2011-01-01

Background A longer acting, double mutant bacterial cocaine esterase (CocE T172R/G173Q; DM CocE) has been shown to protect mice from cocaine-induced lethality, inhibit the reinforcing effects of cocaine in rats, and reverse cocaine’s cardiovascular effects in rhesus monkeys. The current studies evaluated the effectiveness of DM CocE to protect against, and reverse cocaine’s cardiovascular, convulsant, and lethal effects in male and female rats. Methods Pretreatment studies were used to determine the effectiveness and in vivo duration of action for DM CocE to protect rats against the occurrence of cardiovascular changes, convulsion and lethality associated with acute cocaine toxicity. Posttreatment studies were used to evaluate the capacity of DM CocE to rescue rats from the cardiovascular and lethal effects of large doses of cocaine. In addition, male and female rats were studied to determine if there were any potential effects of sex on the capacity of DM CocE to protect against, or reverse acute cocaine toxicity in rats. Results Pretreatment with DM CocE dose-dependently protected rats against cocaine-induced cardiovascular changes, convulsion and lethality, with higher doses active for up to 4 hrs, and shifting cocaine-induced lethality at least 10-fold to the right. In addition to dose-dependently recovering rats from an otherwise lethal dose of cocaine, post-treatment with DM CocE also reversed the cardiovascular effects of cocaine. There were no sex-related differences in the effectiveness of DM CocE to protect against, or reverse acute cocaine toxicity. Conclusions Together, these results support the development of DM CocE for the treatment of acute cocaine toxicity. PMID:21481548

Inactivation of CDK2 is synthetically lethal to MYCN over-expressing cancer cells

PubMed Central

Molenaar, Jan J.; Ebus, Marli E.; Geerts, Dirk; Koster, Jan; Lamers, Fieke; Valentijn, Linda J.; Westerhout, Ellen M.; Versteeg, Rogier; Caron, Huib N.

2009-01-01

Two genes have a synthetically lethal relationship when the silencing or inhibiting of 1 gene is only lethal in the context of a mutation or activation of the second gene. This situation offers an attractive therapeutic strategy, as inhibition of such a gene will only trigger cell death in tumor cells with an activated second oncogene but spare normal cells without activation of the second oncogene. Here we present evidence that CDK2 is synthetically lethal to neuroblastoma cells with MYCN amplification and over-expression. Neuroblastomas are childhood tumors with an often lethal outcome. Twenty percent of the tumors have MYCN amplification, and these tumors are ultimately refractory to any therapy. Targeted silencing of CDK2 by 3 RNA interference techniques induced apoptosis in MYCN-amplified neuroblastoma cell lines, but not in MYCN single copy cells. Silencing of MYCN abrogated this apoptotic response in MYCN-amplified cells. Inversely, silencing of CDK2 in MYCN single copy cells did not trigger apoptosis, unless a MYCN transgene was activated. The MYCN induced apoptosis after CDK2 silencing was accompanied by nuclear stabilization of P53, and mRNA profiling showed up-regulation of P53 target genes. Silencing of P53 rescued the cells from MYCN-driven apoptosis. The synthetic lethality of CDK2 silencing in MYCN activated neuroblastoma cells can also be triggered by inhibition of CDK2 with a small molecule drug. Treatment of neuroblastoma cells with roscovitine, a CDK inhibitor, at clinically achievable concentrations induced MYCN-dependent apoptosis. The synthetically lethal relationship between CDK2 and MYCN indicates CDK2 inhibitors as potential MYCN-selective cancer therapeutics. PMID:19525400

Calcium-Sensing Receptor Tumor Expression and Lethal Prostate Cancer Progression.

PubMed

Ahearn, Thomas U; Tchrakian, Nairi; Wilson, Kathryn M; Lis, Rosina; Nuttall, Elizabeth; Sesso, Howard D; Loda, Massimo; Giovannucci, Edward; Mucci, Lorelei A; Finn, Stephen; Shui, Irene M

2016-06-01

Prostate cancer metastases preferentially target bone, and the calcium-sensing receptor (CaSR) may play a role in promoting this metastatic progression. We evaluated the association of prostate tumor CaSR expression with lethal prostate cancer. A validated CaSR immunohistochemistry assay was performed on tumor tissue microarrays. Vitamin D receptor (VDR) expression and phosphatase and tensin homolog tumor status were previously assessed in a subset of cases by immunohistochemistry. Cox proportional hazards models adjusting for age and body mass index at diagnosis, Gleason grade, and pathological tumor node metastasis stage were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of CaSR expression with lethal prostate cancer. The investigation was conducted in the Health Professionals Follow-up Study and Physicians' Health Study. We studied 1241 incident prostate cancer cases diagnosed between 1983 and 2009. Participants were followed up or cancer-specific mortality or development of metastatic disease. On average, men were followed up 13.6 years, during which there were 83 lethal events. High CaSR expression was associated with lethal prostate cancer independent of clinical and pathological variables (HR 2.0; 95% CI 1.2-3.3). Additionally, there was evidence of effect modification by VDR expression; CaSR was associated with lethal progression among men with low tumor VDR expression (HR 3.2; 95% CI 1.4-7.3) but not in cases with high tumor VDR expression (HR 0.8; 95% CI 0.2-3.0). Tumor CaSR expression is associated with an increased risk of lethal prostate cancer, particularly in tumors with low VDR expression. These results support further investigating the mechanism linking CaSR with metastases.

Prediagnostic circulating sex hormones are not associated with mortality for men with prostate cancer.

PubMed

Gershman, Boris; Shui, Irene M; Stampfer, Meir; Platz, Elizabeth A; Gann, Peter H; Sesso, Howard L; DuPre, Natalie; Giovannucci, Edward; Mucci, Lorelei A

2014-04-01

Sex hormones play an important role in the growth and development of the prostate, and low androgen levels have been suggested to carry an adverse prognosis for men with prostate cancer (PCa). To examine the association between prediagnostic circulating sex hormones and lethal PCa in two prospective cohort studies, the Physicians' Health Study (PHS) and the Health Professionals Follow-up Study (HPFS). We included 963 PCa cases (700 HPFS; 263 PHS) that provided prediagnostic blood samples, in 1982 for PHS and in 1993-1995 for HPFS, in which circulating sex hormone levels were assayed. The primary end point was lethal PCa (defined as cancer-specific mortality or development of metastases), and we also assessed total mortality through March 2011. We used Cox proportional hazards models to evaluate the association of prediagnostic sex hormone levels with time from diagnosis to development of lethal PCa or total mortality. PCa cases were followed for a mean of 12.0±4.9 yr after diagnosis. We confirmed 148 cases of lethal PCa and 421 deaths overall. Using Cox proportional hazard models, we found no significant association between quartile of total testosterone, sex hormone binding globulin (SHBG), SHBG-adjusted testosterone, free testosterone, dihydrotestosterone, androstanediol glucuronide, or estradiol and lethal PCa or total mortality. In subset analyses stratified by Gleason score, TNM stage, age, and interval between blood draw and diagnosis, there was also no consistent association between lethal PCa and sex hormone quartile. We found no overall association between prediagnostic circulating sex hormones and lethal PCa or total mortality. Our null results suggest that reverse causation may be responsible in prior studies that noted adverse outcomes for men with low circulating androgens. Copyright © 2013 European Association of Urology. Published by Elsevier B.V. All rights reserved.

A self-harm series and its relationship with childhood adversity among adolescents in mainland China: a cross-sectional study.

PubMed

Han, Azhu; Wang, Gengfu; Xu, Geng; Su, Puyu

2018-02-01

Self-harm (SH) is an emerging problem among Chinese adolescents. The present study aimed to measure the prevalence of SH behaviours and to explore the relationship between childhood adversity and different SH subtypes among Chinese adolescents. A total of 5726 middle school students were randomly selected in three cities of Anhui province, China, using a stratified cluster sampling method. SH was categorized into five subtypes (highly lethal self-harm, less lethal self-harm with visible tissue damage, self-harm without visible tissue damage, self-harmful behaviours with latency damage and psychological self-harm). Multivariate logistic regression was used to explore the relationships between childhood adversity and different subtypes of adolescent SH. The prevalence rates of highly lethal self-harm, less lethal self-harm with visible tissue damage, self-harm without visible tissue damage, self-harmful behaviours with latency damage and psychological self-harm were 6.1, 20.4, 32.0, 20.0 and 23.0%, respectively. Childhood sexual abuse and physical peer victimization were associated with each SH subtype with adjusted odds ratios (AORs) ranging from 1.23 to 1.76. Highly lethal self-harm was associated with childhood physical peer victimization, sexual abuse, emotional abuse, and emotional neglect. The less lethal SH subtypes (i.e., less lethal self-harm with visible tissue damage, self-harm without visible tissue damage, self-harmful behaviours with latency damage and psychological self-harm) were associated with childhood peer victimization, family life stress event scores and childhood sexual abuse. A high prevalence of SH exists among Chinese adolescents. The association of childhood adversity with SH merits serious attention in both future research and preventive interventions.

Asthma and risk of lethal prostate cancer in the Health Professionals Follow-Up Study.

PubMed

Platz, Elizabeth A; Drake, Charles G; Wilson, Kathryn M; Sutcliffe, Siobhan; Kenfield, Stacey A; Mucci, Lorelei A; Stampfer, Meir J; Willett, Walter C; Camargo, Carlos A; Giovannucci, Edward

2015-08-15

Inflammation, and more generally, the immune response are thought to influence the development of prostate cancer. To determine the components of the immune response that are potentially contributory, we prospectively evaluated the association of immune-mediated conditions, asthma and hayfever, with lethal prostate cancer risk in the Health Professionals Follow-up Study. We included 47,880 men aged 40-75 years with no prior cancer diagnosis. On the baseline questionnaire in 1986, the men reported diagnoses of asthma and hayfever and year of onset. On the follow-up questionnaires, they reported new asthma and prostate cancer diagnoses. We used Cox proportional hazards regression to estimate relative risks (RRs). In total, 9.2% reported ever having been diagnosed with asthma. In all, 25.3% reported a hayfever diagnosis at baseline. During 995,176 person-years of follow-up by 2012, we confirmed 798 lethal prostate cancer cases (diagnosed with distant metastases, progressed to distant metastasis or died of prostate cancer [N = 625]). Ever having a diagnosis of asthma was inversely associated with risk of lethal (RR = 0.71, 95% confidence interval [CI] = 0.51-1.00) and fatal (RR = 0.64, 95% CI = 0.42-0.96) disease. Hayfever with onset in the distant past was possibly weakly positively associated with risk of lethal (RR = 1.10, 95% CI = 0.92-1.33) and fatal (RR = 1.12, 95% CI = 0.91-1.37) disease. Men who were ever diagnosed with asthma were less likely to develop lethal and fatal prostate cancer. Our findings may lead to testable hypotheses about specific immune profiles in the etiology of lethal prostate cancer. © 2015 UICC.

Comparison of injuries due to lethal weapons during and after civil strife in Sri Lanka: A medico-legal study.

PubMed

Vidanapathirana, Muditha; Ruwanpura, Rohan P; Amararatne, Sriyantha Rrg; Ratnaweera, Ajith Rhi

2016-01-01

"Injuries due to lethal weapons" has emerged as a subject of public discussion in Sri Lanka. This study was conducted to describe the nature and characteristics of injuries due to lethal weapons during civil strife and to compare those with injuries after civil strife. A cross-sectional study was conducted on patients reported with injuries caused by lethal weapons from 2004 to 2014. Periods before and after May 19, 2009 were considered as during and after civil strife periods, respectively. A total of 21,210 medico-legal examination forms were studied. There were 358 (1.7%) injuries caused by lethal weapons. Of them, 41% (n = 148) were during and 59% (n = 210) were after the civil strife. During civil strife, 63% occurred during daytime (P < 0.05). Types of lethal weapons that caused injuries were sharp weapons (n = 282), explosives (n = 49), and firearms (n = 27). Of them, 32% of during and 01% of after civil strife were explosive injuries (P < 0.01). Regarding severity, 73% of during and 57% of after civil strife injuries were severe (P < 0.05). During civil strife, 34% injuries were in lower limbs (P < 0.01) and after civil strife, 37% were in upper limbs (P < 0.05). The presence of many similarities indicated that both groups learnt their basis in a society that breeds violence. During civil strife, more injuries occurred during daytime, to lower limbs by explosive weapons and after the civil strife during nighttime, to upper limbs by nonexplosive weapons. Nonexplosive lethal weapon use after civil strife needs further investigation to develop evidence-based interventions.

Comparison of injuries due to lethal weapons during and after civil strife in Sri Lanka: A medico-legal study

PubMed Central

Vidanapathirana, Muditha; Ruwanpura, Rohan P; Amararatne, Sriyantha RRG; Ratnaweera, Ajith RHI

2016-01-01

Background and Aims: “Injuries due to lethal weapons” has emerged as a subject of public discussion in Sri Lanka. This study was conducted to describe the nature and characteristics of injuries due to lethal weapons during civil strife and to compare those with injuries after civil strife. Methods: A cross-sectional study was conducted on patients reported with injuries caused by lethal weapons from 2004 to 2014. Periods before and after May 19, 2009 were considered as during and after civil strife periods, respectively. A total of 21,210 medico-legal examination forms were studied. Results: There were 358 (1.7%) injuries caused by lethal weapons. Of them, 41% (n = 148) were during and 59% (n = 210) were after the civil strife. During civil strife, 63% occurred during daytime (P < 0.05). Types of lethal weapons that caused injuries were sharp weapons (n = 282), explosives (n = 49), and firearms (n = 27). Of them, 32% of during and 01% of after civil strife were explosive injuries (P < 0.01). Regarding severity, 73% of during and 57% of after civil strife injuries were severe (P < 0.05). During civil strife, 34% injuries were in lower limbs (P < 0.01) and after civil strife, 37% were in upper limbs (P < 0.05). Conclusions: The presence of many similarities indicated that both groups learnt their basis in a society that breeds violence. During civil strife, more injuries occurred during daytime, to lower limbs by explosive weapons and after the civil strife during nighttime, to upper limbs by nonexplosive weapons. Nonexplosive lethal weapon use after civil strife needs further investigation to develop evidence-based interventions. PMID:27127743

Altered cytoskeletal organization characterized lethal but not surviving Brtl+/− mice: insight on phenotypic variability in osteogenesis imperfecta

PubMed Central

Bianchi, Laura; Gagliardi, Assunta; Maruelli, Silvia; Besio, Roberta; Landi, Claudia; Gioia, Roberta; Kozloff, Kenneth M.; Khoury, Basma M.; Coucke, Paul J.; Symoens, Sofie; Marini, Joan C.; Rossi, Antonio; Bini, Luca; Forlino, Antonella

2015-01-01

Osteogenesis imperfecta (OI) is a heritable bone disease with dominant and recessive transmission. It is characterized by a wide spectrum of clinical outcomes ranging from very mild to lethal in the perinatal period. The intra- and inter-familiar OI phenotypic variability in the presence of an identical molecular defect is still puzzling to the research field. We used the OI murine model Brtl+/− to investigate the molecular basis of OI phenotypic variability. Brtl+/− resembles classical dominant OI and shows either a moderately severe or a lethal outcome associated with the same Gly349Cys substitution in the α1 chain of type I collagen. A systems biology approach was used. We took advantage of proteomic pathway analysis to functionally link proteins differentially expressed in bone and skin of Brtl+/− mice with different outcomes to define possible phenotype modulators. The skin/bone and bone/skin hybrid networks highlighted three focal proteins: vimentin, stathmin and cofilin-1, belonging to or involved in cytoskeletal organization. Abnormal cytoskeleton was indeed demonstrated by immunohistochemistry to occur only in tissues from Brtl+/− lethal mice. The aberrant cytoskeleton affected osteoblast proliferation, collagen deposition, integrin and TGF-β signaling with impairment of bone structural properties. Finally, aberrant cytoskeletal assembly was detected in fibroblasts obtained from lethal, but not from non-lethal, OI patients carrying an identical glycine substitution. Our data demonstrated that compromised cytoskeletal assembly impaired both cell signaling and cellular trafficking in mutant lethal mice, altering bone properties. These results point to the cytoskeleton as a phenotypic modulator and potential novel target for OI treatment. PMID:26264579

Lethal Injection for Execution: Chemical Asphyxiation?

PubMed Central

Zimmers, Teresa A; Sheldon, Jonathan; Lubarsky, David A; López-Muñoz, Francisco; Waterman, Linda; Weisman, Richard; Koniaris, Leonidas G

2007-01-01

Background Lethal injection for execution was conceived as a comparatively humane alternative to electrocution or cyanide gas. The current protocols are based on one improvised by a medical examiner and an anesthesiologist in Oklahoma and are practiced on an ad hoc basis at the discretion of prison personnel. Each drug used, the ultrashort-acting barbiturate thiopental, the neuromuscular blocker pancuronium bromide, and the electrolyte potassium chloride, was expected to be lethal alone, while the combination was intended to produce anesthesia then death due to respiratory and cardiac arrest. We sought to determine whether the current drug regimen results in death in the manner intended. Methods and Findings We analyzed data from two US states that release information on executions, North Carolina and California, as well as the published clinical, laboratory, and veterinary animal experience. Execution outcomes from North Carolina and California together with interspecies dosage scaling of thiopental effects suggest that in the current practice of lethal injection, thiopental might not be fatal and might be insufficient to induce surgical anesthesia for the duration of the execution. Furthermore, evidence from North Carolina, California, and Virginia indicates that potassium chloride in lethal injection does not reliably induce cardiac arrest. Conclusions We were able to analyze only a limited number of executions. However, our findings suggest that current lethal injection protocols may not reliably effect death through the mechanisms intended, indicating a failure of design and implementation. If thiopental and potassium chloride fail to cause anesthesia and cardiac arrest, potentially aware inmates could die through pancuronium-induced asphyxiation. Thus the conventional view of lethal injection leading to an invariably peaceful and painless death is questionable. PMID:17455994

Acute Toxicity and Efficacy of Current Medical Countermeasures against VM in Guinea Pigs: A Comparison to VX and VR

DTIC Science & Technology

2013-05-01

and diazepam with and without pretreatment with pyridostigmine bromide . The 24 hr median lethal dose (MLD) of VM was determined using a sequential... pyridostigmine bromide . The 24 hr median lethal dose (MLD) of VM was determined using a sequential stage approach. The efficacy of medical...with and without pyridostigmine bromide (PB) pretreatment against lethal intoxication with VM, VR or VX. Methods Animals: Adult male Hartley

Non-Lethal Technologies for the Objective Force

DTIC Science & Technology

2001-06-20

Cartridge (Sponge Grenade) 12 Gauge Non-Lethal Munitions XM1012, XM1013 5.56mm XM95 Rifle Launched Non-Lethal Munition Army Soldier Enhancement...Applications, effective 12 Sep 00. • USAMPS will serve as the U.S. Army Training and Doctrine Command’s single voice for all developments and initiatives to...1996 DoD NLW User’s Conference; Joint Concept for NLW’s & Per JMAA Jan 2000 - Joint Mission Area Analysis (JMAA) - 07/11/2001 12 Area Denial-Personnel

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

Hedrick, P.W.

A number of studies indicates that there is a high sharing of HLA antigens in couples having recurrent spontaneous abortions. The genetic hypothesis to explain this phenomenon suggests that this fetal loss results from homozygosity of recessive lethal or deleterius alleles in gametic disequilibrium with HLA antigens. Theory predicting the lethality rate is derived when antigens are shared at one, two or three loci, given the disequilibrium is absolute. In addition, the effects of partial disequilibrium, inbreeding, and segregation distortion on the lethal proportion are examined.

Toxicity of thermal degradation products of spacecraft materials

NASA Technical Reports Server (NTRS)

Lawrence, W. H.; Turner, J. E.; Sanford, C.; Foster, S.; Baldwin, E.; Oconnor, J.

1982-01-01

Three polymeric materials were evaluated for relative toxicity of their pyrolysis products to rats by inhalation: Y-7683 (LS 200), Y-7684 (Vonar 3 on Fiberglass), and Y-7685 (Vonar 3 on N W Polyester). Criteria employed for assessing relative toxicity were (1) lethality from in-chamber pyrolysis, (2) lethality from an outside-of-chamber pyrolysis MSTL Procedure, and (3) disruption of trained rats' shock-avoidance performance during sub-lethal exposures to in-chamber pyrolysis of the materials.

Effect of Drugs on the Lethality in Mice of the Venoms and Neurotoxins from Sundry Snakes

DTIC Science & Technology

1990-07-10

nicergoline , primaquine, verapamil, and vesamicol protected mice from the lethality6_)f B. caeruleus venom, B. multicinctus venom, r " and/or’l...the venom or toxin was recorded 24 hr later. Diltia.-em. nicergoline . primaquine, verapamil. and vesamicol protected mice from the lethality of B...hydrochloride were purchased from Sigma Chemical Co., St. Louis, MO, U.S.A. Nicergoline (10-methoxy-1,6-dimethylergoline-8-r-methanol 5

A Systems Biology Approach to Link Nuclear Factor Kappa B Activation with Lethal Prostate Cancer

DTIC Science & Technology

2012-05-01

findings contained in this report are those of the author( s ) and should not be construed as an official Department of the Army position, policy or...collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. 1. REPORT...ELEMENT NUMBER 6. AUTHOR( S ) 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME( S ) AND ADDRESS(ES

Transcriptional Profiling of Human Peripheral Blood Mononuclear Cells Exposed to Bacillus anthracis in vitro

DTIC Science & Technology

2013-03-11

are derived from the combination of three polypeptides, namely the Protective antigen (PA, 83 kDa), the edema factor (EF, 89 kDa), and the lethal...p38MAPK-dependent pathways. The T-cell receptors and CD3-mediated antigenic recognition processes are possibly restrained, and the expression of CD79...NY), using a VersArray microarrayer ( Bio -Rad, CA). Arrays were post- processed using UV-cross linking at 1200 mJ/cm2, followed by baking for 4 hrs

[Spontaneous and induced sterility by ethyl methanesulfonate (EMS) in Nigella damascena L].

PubMed

Gilot-Delhalle, J

1976-01-01

EMS-induced sterility could be very partially due to chromosomal aberrations appearing during male and female meiosis or even to mechanical abnormalities of the double fertilization. The sterility could be also related to diplontic origin (lethal factors or small deficiencies appearing in homozygous state on account of self-pollinization). Owing to our histological and genetical data, a female gametophytic origin could be mainly ascribed to EMS induced sterility. It could arise from a damage of the feeding function of the nucellus.

Multi-factor Analysis of Pre-control Fracture Simulations about Projectile Material

NASA Astrophysics Data System (ADS)

Wan, Ren-Yi; Zhou, Wei

2016-05-01

The study of projectile material pre-control fracture is helpful to improve the projectile metal effective fragmentation and the material utilization rate. Fragments muzzle velocity and lethality can be affected by the different explosive charge and the way of initiation. The finite element software can simulate the process of projectile explosive rupture which has a pre-groove in the projectile shell surface and analysis of typical node velocity change with time, to provides a reference for the design and optimization of precontrol frag.

New findings on the purification and characterization of an anti-bothropic factor from Didelphis marsupialis (opossum) serum.

PubMed

Perales, J; Muños, R; Graterol, S; Oviedo, O; Moussatché, H

1989-01-01

We have used DEAE-Sephacel and Sephacryl S-200 to separate protein fractions from Didelphis marsupialis serum capable of protecting mice from the lethal effect of Bothrops jararaca venom. The fractions separated were homogeneous by conventional electrophoresis using cellulose acetate and polyacrylamide; however, they were heterogeneous on PAGE-SDS, showing similar electrophoretic patterns with or without mercaptoethanol. The protein bands obtained were glycoproteins with a molecular weight of 42,000 to 58,000 Daltons.

Matrix Assisted Laser Desorption Ionization Mass Spectrometric Analysis of Bacillus anthracis: From Fingerprint Analysis of the Bacterium to Quantification of its Toxins in Clinical Samples

NASA Astrophysics Data System (ADS)

Woolfitt, Adrian R.; Boyer, Anne E.; Quinn, Conrad P.; Hoffmaster, Alex R.; Kozel, Thomas R.; de, Barun K.; Gallegos, Maribel; Moura, Hercules; Pirkle, James L.; Barr, John R.

A range of mass spectrometry-based techniques have been used to identify, characterize and differentiate Bacillus anthracis, both in culture for forensic applications and for diagnosis during infection. This range of techniques could usefully be considered to exist as a continuum, based on the degrees of specificity involved. We show two examples here, a whole-organism fingerprinting method and a high-specificity assay for one unique protein, anthrax lethal factor.

Allelic Variation on Murine Chromosome 11 Modifies Host Inflammatory Responses and Resistance to Bacillus anthracis

DTIC Science & Technology

2011-12-01

Song GY (2003) Mechanisms of immune resolution. Crit Care Med 31: S558–571. 69. Martinon F (2010) Update on biology: uric acid and the activation of...Alox12e and Alox15 belong to a family of arachidonate lipoxygenases responsible for production of anti- inflammatory lipoxins from arachidonic acid ...lethal factor. Protein Expr Purif 18: 293–302. 71. Gupta PK, Moayeri M, Crown D, Fattah RJ, Leppla SH (2008) Role of N- terminal amino acids in the

Epithelial Plasticity in Castration-Resistant Prostate Cancer: Biology of the Lethal Phenotype

DTIC Science & Technology

2011-07-01

Sorg BS, Albrecht T et al. Alternative inclusion of fibroblast growth factor receptor 2 exon IIIc in Dunning prostate tumors reveals unexpected... exon 658IIIc in Dunning prostate tumors reveals unexpected epithelial 659mesenchymal plasticity. Proc Natl Acad Sci U S A 2006;103: 66014116–21. 24...variant isoforms (such as, for example FGFR2 that includes or excludes either exon IIIc or exon IIIb), or CD133, or any combination of two or more

The lethality test used for estimating the potency of antivenoms against Bothrops asper snake venom: pathophysiological mechanisms, prophylactic analgesia, and a surrogate in vitro assay.

PubMed

Chacón, Francisco; Oviedo, Andrea; Escalante, Teresa; Solano, Gabriela; Rucavado, Alexandra; Gutiérrez, José María

2015-01-01

The potency of antivenoms is assessed by analyzing the neutralization of venom-induced lethality, and is expressed as the Median Effective Dose (ED50). The present study was designed to investigate the pathophysiological mechanisms responsible for lethality induced by the venom of Bothrops asper, in the experimental conditions used for the evaluation of the neutralizing potency of antivenoms. Mice injected with 4 LD50s of venom by the intraperitoneal route died within ∼25 min with drastic alterations in the abdominal organs, characterized by hemorrhage, increment in plasma extravasation, and hemoconcentration, thus leading to hypovolemia and cardiovascular collapse. Snake venom metalloproteinases (SVMPs) play a predominat role in lethality, as judged by partial inhibition by the chelating agent CaNa2EDTA. When venom was mixed with antivenom, there was a venom/antivenom ratio at which hemorrhage was significantly reduced, but mice died at later time intervals with evident hemoconcentration, indicating that other components in addition to SVMPs also contribute to plasma extravasation and lethality. Pretreatment with the analgesic tramadol did not affect the outcome of the neutralization test, thus suggesting that prophylactic (precautionary) analgesia can be introduced in this assay. Neutralization of lethality in mice correlated with neutralization of in vitro coagulant activity in human plasma. Copyright © 2014 Elsevier Ltd. All rights reserved.

Sensitivity of seven PCRs for early detection of koi herpesvirus in experimentally infected carp, Cyprinus carpio L., by lethal and non-lethal sampling methods.

PubMed

Monaghan, S J; Thompson, K D; Adams, A; Bergmann, S M

2015-03-01

Koi herpesvirus (KHV) causes an economically important, highly infectious disease in common carp and koi, Cyprinus carpio L. Since the occurrence of mass mortalities worldwide, highly specific and sensitive molecular diagnostic methods have been developed for KHV detection. The sensitivity and reliability of these assays have essentially focused at the detection of low viral DNA copy numbers during latent or persistent infections. However, the efficacy of these assays has not been investigated with regard to low-level viraemia during acute infection stages. This study was conducted to compare the sensitivity of seven different polymerase chain reaction (PCR) assays to detect KHV during the first hours and days post-infection (hpi; dpi), using lethal and non-lethal sampling methods. The results highlight the limitations of the assays for detecting virus during the first 4 dpi despite rapid mortality in experimentally infected carp. False-negative results were associated with time post-infection and the tissue sampled. Non-lethal sampling appears effective for KHV screening, with efficient detection in mucus samples obtained from external swabs during this early infection period (<5 dpi), while biopsies from gills and kidney were negative using the same PCR assays. Non-lethal sampling may improve the reliability of KHV detection in subclinical, acutely infected carp. © 2014 John Wiley & Sons Ltd.

[Secondary metabolites, lethality and antimicrobial activity of extracts from three corals and three marine mollusks from Sucre, Venezuela].

PubMed

Ordaz, Gabriel; D'Armas, Haydelba; Yáñez, Dayanis; Hernández, Juan; Camacho, Angel

2010-06-01

The study of biochemical activity of extracts obtained from marine organisms is gaining interest as some have proved to have efficient health or industrial applications. To evaluate lethality and antimicrobial activities, some chemical tests were performed on crude extracts of the octocorals Eunicea sp., Muricea sp. and Pseudopterogorgia acerosa and the mollusks Pteria colymbus, Phyllonotus pomum and Chicoreus brevifrons, collected in Venezuelan waters. The presence of secondary metabolites like alkaloids, unsaturated sterols and pentacyclic triterpenes in all invertebrates, was evidenced. Additionally, sesquiterpenlactones, saponins, tannins, cyanogenic and cardiotonic glycosides were also detected in some octocoral extracts, suggesting that biosynthesis of these metabolites is typical in this group. From the lethality bioassays, all extracts resulted lethal to Artemia salina (LC50<1000 microg/ml) with an increased of lethal activity with exposition time. P. pomum extract showed the highest lethality rate (LC50=46.8 microg/ml). Compared to the octocorals, mollusks extracts displayed more activity and a greater action spectrum against different bacterial strains, whereas octocorals also inhibited some fungi strains growth. Staphylococcus aureus was the most susceptible to the antimicrobial power of the extracts (66.7%), whereas Pseudomonas aeruginosa, Candida albicans and Aspergillus niger were not affected. The antibiosis shown by marine organisms extracts indicates that some of their biosynthesized metabolites are physiologically active, and may have possible cytotoxic potential or as a source of antibiotic components.

RADIATION INDUCED VIABILITY MUTATIONS IN THE HONEY BEE

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

Lee, W.R.

The frequency of recessive detrimental mutations expressed in the haploid drone honey bee was investigated and compared with recessive and dominant lethal mutations detected in the haploid drone and diploid worker. A single queen was inseminated by a drone homozygous for three genetic markers. Viability of progeny was determined, and hybrid daughters bearing the genetic markers were stored in colonies. The spermatheca of the queen was then irradiated with 2600 r kvp x rays. Morphological defects and viability were studied in progeny and grand-progeny. A total of 92 pairs was tested during one season. Results showed that 60.8% of themore » sperm cells receiving radiation contained at least one or more dominant lethals. Correcting for the saturation effect on the assumption of independence of each dominant lethal, an average proportion of 0.94 dominant lethals were found per cell. The average reduction in embryonic viability was 28%. Forty per cent of the queens tested contained one or more recessive lethals. Corrections in procedure and plans for future work, as well as work in progress, are described. (H.M.G.)« less

Chitin synthase III: synthetic lethal mutants and "stress related" chitin synthesis that bypasses the CSD3/CHS6 localization pathway.

PubMed

Osmond, B C; Specht, C A; Robbins, P W

1999-09-28

We screened Saccharomyces strains for mutants that are synthetically lethal with deletion of the major chitin synthase gene CHS3. In addition to finding, not surprisingly, that mutations in major cell wall-related genes such as FKS1 (glucan synthase) and mutations in any of the Golgi glycosylation complex genes (MNN9 family) are lethal in combination with chs3Delta, we found that a mutation in Srv2p, a bifunctional regulatory gene, is notably lethal in the chs3 deletion. In extending studies of fks1-chitin synthase 3 interactions, we made the surprising discovery that deletion of CSD3/CHS6, a gene normally required for Chs3p delivery and activity in vivo, was not lethal with fks1 and, in fact, that lack of Csd3p/Chs6p did not decrease the high level of stress-related chitin made in the fks1 mutant. This finding suggests that "stress response" chitin synthesis proceeds through an alternate Chs3p targeting pathway.

Chitin synthase III: Synthetic lethal mutants and “stress related” chitin synthesis that bypasses the CSD3/CHS6 localization pathway

PubMed Central

Osmond, Barbara C.; Specht, Charles A.; Robbins, Phillips W.

1999-01-01

We screened Saccharomyces strains for mutants that are synthetically lethal with deletion of the major chitin synthase gene CHS3. In addition to finding, not surprisingly, that mutations in major cell wall-related genes such as FKS1 (glucan synthase) and mutations in any of the Golgi glycosylation complex genes (MNN9 family) are lethal in combination with chs3Δ, we found that a mutation in Srv2p, a bifunctional regulatory gene, is notably lethal in the chs3 deletion. In extending studies of fks1-chitin synthase 3 interactions, we made the surprising discovery that deletion of CSD3/CHS6, a gene normally required for Chs3p delivery and activity in vivo, was not lethal with fks1 and, in fact, that lack of Csd3p/Chs6p did not decrease the high level of stress-related chitin made in the fks1 mutant. This finding suggests that “stress response” chitin synthesis proceeds through an alternate Chs3p targeting pathway. PMID:10500155

Synthetic lethality in DNA repair network: A novel avenue in targeted cancer therapy and combination therapeutics.

PubMed

Bhattacharjee, Sonali; Nandi, Saikat

2017-12-01

Synthetic lethality refers to a lethal phenotype that results from the simultaneous disruptions of two genes, while the disruption of either gene alone is viable. Many DNA double strand break repair (DSBR) genes have synthetic lethal relationships with oncogenes and tumor suppressor genes, which can be exploited for targeted cancer therapy, an approach referred to as combination therapy. DNA double-strand breaks (DSBs) are one of the most toxic lesions to a cell and can be repaired by non-homologous end joining (NHEJ) or homologous recombination (HR). HR and NHEJ genes are particularly attractive targets for cancer therapy because these genes have altered expression patterns in cancer cells when compared with normal cells and these genetic abnormalities can be targeted for selectively killing cancer cells. Here, we review recent advances in the development of small molecule inhibitors against HR and NHEJ genes to induce synthetic lethality and address the future directions and clinical relevance of this approach. © 2017 IUBMB Life, 69(12):929-937, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

Assessing reproductive status in elasmobranch fishes using steroid hormones extracted from skeletal muscle tissue

PubMed Central

Prohaska, Bianca K.; Tsang, Paul C. W.; Driggers, William B.; Hoffmayer, Eric R.; Wheeler, Carolyn R.; Brown, A. Christine; Sulikowski, James A.

2013-01-01

Elasmobranch fishes (sharks, skates, and rays) are particularly susceptible to anthropogenic threats, making a thorough understanding of their life history characteristics essential for proper management. Historically, elasmobranch reproductive data have been collected by lethal sampling, an approach that is problematic for threatened and endangered species. However, recent studies have demonstrated that non-lethal approaches can be as effective as lethal ones for assessment of the reproductive status of an animal. For example, plasma has been used to examine concentrations of steroid hormones. Additionally, skeletal muscle tissue, which can be obtained non-lethally and with minimal stress, can also be used to quantify concentrations of steroid hormones. Skeletal muscle progesterone, testosterone, and estradiol concentrations were determined to be statistically significant indicators of reproductive status in the oviparous Leucoraja erinacea, the yolk-dependent viviparous Squalus acanthias, and the yolk-sac placental viviparous Rhizoprionodon terraenovae. The results of the present study demonstrate that steroid hormones present in non-lethally harvested skeletal muscle tissue can be used as reliable indicators of reproductive status in elasmobranchs. PMID:27293612

Whole body protection against lethal ionizing radiation in mice by REC-2001: a semi-purified fraction of Podophyllum hexandrum.

PubMed

Lata, M; Prasad, J; Singh, S; Kumar, R; Singh, L; Chaudhary, P; Arora, R; Chawla, R; Tyagi, S; Soni, N L; Sagar, R K; Devi, M; Sharma, R K; Puri, S C; Tripathi, R P

2009-01-01

The current study has concentrated on assessment of the radioprotective potential of REC-2001, a semi-purified fraction of rhizomes of Podophyllum hexandrum, in Swiss albino Strain 'A' mice exposed to 10 Gy whole-body gamma radiation. Animals were treated with 10 and 15 mg/kg b wt (i.p.) of REC-2001 1h prior to exposure to a lethal dose of gamma-radiation (10 Gy) and observed upto 30 days. For analysis of maximum tolerable dose (MTD), LD(50) and acute toxic dose, different concentrations of the extract were administered to animals and their mortality and morbidity status was observed upto 72 h and one week, respectively. Dose reduction factor (DRF) was determined by exposing REC-2001 pre-treated mice to supra-lethal doses of gamma-radiation. Endogenous spleen colony forming units (CFU), DNA strand breaks in thymocytes (alkaline halo assay) and lipid degradation was studied to understand the mechanism of radioprotection. A single dose of REC-2001 (10 and 15 mg/kg b wt i.p.) exhibited >90% survival in the pre-treated irradiated group versus no survival in radiation control group. Single doses of upto 75 mg/kg b wt (i.p.) did not cause any mortality (MTD) in mice. REC-2001, a dose of 90 mg/kg b wt, resulted in 50% mortality (LD(50)), while the LD(100) was 115 mg/kg b wt REC-2001 exhibited a DRF of 1.62. CFU counts in the REC-2001 treated group were found significantly high (5.33/spleen) as compared to controls. Exposure of thymocytes to 10 Gy radiation resulted in increased halo diameter (45+/-3 microm) in comparison to untreated controls (8+/-1 microm). REC-2001 administration (500 microg/ml) decreased the halo diameter to 15+/-2 microm. Radiation-induced lipid degradation was also inhibited by REC-2001. The present study has revealed that REC-2001 is a promising radioprotective fraction that can be effectively used against lethal doses of gamma-radiation after further investigations in higher animal models.

Using host-pathogen protein interactions to identify and characterize Francisella tularensis virulence factors.

PubMed

Wallqvist, Anders; Memišević, Vesna; Zavaljevski, Nela; Pieper, Rembert; Rajagopala, Seesandra V; Kwon, Keehwan; Yu, Chenggang; Hoover, Timothy A; Reifman, Jaques

2015-12-29

Francisella tularensis is a select bio-threat agent and one of the most virulent intracellular pathogens known, requiring just a few organisms to establish an infection. Although several virulence factors are known, we lack an understanding of virulence factors that act through host-pathogen protein interactions to promote infection. To address these issues in the highly infectious F. tularensis subsp. tularensis Schu S4 strain, we deployed a combined in silico, in vitro, and in vivo analysis to identify virulence factors and their interactions with host proteins to characterize bacterial infection mechanisms. We initially used comparative genomics and literature to identify and select a set of 49 putative and known virulence factors for analysis. Each protein was then subjected to proteome-scale yeast two-hybrid (Y2H) screens with human and murine cDNA libraries to identify potential host-pathogen protein-protein interactions. Based on the bacterial protein interaction profile with both hosts, we selected seven novel putative virulence factors for mutant construction and animal validation experiments. We were able to create five transposon insertion mutants and used them in an intranasal BALB/c mouse challenge model to establish 50 % lethal dose estimates. Three of these, ΔFTT0482c, ΔFTT1538c, and ΔFTT1597, showed attenuation in lethality and can thus be considered novel F. tularensis virulence factors. The analysis of the accompanying Y2H data identified intracellular protein trafficking between the early endosome to the late endosome as an important component in virulence attenuation for these virulence factors. Furthermore, we also used the Y2H data to investigate host protein binding of two known virulence factors, showing that direct protein binding was a component in the modulation of the inflammatory response via activation of mitogen-activated protein kinases and in the oxidative stress response. Direct interactions with specific host proteins and the ability to influence interactions among host proteins are important components for F. tularensis to avoid host-cell defense mechanisms and successfully establish an infection. Although direct host-pathogen protein-protein binding is only one aspect of Francisella virulence, it is a critical component in directly manipulating and interfering with cellular processes in the host cell.

An Evaluation of the Impacts of Changing Firearms Legislation on Australian Female Firearm Homicide Victimization Rates.

PubMed

McPhedran, Samara

2018-05-01

Reducing lethal violence against women requires comprehensive measures addressing individual, social, economic, cultural, and situational factors. Regarding situational factors, access to weapons-and firearm access in particular-has received notable research attention. However, most study comes from the United States of America, and findings may not apply elsewhere. The current study examines whether changing gun laws in Australia affected female firearm homicide victimization. Female firearm homicide victimization may have been affected; however, no significant impacts were found for male firearm homicide victimization. Findings suggest there may be value in preventing legal access to firearms by persons who have a history of intimate partner violence, although considerable further study is required.

Histone methylations in heart development, congenital and adult heart diseases.

PubMed

Zhang, Qing-Jun; Liu, Zhi-Ping

2015-01-01

Heart development comprises myocyte specification, differentiation and cardiac morphogenesis. These processes are regulated by a group of core cardiac transcription factors in a coordinated temporal and spatial manner. Histone methylation is an emerging epigenetic mechanism for regulating gene transcription. Interplay among cardiac transcription factors and histone lysine modifiers plays important role in heart development. Aberrant expression and mutation of the histone lysine modifiers during development and in adult life can cause either embryonic lethality or congenital heart diseases, and influences the response of adult hearts to pathological stresses. In this review, we describe current body of literature on the role of several common histone methylations and their modifying enzymes in heart development, congenital and adult heart diseases.

The polyphosphate–factor XII pathway drives coagulation in prostate cancer-associated thrombosis

PubMed Central

Nickel, Katrin F.; Ronquist, Göran; Langer, Florian; Labberton, Linda; Fuchs, Tobias A.; Bokemeyer, Carsten; Sauter, Guido; Graefen, Markus; Mackman, Nigel; Stavrou, Evi X.; Ronquist, Gunnar

2015-01-01

Cancer is a leading cause of thrombosis. We identify a new procoagulant mechanism that contributes to thromboembolism in prostate cancer and allows for safe anticoagulation therapy development. Prostate cancer-mediated procoagulant activity was reduced in plasma in the absence of factor XII or its substrate of the intrinsic coagulation pathway factor XI. Prostate cancer cells and secreted prostasomes expose long chain polyphosphate on their surface that colocalized with active factor XII and initiated coagulation in a factor XII-dependent manner. Polyphosphate content correlated with the procoagulant activity of prostasomes. Inherited deficiency in factor XI or XII or high-molecular-weight kininogen, but not plasma kallikrein, protected mice from prostasome-induced lethal pulmonary embolism. Targeting polyphosphate or factor XII conferred resistance to prostate cancer-driven thrombosis in mice, without increasing bleeding. Inhibition of factor XII with recombinant 3F7 antibody reduced the increased prostasome-mediated procoagulant activity in patient plasma. The data illustrate a critical role for polyphosphate/factor XII-triggered coagulation in prostate cancer-associated thrombosis with implications for anticoagulation without therapy-associated bleeding in malignancies. PMID:26153520

Non-Lethal Weapons: Setting Our Phasers on Stun? Potential Stratetgic Blessings and Curses of Non-Lethal Weapons on the Battlefield

DTIC Science & Technology

2003-08-01

improve our ability to verify compliance with the treaty’s global ban on biological weapons and would put national security and confidential business ...he was Assistant Professor of Aeronautics at the U.S. Air Force Academy, Colorado, where he was also instructor pilot in the T - 41 flight-screening...fielded on a greater scale are explored. The ability of non-lethal weapons to positively influence the global war on terrorism is also assessed. It

Defect of Hepatocyte Growth Factor Activator Inhibitor Type 1/Serine Protease Inhibitor, Kunitz Type 1 (Hai-1/Spint1) Leads to Ichthyosis-Like Condition and Abnormal Hair Development in Mice

PubMed Central

Nagaike, Koki; Kawaguchi, Makiko; Takeda, Naoki; Fukushima, Tsuyoshi; Sawaguchi, Akira; Kohama, Kazuyo; Setoyama, Mitsuru; Kataoka, Hiroaki

2008-01-01

Hepatocyte growth factor activator inhibitor type 1 (HAI-1)/serine protease inhibitor, Kunitz type 1 (SPINT1) is a membrane-bound, serine proteinase inhibitor initially identified as an inhibitor of hepatocyte growth factor activator. It also inhibits matriptase and prostasin, both of which are membrane-bound serine proteinases that have critical roles in epidermal differentiation and function. In this study, skin and hair phenotypes of mice lacking the Hai-1/Spint1 gene were characterized. Previously, we reported that the homozygous deletion of Hai-1/Spint1 in mice resulted in embryonic lethality attributable to impaired placental development. To test the role of Hai-1/Spint1 in mice, the placental function of Hai-1/Spint1-mutant mice was rescued. Injection of Hai-1/Spint1+/+ blastocysts with Hai-1/Spint1−/− embryonic stem cells successfully generated high-chimeric Hai-1/Spint1−/− embryos (B6Hai-1−/−High) with normal placentas. These embryos were delivered without apparent developmental abnormalities, confirming that embryonic lethality of Hai-1/Spint1−/− mice was caused by placental dysfunction. However, newborn B6Hai-1−/−High mice showed growth retardation and died by 16 days. These mice developed scaly skin because of hyperkeratinization, reminiscent of ichthyosis, and abnormal hair shafts that showed loss of regular cuticular septation. The interfollicular epidermis showed acanthosis with enhanced Akt phosphorylation. Immunoblot analysis revealed altered proteolytic processing of profilaggrin in Hai-1/Spint1-deleted skin with impaired generation of filaggrin monomers. These findings indicate that Hai-1/Spint1 has critical roles in the regulated keratinization of the epidermis and hair development. PMID:18832587

The effect of deletion of the edema factor on Bacillus anthracis pathogenicity in guinea pigs and rabbits.

PubMed

Levy, Haim; Weiss, Shay; Altboum, Zeev; Schlomovitz, Josef; Rothschild, Nili; Glinert, Itai; Sittner, Assa; Kobiler, David

2012-01-01

Bacillus anthracis secretes three major components, which assemble into two bipartite toxins: lethal toxin (LT), composed of lethal factor (LF) and protective antigen (PA) and edema toxin (ET), composed of edema factor (EF) and PA. EF is a potent calmodulin-dependent adenylate cyclase, which is internalized into the target cell following PA binding. Once inside the cell, EF elevates cAMP levels, interrupting intracellular signaling. Effects of ET were demonstrated on monocytes, neutrophils and T-cells. In an earlier work we demonstrated that a deletion of LF in a fully virulent strain had no effect in guinea pigs and a significant, but not major, effect in the rabbit model. These results suggested that EF might play an important role in the development of infection and mortality following exposure to B. anthracis spores. To evaluate the role of EF in B. anthracis pathogenicity we deleted the cya gene, which encodes the EF protein, in the fully virulent Vollum strain. The Δcya mutant was fully virulent in the guinea pig model as determined by LD(50) experiments. In the rabbit model, when infected subcutaneously, the absence of EF had no effect on the virulence of the mutant. However an increase of two orders of magnitude in the LD(50) was demonstrated when the rabbits were infected by intranasal instillation accompanied with partial mortality and increased mean time to death. These results argue that in the guinea pig model the presence of one of the toxins, ET or LT is sufficient for the development of the infection. In the rabbit model ET plays a role in respiratory infection, most probably mediating the early steps of host colonization. Copyright © 2011 Elsevier Ltd. All rights reserved.

A DWARF MUTATION IN THE RABBIT

PubMed Central

Greene, Harry S. N.

1940-01-01

An hereditary type of dwarfism in the rabbit has been described. In contrast to the dwarfs described in other animals, this type is evident at birth and conforms to the classification, nannosomia primordialis, as used in human pathology. In homozygous form the variation is lethal and produces a miniature individual approximately one-third the size of its normal sibs. Heterozygous animals are approximately two-thirds the size of normal sibs at birth and never attain an equal stature. The expression of the variation is modified by genetic factors carried by a line of cretinoid animals and, rarely, dwarfs derived from crosses with this line survive for 1 to 2 months. The striking changes in such survivors are hypertrophy and hyperplasia of the acidophilic cells of the pituitary and atrophy of the gonads. Such changes are not present in ordinary dwarfs and it is concluded that the acidophilic hyperplasia represents the influence of the modifying factors of the cretinoid line and supplies the growth hormone responsible for survival. The gonadotropic hormone is not supplied by the secretory activity of these cells and as a result the gonads atrophy. The evidence at hand indicates that the primary effect of the dwarfing gene is an inhibition of the secretory functions of the pituitary. In homozygous individuals, the inhibition is complete and the variation is expressed as a lethal dwarf. In heterozygous animals, the function of the organ is altered, producing an undersized individual. The modifying factors of the cretinoid line act either to partially remove the inhibition or to alter the constitution of the animal so that life is possible for a short period without the full complement of pituitary hormones. PMID:19871001