Human NR5A1/SF-1 mutations show decreased activity on BDNF (brain-derived neurotrophic factor), an important regulator of energy balance: testing impact of novel SF-1 mutations beyond steroidogenesis

CONTEXT Human NR5A1/SF-1 mutations cause 46,XY disorder of sex development (DSD) with broad phenotypic variability, and rarely cause adrenal insufficiency although SF-1 is an important transcription factor for many genes involved in steroidogenesis. In addition, the Sf-1 knockout mouse develops obesity with age. Obesity might be mediated through Sf-1 regulating activity of brain-derived neurotrophic factor (BDNF), an important regulator of energy balance in the ventromedial hypothalamus. OBJECTIVE To characterize novel SF-1 gene variants in 4 families, clinical, genetic and functional studies were performed with respect to steroidogenesis and energy balance. PATIENTS 5 patients with 46,XY DSD were found to harbor NR5A1/SF-1 mutations including 2 novel variations. One patient harboring a novel mutation also suffered from adrenal insufficiency. METHODS SF-1 mutations were studied in cell systems (HEK293, JEG3) for impact on transcription of genes involved in steroidogenesis (CYP11A1, CYP17A1, HSD3B2) and in energy balance (BDNF). BDNF regulation by SF-1 was studied by promoter assays (JEG3). RESULTS Two novel NR5A1/SF-1 mutations (Glu7Stop, His408Profs*159) were confirmed. Glu7Stop is the 4th reported SF-1 mutation causing DSD and adrenal insufficiency. In vitro studies revealed that transcription of the BDNF gene is regulated by SF-1, and that mutant SF-1 decreased BDNF promoter activation (similar to steroid enzyme promoters). However, clinical data from 16 subjects carrying SF-1 mutations showed normal birth weight and BMI. CONCLUSIONS Glu7Stop and His408Profs*159 are novel SF-1 mutations identified in patients with 46,XY DSD and adrenal insufficiency (Glu7Stop). In vitro, SF-1 mutations affect not only steroidogenesis but also transcription of BDNF which is involved in energy balance. However, in contrast to mice, consequences on weight were not found in humans with SF-1 mutations.

Instrument for testing the impact response of different materials. Application to apples and pears

Based on two research projects, a device for testing the response to-impact of fruits and related materials has been designed and tested during the last three years. As it is not related directly to potatoes, this contribution focuses mainly on the principles of impact and static loading and on the description of the device, and the type of results obtained up to now in different fruits.

Impact of lung function testing on hemodynamic values : concordance between non-invasive and invasive measures

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

Evaluation of innovative state and community alcohol projects: breath alcohol testing program, effectiveness, impact and transferability. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Dynamic testing for side crush MRB-to-car side impact test of a 90 degree moving rigid barrier to a 1980 Ford LTD: Test #1 - 20.9 mph, test #2 - 42.1 mph. Test report.

Mode of access: Internet.

Dynamic testing for side crush MRB-to-car side impact test of a 90 degree moving rigid barrier to a 1983 Ford Escort: test #1 - 16.1 mph, test #2 - 32.2 mph. Test report.

Mode of access: Internet.

Dynamic testing for side crush MRB-to-car side impact test of a 90 [degree] moving rigid barrier to a 1980 Chevrolet Citation: test #1 - 18.5 mph, test #2 - 46.6 mph. Test report.

Mode of access: Internet.

Side impact crash testing of roadside structures. Final report.

Federal Highway Administration, Washington, D.C.

Dynamic testing of luminaire supports with an improved pendulum impact facility. Final report.

Mode of access: Internet.

The impact of neurodynamic testing on the perception of experimentally induced muscle pain

Neurodynamic tests such as the straight leg raising (SLR) and slump test are frequently used for assessment of mechanosensitivity of neural tissues. However, there is ongoing debate in the literature regarding the contributions of neural and non-neural tissues to the elicited symptoms because many structures are affected by these tests. Sensitizing manoeuvres are limb or spinal movements added to neurodynamic tests, which aim to identify the origin of the symptoms by preferentially loading or unloading neural structures. A prerequisite for the use of sensitizing manoeuvres to identify neural involvement is that the addition of sensitizing manoeuvres has no impact on pain perception when the origin of the pain is non-neural. In this study, experimental muscle pain was induced by injection of hypertonic saline in tibialis anterior or soleus in 25 asymptomatic, naive volunteers. A first experiment investigated the impact of hip adduction, abduction, medial and lateral rotation in the SLR position. In a second experiment, the different stages of the slump test were examined. The intensity and area of experimentally induced muscle pain did not increase when sensitizing manoeuvres were added to the SLR or throughout the successive stages of the slump test. The findings of this study lend support to the validity of the use of sensitizing manoeuvres during neurodynamic testing. (C) 2004 Elsevier Ltd. All rights reserved.

The impact of *experience, industry characteristics, and individual differences on audit risk and the extent of testing decisions: An empirical investigation

The first part of the study examined the effect of industry risk changes on perceived audit risk at the financial statement level and whether these changes depended on individual differences such as experience and tolerance for ambiguity. ^ Forty-eight auditors from two offices of one of the “Big 5” CPA firms participated in this study. The ANOVA results supported the effect of industry risk in the assessment of audit risk at the financial statement level. Higher industry risk was associated with higher perceived audit risk. Tolerance for ambiguity was also significant in explaining the changes in the assessment of audit risk. Auditors with a high tolerance for ambiguity perceived lower audit risk than auditors with a low tolerance for ambiguity. Although ANOVA results did not find experience to be significant, a t-test for experience showed it to be marginally significant and inversely related to audit risk. ^ The second part of this study examined whether differences in perceived audit risk at the financial statement level altered the extent, nature or timing of the planned auditing procedures. The results of the MANOVA suggested an overall audit risk effect at the financial statement level. Perceived audit risk was significant in explaining the variation in the number of hours planned for the total cycle and the number of hours p1anned for the tests of balances and details. Perceived audit risk was not significant in determining the analytical review procedures planned, but assessed inherent risk at the cycle level was significant. The higher the inherent risk the more analytical procedures were planned. Perceived audit risk was not significant in explaining the timing of the procedures, but individual differences were significant. The results showed that experienced auditors and those with a high tolerance for ambiguity were less likely to postpone the performance of the interim procedures or the time at which the majority of audit work would be done. ^

Impact of Genetic Testing and Family Health History Based Risk Counseling on Behavior Change and Cognitive Precursors for Type 2 Diabetes.

Family health history (FHH) in the context of risk assessment has been shown to positively impact risk perception and behavior change. The added value of genetic risk testing is less certain. The aim of this study was to determine the impact of Type 2 Diabetes (T2D) FHH and genetic risk counseling on behavior and its cognitive precursors. Subjects were non-diabetic patients randomized to counseling that included FHH +/- T2D genetic testing. Measurements included weight, BMI, fasting glucose at baseline and 12 months and behavioral and cognitive precursor (T2D risk perception and control over disease development) surveys at baseline, 3, and 12 months. 391 subjects enrolled of which 312 completed the study. Behavioral and clinical outcomes did not differ across FHH or genetic risk but cognitive precursors did. Higher FHH risk was associated with a stronger perceived T2D risk (pKendall < 0.001) and with a perception of "serious" risk (pKendall < 0.001). Genetic risk did not influence risk perception, but was correlated with an increase in perception of "serious" risk for moderate (pKendall = 0.04) and average FHH risk subjects (pKendall = 0.01), though not for the high FHH risk group. Perceived control over T2D risk was high and not affected by FHH or genetic risk. FHH appears to have a strong impact on cognitive precursors of behavior change, suggesting it could be leveraged to enhance risk counseling, particularly when lifestyle change is desirable. Genetic risk was able to alter perceptions about the seriousness of T2D risk in those with moderate and average FHH risk, suggesting that FHH could be used to selectively identify individuals who may benefit from genetic risk testing.

Learning from one another: evaluating the impact of horizontal knowledge exchange for environmental management and governance

There is increasing advocacy for inclusive community-based approaches to environmental management, and growing evidence that involving communities improves the sustainability of social-ecological systems. Most community-based approaches rely on partnerships and knowledge exchange between communities, civil society organizations, and professionals such as practitioners and/or scientists. However, few models have actively integrated more horizontal knowledge exchange from community to community. We reflect on the transferability of community owned solutions between indigenous communities by exploring challenges and achievements of community peer-to-peer knowledge exchange as a way of empowering communities to face up to local environmental and social challenges. Using participatory visual methods, indigenous communities of the North Rupununi (Guyana) identified and documented their community owned solutions through films and photostories. Indigenous researchers from this community then shared their solutions with six other communities that faced similar challenges within Guyana, Suriname, Venezuela, Colombia, French Guiana, and Brazil. They were supported by in-country civil society organizations and academics. We analyzed the impact of the knowledge exchange through interviews, field reports, and observations. Our results show that indigenous community members were significantly more receptive to solutions emerging from, and communicated by, other indigenous peoples, and that this approach was a significant motivating force for galvanizing communities to make changes in their community. We identified a range of enabling factors, such as building capacity for a shared conceptual and technical understanding, that strengthens the exchange between communities and contributes to a lasting impact. With national and international policy-makers mobilizing significant financial resources for biodiversity conservation and climate change mitigation, we argue that the promotion of community owned solutions through community peer-to-peer exchange may deliver more long-lasting, socially and ecologically integrated, and investment-effective strategies compared to top-down, expert led, and/or foreign-led initiatives.

Multi-Scale Dynamic Study of Secondary Impact During Drop Testing of Surface Mount Packages

This dissertation focuses on design challenges caused by secondary impacts to printed wiring assemblies (PWAs) within hand-held electronics due to accidental drop or impact loading. The continuing increase of functionality, miniaturization and affordability has resulted in a decrease in the size and weight of handheld electronic products. As a result, PWAs have become thinner and the clearances between surrounding structures have decreased. The resulting increase in flexibility of the PWAs in combination with the reduced clearances requires new design rules to minimize and survive possible internal collisions impacts between PWAs and surrounding structures. Such collisions are being termed ‘secondary impact’ in this study. The effect of secondary impact on board-level drop reliability of printed wiring boards (PWBs) assembled with MEMS microphone components, is investigated using a combination of testing, response and stress analysis, and damage modeling. The response analysis is conducted using a combination of numerical finite element modeling and simplified analytic models for additional parametric sensitivity studies.

Probabilistic design optimization of horizontal axis wind turbine rotors

Considerable interest in renewable energy has increased in recent years due to the concerns raised over the environmental impact of conventional energy sources and their price volatility. In particular, wind power has enjoyed a dramatic global growth in installed capacity over the past few decades. Nowadays, the advancement of wind turbine industry represents a challenge for several engineering areas, including materials science, computer science, aerodynamics, analytical design and analysis methods, testing and monitoring, and power electronics. In particular, the technological improvement of wind turbines is currently tied to the use of advanced design methodologies, allowing the designers to develop new and more efficient design concepts. Integrating mathematical optimization techniques into the multidisciplinary design of wind turbines constitutes a promising way to enhance the profitability of these devices. In the literature, wind turbine design optimization is typically performed deterministically. Deterministic optimizations do not consider any degree of randomness affecting the inputs of the system under consideration, and result, therefore, in an unique set of outputs. However, given the stochastic nature of the wind and the uncertainties associated, for instance, with wind turbine operating conditions or geometric tolerances, deterministically optimized designs may be inefficient. Therefore, one of the ways to further improve the design of modern wind turbines is to take into account the aforementioned sources of uncertainty in the optimization process, achieving robust configurations with minimal performance sensitivity to factors causing variability. The research work presented in this thesis deals with the development of a novel integrated multidisciplinary design framework for the robust aeroservoelastic design optimization of multi-megawatt horizontal axis wind turbine (HAWT) rotors, accounting for the stochastic variability related to the input variables. The design system is based on a multidisciplinary analysis module integrating several simulations tools needed to characterize the aeroservoelastic behavior of wind turbines, and determine their economical performance by means of the levelized cost of energy (LCOE). The reported design framework is portable and modular in that any of its analysis modules can be replaced with counterparts of user-selected fidelity. The presented technology is applied to the design of a 5-MW HAWT rotor to be used at sites of wind power density class from 3 to 7, where the mean wind speed at 50 m above the ground ranges from 6.4 to 11.9 m/s. Assuming the mean wind speed to vary stochastically in such range, the rotor design is optimized by minimizing the mean and standard deviation of the LCOE. Airfoil shapes, spanwise distributions of blade chord and twist, internal structural layup and rotor speed are optimized concurrently, subject to an extensive set of structural and aeroelastic constraints. The effectiveness of the multidisciplinary and robust design framework is demonstrated by showing that the probabilistically designed turbine achieves more favorable probabilistic performance than those of the initial baseline turbine and a turbine designed deterministically.