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Divergent migratory strategies among populations can result in population‐level differences in timing of reproduction (allochrony) and local adaptation. However, the mechanisms underlying among‐population variation in timing are insufficiently understood, particularly in females. We studied differences in reproductive development and its related mechanisms along the hypothalamic–pituitary–gonadal axis (HPG) in closely related migratory and sedentary (i.e. resident) female dark‐eyed juncos (Junco hyemalis) living together in sympatry during early spring. Despite exposure to the same environmental cues in early spring, residents initiate breeding prior to the departure of migrants for their breeding grounds. We investigated whether residents would be more reproductively developed than migrants based on their behavioural differences. Alternatively, females could exhibit similar reproductive development in response to the same environmental cues despite differences in migratory behaviour. To compare their degree of reproductive development during seasonal sympatry and the underlying mechanisms of these differences, we collected ovarian and liver tissue in early spring prior to migration and compared transcript abundance of genes associated with reproduction using quantitative PCR. We also used stable hydrogen isotopes to infer relative breeding and wintering latitude of migrants. We found higher transcript abundance of luteinizing hormone receptor and aromatase in the ovary in addition to significantly heavier ovaries in residents than in migrants. Together, these results suggest greater sensitivity and response to upstream endocrine stimulation in resident females. Transcript abundance for other receptors in the ovary and liver associated with reproduction, however, did not differ between populations. When comparing ovarian development within migrants, females with lower hydrogen isotopes (indicating higher breeding latitudes) had smaller ovaries, suggesting that longer‐distance migrations may further delay reproductive development. Based on differences in ovary mass and transcript abundance, we conclude that females that differ in migratory strategy also differ in timing of reproductive development. These results support that divergent migratory behaviour drives allochrony and could enable reproductive isolation between populations; mechanistic differences at the level of gonadal stimulation can explain these differences in timing of reproductive development. A free Plain Language Summary can be found within the Supporting Information of this article.

Clinical studies show that the development of lung adenocarcinomas (LACs) is correlated with smoking habits. Nicotine, the addictive component of cigarettes, accelerates human LAC proliferation thr...

Capsaicin, spicy ingredient of chili peppers, is used to topically treat pain and inflammation associated with a variety of diseases. Data from our laboratory shows that capsaicin displays apoptoti...

Small cell lung cancer (SCLC) is characterized by aggressive clinical course and a dismal survival rate. The present study examines the apoptotic activity of capsaicin (the pungent ingredient of chili peppers) in human SCLC. We observed that capsaicin induced apoptosis in a panel of human SCLC in a concentration-dependent and time-dependent manner. Most importantly, capsaicin caused robust apoptosis in a panel of human SCLC cell lines, but did not affect normal human lung epithelial cells. The dietary administration of capsaicin decreased the growth H69 and DMS53 human SCLC tumors in nude mice and in chicken chorioallantoic membrane (CAM) models. The apoptotic activity of capsaicin was reversed with the generalized TRPV antagonist ruthenium red, indicating that TRPV receptors are involved in capsaicin induced apoptosis. However, antagonists to TRPV1, namely capsazepine and SB-366791, did not affect the apoptotic activity of capsaicin, suggesting the involvement of a TRPV1-independent mechanism. In contras...

Cigarette smoking bears a strong association with the development of lung cancer. Nicotine is the addictive component of cigarettes. Several convergent studies show that nicotine facilitates the growth and angiogenesis of human lung cancers. The biological activity of nicotine is mediated by nicotinic acetylcholine receptors (nAChRs). The endogenous ligand of nAChRs is acetylcholine (ACh). Data from our laboratory and other research groups show that lung cancers express all of the genes for synthesis, transport and degradation of ACh. These include nAChRs, choline acetyltransferase (ChAT), vesicular acetylcholine transporter (VAChT), choline transporter (ChT1) and acetylcholinesterase (AChE). Nicotine upregulates the ACh-signaling loop in human lung cancer cells. Therefore, we conjectured that disruption of ACh-signaling pathway should suppress the growth of human cancers. We show that alpha7-nAChR antagonists robustly suppress angiogenesis in human lung and retinal microvascular endothelial cells. The anti-angiogenic activity of alpha7-nAChR antagonists was also observed in chicken chorioallantoic membrane (CAM) and nude mouse models. Similarly, vesamicol, a small molecule antagonist of VAChT, decreases nicotine-induced tumor growth in human NSCLCs. Our studies suggest that the acetylcholine signaling pathway may be have potential applications in the therapy of human lung cancers. Our results are also relevant to lung cancer patients who are exposed to nicotine via secondhand smoke, nicotine patches, gums or electronic cigarettes. Citation Format: Piyali Dasgupta, Kathleen C. Brown, Jamie K. Lau, Aaron M. Dom, Brent A. Thornhill, Clayton M. Crabtree, Theodore R. Witte, W E. Hardman, Cody A. Stover, A B. Carpenter, Yi C. Chen. Disruption of the acetylcholine signaling pathway suppresses the growth and angiogenesis of human lung cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5229. doi:10.1158/1538-7445.AM2015-5229

The nutritional compound capsaicin has been shown to display anti-neoplastic activity in breast, prostate and colon tumors xenografted in nude mice. Based on these data from other research laboratories, we wanted to determine the bioavailability of capsaicin in nude mice in vivo. We found that capsaicin was rapidly metabolized primarily in the liver. The bioavailability of intact capsaicin was highest in the lung. Therefore, we hypothesized that capsaicin should suppress the growth of lung tumors. We found that capsaicin induced robust apoptosis in human SCLC cell lines. Capsaicin decreased the growth rates of human SCLC tumors in two in vivo models, namely the CAM model and the nude mouse model. HPLC studies showed intact capsaicin in the tumors excised from nude mice. The heat-sensation activity of capsaicin is mediated by the transient receptor potential vanilloid (TRPV) family of proteins. Capsaicin functions as an agonist of the TRPV1 receptor. The apoptotic activity of capsaicin was found to be mediated by TRPV6 and not TRPV1. Preliminary data shows that capsaicin increases the expression of the TRPV6 receptor, causing apoptosis in human SCLCs. Citation Format: John D. Hurley, William D. Rollyson, Cody A. Stover, Kathleen C. Brown, Haley E. Perry, Cathryn D. Stevenson, Clayton M. Crabtree, Aaron M. Dom, Jamie K. Lau, Theodore R. Witte, W E. Hardman, Piyali Dasgupta. Bioavailability and anti-tumor activity of capsaicin in human small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1678. doi:10.1158/1538-7445.AM2015-1678

The US Navy is evolving a strategy to develop and demonstrate prognostics and health management for propulsion and mechanical systems. How this overall strategy has evolved and its current status are presented. The SH-60 program was initiated as the first proof-of-concept effort to develop, demonstrate, and integrate available and advanced mechanical diagnostic technologies for propulsion and power drive system monitoring. Included in these technologies were various rule based and model based analysis techniques which were applied to demonstrate and validate various levels of diagnostic and prognostic capabilities. These are discussed and updated. Using past and recent "seeded faults" tests as case examples, various diagnostic methods were used to identify the faults, and various means of applying prognostics and health management are discussed. The most recent examples of "seeded faults" and related tests are also discussed as case studies, demonstrating various degrees of diagnostic, prognostic and health management capabilities. The current philosophy and thinking in respect to prognostics for mechanical systems is embellished, using examples from past and more recent "seeded fault" databases. Of particular interest is discussions of tests focused on demonstrating the understanding of fault to failure progression characteristics and the physics of failures. Accomplishments are discussed and additional needed testing and demonstration requirements are defined. Finally, status and future planned efforts for the USN Helicopter Transmission Test Facility (HTTF) and other related test resources are presented.

Measurement performance comparisons are examined between a point-and-shoot Robust Laser Interferometer (RLI) and an RLI fiber optic prototype system design successfully demonstrated during seeded fault testing at Pratt and Whitney in support of technology investigations conducted for the Joint Strike Fighter (JSF) Program. The baseline point-and-shoot RLI system measurement capability is reviewed, including observation of the existence and character of time shock pulses, the measurement of envelope detection fault frequencies, and changes in the amplitude and character of spectra. The system designs and experimental approaches for developing the comparison measurements are outlined. The functional areas selected for comparison include background noise, large vibration and dynamic range measurements, large amplitude complex vibration measurements, and high frequency performance. While additional work is required for the RLI, it has been demonstrated that wideband vibration measurements, including measurement of acoustic emissions, can be provided by both baseline point-and-shoot and fiber optic RLI designs.

The Naval Air Warfare Center has developed a Helicopter Integrated Diagnostic System (HIDS) which performs mechanical diagnostics on a helicopter's drive system. Diagnostic indicators indicative of the mechanical health of the drive system components are derived from vibration data through a combination of statistical and signal processing methods. This paper discusses the application of a multivariate statistical process known as Hotelling's T2 analyysis to HIDS diagnostic indicators. Multivariate analysis uses a composite function of multiple quality indicators to produce a single, trendable indicator that characterizes the state of the monitored process. A statistically valid method of creating and adjusting an alarm threshold for the resultant composite indicator is inherent in the method. When applied to mechanical diagnostic indicators from helicopter drive system seeded fault tests, the method produced timely and unambiguous fault identification with a reduced number of false alarms as compared to current diagnostic methods.

The SH-60 Helicopter Integrated Diagnostic System (HIDS) program was initiated as a proof-of-concept effort to develop, demonstrate, and integrate available and advanced mechanical diagnostic technologies for propulsion and power drive system monitoring. Included in these technologies were various rule based and model based analysis techniques which were applied to demonstrate and validate various levels of diagnostic and prognostic capabilities. These will be discussed. Since spalling of the SB 2205 roller bearing integral inner race is the most common dynamic component cause for gearbox removal in the SH-60, it was tested as part of the HIDS effort. Using this as a case example, diagnostic methods are used to identify the fault, and means of applying prognostics are discussed. Other more recent examples of "seeded faults" are also discussed as case studies demonstrating various degrees of diagnostic and prognostic capabilities. Relative rating of the performance of the different analysis techniques evaluated will also be discussed. As used in this paper, prognostics is the capability to provide early detection of the precursor and/or incipient fault condition to a component or sub-element failure condition; and to have the technology and means to manage and predict the progression of this fault condition to component failure. This prognostic philosophy is further embellished; using examples from the HIDS past and current "seeded fault" data base to define accomplishments and discuss additional demonstration requirements. Finally, a full description, major accomplishments, status and planned efforts for the current Helicopter Transmission Test Facility (HTTF) are presented.

Wideband vibration measurements from seeded fault testing conducted at Pratt and Whitney have been examined to determine the practicality of using such measurements to monitor bearing stress. The measurements were taken using a robust laser interferometer (RLI) in support of technology investigations conducted for prognostic health monitoring (PHM) for the Joint Strike Fighter (JSF) Program. Data from Bearing 1 was examined, where the changes in bearing stress resulted from: changes in operational speed; seeded physical faults and changes in lubrication availability and quality. The RLI measurements were made by measuring the bearing vibrations that were transmitted from the outer race (and its housing) through, or along, the scavenge oil pipe to the outer surface of the engine. Bearing stress and the general health of the 1 bearing were examined from a variety of viewpoints, including the observation of the existence of and character of time series shock pulses, the measurement of enveloped detection bearing fault frequencies, and changes in the amplitude and character of spectrums. While remaining work is required for both RLI system refinement and the development of appropriate analytical tools, it has been demonstrated that acoustic emissions in broadband vibrations should be expected to provide a viable indication of bearing stress.

The evolution of automated diagnostic systems for helicopter mechanical systems has been aided by a Navy program of systematic testing of drive train components having known anomalies (seeded faults) while simultaneously executing a suite of diagnostic techniques to identify and classify the mechanical anomalies. This program, called the Helicopter Integrated Diagnostic System (HIDS) has been carried out using an iron bird test stand (SH-60) at NAWC - Trenton, and SH-60B/F flight vehicles at NAWC - Patuxent River. The SH-60 HIDS program has been the Navy's cornerstone effort to develop, demonstrate, and justify integrated mechanical diagnostic system capabilities for its helicopter fleets. The objectives of the program were to: 1. Acquire raw data for multiple cases of "good" and seeded fault mechanical components on a fully instrumented drive train to support the evaluation of diagnostic algorithms and fault isolation matrices. 2. Analyze vibration and other diagnostic indicators 3. Demonstrate the ability to integrate and automate the data acquisition, diagnostic, fault evaluation and communication processes in a flight worthy system. 4. Integrate and evaluate comprehensive engine monitoring, gearbox and drive train vibration diagnostics, advanced oil debris monitoring, inflight rotor track and balance, parts life usage tracking, automated flight regime recognition, power assurance checks and trending, and automated maintenance forecasting in a well-coordinated on-board and ground-based system. 5. Provide an extensive library of high quality vibration data on baseline and seeded fault components. 6. Provide a "showcase", state-of-the-art, fully functional Integrated Mechanical Diagnostic system to act as a catalyst demonstration. This paper describes the overall program, the goals and objectives, the facilities used, the system evaluated, accomplishments, results and conclusions obtained to date, The results of extensive gearbox and power-train "seeded fault" testing are presented. Lessons learned that can be applied to future Helicopter Usage Monitoring Systems (HUMS) and/or Integrated Mechanical Diagnostic (IMD) systems are also discussed.

If the plasma membrane and its associated transport proteins are solely responsible for maintenance of the asymmetric solute distribution then disruption of the plasma membrane would quickly lead to the symmetric distribution of all unattached inorganic ions between the cell and the extracellular environment. To test this hypothesis fresh pig lenses were incubated in Hanks ’ balanced salt solution in either absence or presence of non-ionic detergents (0.2 % Triton X-100 or 0.2 % Brij 58). Both detergents caused permeabilization of every lens fiber cell as shown by electron microscopy. The flux kinetics of K+, Mg2 +, Na+, Ca2 +, water and protein out of and into the permeabilized lens fiber cells was measured. Triton X-100 caused a faster flux rate of all solutes than did Brij 58. The Triton X-100 induced flux of solutes and water was associated with a decrease in lens ATP. Incubation of untreated lenses in solutions of different osmotic pressures at 0 °C demonstrated that the major fraction of lens water was osmotically unresponsive. Thus the asymmetric distribution of solutes in lens fiber cells is dependent on an intact plasma membrane and on a co-operative ATP-dependent association between K+, Mg2 +, water and cytomatrix proteins.

B2 Maternal diet may influence development of the offspring and may influence future cancer risk. Maternal consumption of diet high in n-6 (omega 6) polyunsaturated fats has been shown to increase risk for mammary gland cancer (Hilakivi-Clarke et al, 1997). We wanted to know if the substitution of corn oil with canola oil in the maternal diet might reduce the risk for breast cancer. Such a change would decrease dietary n-6 fat and increase n-3 fat. A study was devised to determine whether exposure to a diet that has less omega 6 and more omega 3 FAs during gestation and lactation would reduce the risk for mammary cancer in female offspring. Female SV 129 mice were divided into two groups and placed on diets either containing 10% w/w corn oil (corn oil is 50% omega 6 and < 0.5% omega 3) or 10% w/w canola oil (canola oil is 20% omega 6 and 10% omega 3). After two weeks the females were bred with homozygous C31 Tag transgenic male mice. The transgenic mice bear a transgene for the SV40 large T antigen with a prostatic steroid binding protein promoter. The female progeny, hemizygous for the transgene, are the experimental mice for this study. On a standard diet, females would be expected to develop mammary gland cancer by 6 months of age. At weaning, female progeny from each litter were all maintained on the basal corn oil containing diet. The female hemizygous mice were euthanized at 3weeks, 110, 130, 150 and 170 days. Results showed that the total tumor weight, number of glands with tumor and fraction of mice with tumors were higher in progeny of mother fed a corn oil diet than in progeny of mother fed a canola oil diet. No significant difference in the body weight of progeny from corn oil and canola fed mothers. At weaning the lipid composition of the inguinal fat pad, mammary gland and liver shows a higher level of omega 3 fatty acids in the offspring of mice fed the high n-3 diet. Mammary gland gene expression assay performed on three weeks and 130 days old mice reveals up as well as down regulation in several genes in canola versus corn group. The up regulated genes include CCAAT-enhancer binding protein beta (CEBPβ), a transcription factor that is involved in mammary gland differentiation (550-fold at 130days) and Early growth response 1 (Egr1), a tumor suppressor gene (13-fold at 130days). Genes down regulated include Bcl2-like 1(Bcl2l1), an antiapoptotic gene (-2.03-fold at 3weeks) and Fatty acid synthase (Fas), an enzyme involved in fatty acid synthesis and active in cancer cells (-7.09 at 130days). Western blot analysis confirmed the differential gene expression of CEBPβ and Fas. Citation Information: Cancer Prev Res 2008;1(7 Suppl):B2.

A US Navy strategy was generated and is still evolving to develop and demonstrate diagnostics and prognostics for helicopter drive trains. The SH-60 program was initiated as a proof-of-concept effort to develop, demonstrate, and integrate available and advanced mechanical diagnostic technologies for propulsion and power drive system monitoring. Included in these technologies were various rule based and model based analysis techniques which were applied to demonstrate and validate various levels of diagnostic and prognostic capabilities. Since spalling of the SB 2205 roller bearing integral inner race is the most common dynamic component cause for gearbox removal in the SH-60, it was tested as part of the original HIDS effort. Using this as a case example, diagnostic methods are used to identify the fault, and means of applying prognostics are discussed. Other more recent examples of "seeded faults" are also discussed as case studies demonstrating various degrees of diagnostic and prognostic capabilities. These include the evaluation of an epicyclic planet gear separation algorithm developed by the DSTO, Australia. Multivariate analysis reasoners, and information fusion requirements and approaches are also discussed. Most recently a strategy is evolving to more fully develop and demonstrate the predictive aspects of prognostics. Finally a full description, recent accomplishments, status and plans for the NAWCAD Helicopter Transmission Test Facility is presented.

Forty-four cases of liver fluke infestation (fascioliasis hepatica) were diagnosed near Chepstow, Monmouthshire, in 1968. Intramuscular emetine hydrochloride and oral chloroquine given to the adults and children, respectively, were well tolerated. Assessment by repeated stool examination, complement fixation and liver function tests, and full blood counts indicated that treatment had been effective in most cases. It is recommended that both the growth and the sale of watercress should be strictly controlled.

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