The Impact of Aging and Estrogen Therapy on Synaptic Mitochondrial Bioenergetics in an Alzheimer\u27s Mouse Model

Mitochondrial dysfunction, such as reductions in ATP production via oxidative phosphorylation, is a recognized pathological symptom of neurodegenerative diseases including Alzheimer\u27s disease (AD). One of the known risk factors for the development of AD is the inheritance of a specific genotype of a lipid transporting protein known as apolipoprotein E (apoE). How apoE contributes to the development and progression of AD is poorly understood. The purpose of this study was to determine if a relationship exists between mitochondrial dysfunction and genetic predisposition to AD via apoE. Mitochondrial bioenergetics and enzymatic activity were investigated in an AD mouse model (apoE KO) and in wild-type (WT) mice. Since AD develops with age, mitochondrial function was studied in both young (4-6 months old) and old (12-22 months old) mice. Additionally, estrogen therapy was utilized as a possible therapeutic to prevent mitochondrial dysfunction. We isolated mitochondria located in nerve cell terminals (synaptosomes) using Percoll gradient centrifugation from WT (C57BL/6J) and apoE KO (Apoetn1Unc) mice. Mitochondria were isolated from the following three treatment groups: mice possessing ovaries injected with vehicle control solution (Sham), ovariectomized mice with vehicle control injection (OVX), and ovariectomized mice with 50 ng/g injection of 17β-estradiol (OVX + E2). Mitochondrial function was evaluated based on oxygen consumption of permeabilized and non-permeabilized synaptosomes and was measured using the OROBOROS Oxygraph-2k at 37°C. Succinate dehydrogenase (SDH) and citrate synthase (CS) activity was also assayed to help elucidate the bioenergetic profile of the isolated synaptosomes. Our results revealed no significant differences in oxygen consumption from intact and permeabilized synaptosomes between Sham and OVX young WT and apoE KO mice. Additionally, no significant differences were detected in SDH and CS activity between young WT and apoE KO mice. However, estrogen treatment dramatically increased oxygen consumption and enzymatic activity in apoE KO for all respiration parameters, whereas, a minimal effect was observed in WT mice. No significant differences in oxygen consumption from permeabilized and intact synaptosomes were detected between young and old OVX and OVX + E2 treated mice, but old Sham mice had significantly higher oxygen consumption rates compared to young Sham mice for most all permeabilized parameters in both WT and apoE KO mice. Estrogen treatment had no effect on mitochondrial respiration in old mice, but estrogen treated old apoE KO mice had significantly higher SDH activity compared to its Sham. Increases in respiration and enzymatic activity prompted investigation of mitochondrial quantity via Western blot. We used the voltage dependent-anion-channel (VDAC) as a mitochondrial quantity marker. The results revealed that estrogen treatment increased mitochondrial quantity in estrogen treated young apoE KO and old Sham mice. We speculate that increases in mitochondrial quantity in young apoE KO mice and old Sham mice were due to estrogen and reactive oxygen species (ROS) induced mitochondrial biogenesis, respectively. Our data suggests that predisposition of AD via apoE inheritance is not an underlying source of mitochondrial abnormalities; however, the effectiveness of estrogen as a neuro-therapeutic may be dependent upon an individual\u27s apoE genotype, as well as, their age

The Impact of Aging and Estrogen Therapy on Synaptic Mitochondrial Bioenergetics in an Alzheimer\u27s Mouse Model

Mitochondrial dysfunction, such as reductions in ATP production via oxidative phosphorylation, is a recognized pathological symptom of neurodegenerative diseases including Alzheimer\u27s disease (AD). One of the known risk factors for the development of AD is the inheritance of a specific genotype of a lipid transporting protein known as apolipoprotein E (apoE). How apoE contributes to the development and progression of AD is poorly understood. The purpose of this study was to determine if a relationship exists between mitochondrial dysfunction and genetic predisposition to AD via apoE. Mitochondrial bioenergetics and enzymatic activity were investigated in an AD mouse model (apoE KO) and in wild-type (WT) mice. Since AD develops with age, mitochondrial function was studied in both young (4-6 months old) and old (12-22 months old) mice. Additionally, estrogen therapy was utilized as a possible therapeutic to prevent mitochondrial dysfunction. We isolated mitochondria located in nerve cell terminals (synaptosomes) using Percoll gradient centrifugation from WT (C57BL/6J) and apoE KO (Apoetn1Unc) mice. Mitochondria were isolated from the following three treatment groups: mice possessing ovaries injected with vehicle control solution (Sham), ovariectomized mice with vehicle control injection (OVX), and ovariectomized mice with 50 ng/g injection of 17β-estradiol (OVX + E2). Mitochondrial function was evaluated based on oxygen consumption of permeabilized and non-permeabilized synaptosomes and was measured using the OROBOROS Oxygraph-2k at 37°C. Succinate dehydrogenase (SDH) and citrate synthase (CS) activity was also assayed to help elucidate the bioenergetic profile of the isolated synaptosomes. Our results revealed no significant differences in oxygen consumption from intact and permeabilized synaptosomes between Sham and OVX young WT and apoE KO mice. Additionally, no significant differences were detected in SDH and CS activity between young WT and apoE KO mice. However, estrogen treatment dramatically increased oxygen consumption and enzymatic activity in apoE KO for all respiration parameters, whereas, a minimal effect was observed in WT mice. No significant differences in oxygen consumption from permeabilized and intact synaptosomes were detected between young and old OVX and OVX + E2 treated mice, but old Sham mice had significantly higher oxygen consumption rates compared to young Sham mice for most all permeabilized parameters in both WT and apoE KO mice. Estrogen treatment had no effect on mitochondrial respiration in old mice, but estrogen treated old apoE KO mice had significantly higher SDH activity compared to its Sham. Increases in respiration and enzymatic activity prompted investigation of mitochondrial quantity via Western blot. We used the voltage dependent-anion-channel (VDAC) as a mitochondrial quantity marker. The results revealed that estrogen treatment increased mitochondrial quantity in estrogen treated young apoE KO and old Sham mice. We speculate that increases in mitochondrial quantity in young apoE KO mice and old Sham mice were due to estrogen and reactive oxygen species (ROS) induced mitochondrial biogenesis, respectively. Our data suggests that predisposition of AD via apoE inheritance is not an underlying source of mitochondrial abnormalities; however, the effectiveness of estrogen as a neuro-therapeutic may be dependent upon an individual\u27s apoE genotype, as well as, their age

Influence network linkages across implementation strategy conditions in a randomized controlled trial of two strategies for scaling up evidence-based practices in public youth-serving systems.

BackgroundGiven the importance of influence networks in the implementation of evidence-based practices and interventions, it is unclear whether such networks continue to operate as sources of information and advice when they are segmented and disrupted by randomization to different implementation strategy conditions. The present study examines the linkages across implementation strategy conditions of social influence networks of leaders of youth-serving systems in 12 California counties participating in a randomized controlled trial of community development teams (CDTs) to scale up use of an evidence-based practice.MethodsSemi-structured interviews were conducted with 38 directors, assistant directors, and program managers of county probation, mental health, and child welfare departments. A web-based survey collected additional quantitative data on information and advice networks of study participants. A mixed-methods approach to data analysis was used to create a sociometric data set (n = 176) to examine linkages between treatment and standard conditions.ResultsOf those network members who were affiliated with a county (n = 137), only 6 (4.4%) were directly connected to a member of the opposite implementation strategy condition; 19 (13.9%) were connected by two steps or fewer to a member of the opposite implementation strategy condition; 64 (46.7%) were connected by three or fewer steps to a member of the opposite implementation strategy condition. Most of the indirect steps between individuals who were in different implementation strategy conditions were connections involving a third non-county organizational entity that had an important role in the trial in keeping the implementation strategy conditions separate. When these entities were excluded, the CDT network exhibited fewer components and significantly higher betweenness centralization than did the standard condition network.ConclusionAlthough the integrity of the RCT in this instance was not compromised by study participant influence networks, RCT designs should consider how influence networks may extend beyond boundaries established by the randomization process in implementation studies.Trial registrationNCT00880126

Electrical Cable Design for Urban Air Mobility Aircraft

Urban Air Mobility (UAM) describes a new type of aviation focused on efficient flight within urban areas for moving people and goods. There are many different configurations of UAM vehicles, but they generally use an electric motor driving a propeller or ducted fan powered by batteries or a hybrid electric power generation system. Transmission cables are used to move energy from the storage or generation system to the electric motors. Though terrestrial power transmission cables are well established technology, aviation applications bring a whole host of new design challenges that are not typical considerations in terrestrial applications. Aircraft power transmission cable designs must compromise between resistance-per-length, weight-per-length, volume constraints, and other essential qualities. In this paper we use a multidisciplinary design optimization to explore the sensitivity of these qualities to a representative tiltwing turboelectric UAM aircraft concept. This is performed by coupling propulsion and thermal models for a given mission criteria. Results presented indicate that decreasing cable weight at the expense of increasing cable volume or cooling demand is effective at minimizing maximum takeoff weight (MTO). These findings indicate that subsystem designers should update their modeling approach in order to contribute to system-level optimality for highly-coupled novel aircraft. Mobility (UAM) vehicles have the potential to change urban and intra-urban transport in new and interesting ways. In a series of two papers Johnson et al.1 and Silva et al.2 presented four reference vehicle configurations that could service different niches in the UAM aviation category. Of those, this paper focuses on the Vertical Take-off and Landing (VTOL) tiltwing configuration shown in Figure 1. This configuration uses a turboelectric power system, feeding power from a turbo-generator through a system of transmission cables to four motors spinning large propellers on the wings. Previous work on electric cable subsystems leaves much yet to be explored, especially in the realm of subsystem coupling. Several aircraft optimization studies1, 3, 4 only considered aircraft electrical cable weight and ignored thermal effects. Electric and hybrid-electric aircraft studies by Mueller et al.5 and Hoelzen et al.6 selected a cable material but did not investigate alternative materials. Advanced cable materials have been examined by a number of authors: Alvarenga7 examined carbon nanotube (CNT) conductors for low-power applications. De Groh8, 9 examined CNT conductors for motor winding applications. Behabtu et al.,10 and Zhao et al.11 examined CNT conductors for a general applications. There were some studies that examined the thermal effects of cables but they did not allow the cable material to change; El-Kady12 optimized ground-cable insulation and cooling subject constraints. Vratny13 selected cable material based on vehicle power demand, and required resulting cable heat to be dissipated by the Thermal Management System (TMS). None of these previous studies allowed for the selection of the cable material based on a system level optimization goal. Instead, they focused on sub-system optimality such as minimum weight, which comes at the expense of incurring additional costs for other subsystems. Dama14 selected overhead transmission line materials using a weighting function and thermal constraints. However, that work was not coupled with any aircraft subsystems like a TMS. The traditional aircraft design approach, which relies on assembling groups of optimal subsystems, breaks down when considering novel aircraft concepts like the tiltwing vehicle. In a large part, this is because novel concepts have a much higher degree of interaction or coupling between subsystems. For example, when a cable creates heat, this heat needs to be dissipated by the TMS, which needs power supplied by the turbine, and delivering the power creates more heat. The cable, the TMS, and the turbine are all coupled. A change to one subsystem will affect all the other subsystems, much to the consternation of subsystem design experts. Multidisciplinary optimization is the design approach that can address these challenges. However, to fully take advantage of this, we must change the way we think about subsystem design. Specifically, we must move away from point design, and focus on creating solution spaces. The work presented in this paper uses the multidisciplinary optimization approach with aircraft level models to study the system-level sensitivity of cable traits: weight-per-length and resistance-per-length. Additionally, we examined the effects of vehicle imposed volume constraints on these traits. This is useful for three purposes: (1) to demonstrate a framework that can perform a coupled analysis between the aircraft thermal and propulsion systems, (2) to provide a method by which future cable designs can be evaluated against each other given a system-level design goal, (3) to provide insight into what cable properties may be promising for future research. This last element is explored given the caveat that the models contained in this analysis do not represent high-fidelity systems. Thus, while we can demonstrate coupling in between systems, the exact system-level sensitivity to a given parameter may change if a subsystem model or the assumptions governing that model change. The organization of this paper is as follows, in Sec II we outline a method to combine the VTOL vehicle design and cable information in order to produce cables sensitivity studies. Results analysis and discussion are contained in Sec III. Conclusions are presented in Sec IV

Load Flow Analysis with Analytic Derivatives for Electric Aircraft Design Optimization

Many of the aircraft concepts of the future are exploring the use of hybrid-, turbo- or all-electric propulsion systems to improve performance and decrease environmental impacts. These aircraft concepts range from small rotorcraft for urban air mobility to conventional commercial transports to large blended wing body designs. Developing the conceptual design for these vehicles presents a challenge, however, as traditional aircraft design tools often were not developed to handle these unique propulsion system architectures. Previous studies on these vehicles have therefore relied on relatively simple models of the electrical transmission and distribution system. This paper presents the development of a hybrid AC-DC load flow (or power flow) analysis capability to enhance the conceptual design of these concept vehicles. Specifically, the desire was to create a load flow analysis capability within the OpenMDAO framework that is also being used to develop a set of compatible tools for rapid optimization of conceptual designs. This load flow analysis capability is unique in its flexible object-oriented structure and implementation of analytic derivatives to facilitate the use of solvers and gradient based optimization in the design process. The developed hybrid load flow analysis capability is first verified against a published 13-bus example then used to model the electrical distribution system for a turbo-electric tiltwing aircraft

Phenotypic and Genotypic Characterization of Escherichia coli Isolated from Untreated Surface Waters

A common member of the intestinal microbiota in humans and animals is Escherichia coli. Based on the presence of virulence factors, E. coli can be potentially pathogenic. The focus of this study was to isolate E. coli from untreated surface waters (37 sites) in Illinois and Missouri and determine phenotypic and genotypic diversity among isolates. Water samples positive for fecal coliforms based on the Colisure® test were streaked directly onto Eosin Methylene Blue (EMB) agar (37°C) or transferred to EC broth (44.5°C). EC broth cultures producing gas were then streaked onto EMB agar. Forty-five isolates were identified as E. coli using API 20E and Enterotube II identification systems, and some phenotypic variation was observed in metabolism and fermentation. Antibiotic susceptibility of each isolate was also determined using the Kirby-Bauer Method. Differential responses to 10 antimicrobial agents were seen with 7, 16, 2, and 9 of the isolates resistant to ampicillin, cephalothin, tetracycline, and triple sulfonamide, respectively. All of the isolates were susceptible or intermediate to amoxicillin, ciprofloxacin, polymyxin B, gentamicin, imipenem, and nalidixic acid. Genotypic variation was assessed through multiplex Polymerase Chain Reaction for four virulence genes (stx1 and stx2 [shiga toxin], eaeA [intimin]; and hlyA [enterohemolysin]) and one housekeeping gene (uidA [-D-glucuronidase]). Genotypic variation was observed with two of the isolates possessing the virulence gene (eaeA) for intimin. These findings increase our understanding of the diversity of E. coli in the environment which will ultimately help in the assessment of this organism and its role in public health

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

A View of Tropical Cyclones from Above: The Tropical Cyclone Intensity Experiment

Tropical cyclone (TC) outflow and its relationship to TC intensity change and structure were investigated in the Office of Naval Research Tropical Cyclone Intensity (TCI) field program during 2015 using dropsondes deployed from the innovative new High-Definition Sounding System (HDSS) and remotely sensed observations from the Hurricane Imaging Radiometer (HIRAD), both on board the NASA WB-57 that flew in the lower stratosphere. Three noteworthy hurricanes were intensively observed with unprecedented horizontal resolution: Joaquin in the Atlantic and Marty and Patricia in the eastern North Pacific. Nearly 800 dropsondes were deployed from the WB-57 flight level of ∼60,000 ft (∼18 km), recording atmospheric conditions from the lower stratosphere to the surface, while HIRAD measured the surface winds in a 50-km-wide swath with a horizontal resolution of 2 km. Dropsonde transects with 4–10-km spacing through the inner cores of Hurricanes Patricia, Joaquin, and Marty depict the large horizontal and vertical gradients in winds and thermodynamic properties. An innovative technique utilizing GPS positions of the HDSS reveals the vortex tilt in detail not possible before. In four TCI flights over Joaquin, systematic measurements of a major hurricane’s outflow layer were made at high spatial resolution for the first time. Dropsondes deployed at 4-km intervals as the WB-57 flew over the center of Hurricane Patricia reveal in unprecedented detail the inner-core structure and upper-tropospheric outflow associated with this historic hurricane. Analyses and numerical modeling studies are in progress to understand and predict the complex factors that influenced Joaquin’s and Patricia’s unusual intensity changes

Development of the PSYCHS: Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS

Aim: To harmonize two ascertainment and severity rating instruments commonly used for the clinical high risk syndrome for psychosis (CHR-P): the Structured Interview for Psychosis-risk Syndromes (SIPS) and the Comprehensive Assessment of At-Risk Mental States (CAARMS). Methods: The initial workshop is described in the companion report from Addington et al. After the workshop, lead experts for each instrument continued harmonizing attenuated positive symptoms and criteria for psychosis and CHR-P through an intensive series of joint videoconferences. Results: Full harmonization was achieved for attenuated positive symptom ratings and psychosis criteria, and modest harmonization for CHR-P criteria. The semi-structured interview, named Positive SYmptoms and Diagnostic Criteria for the CAARMS Harmonized with the SIPS (PSYCHS), generates CHR-P criteria and severity scores for both CAARMS and SIPS. Conclusions: Using the PSYCHS for CHR-P ascertainment, conversion determination, and attenuated positive symptom severity rating will help in comparing findings across studies and in meta-analyses

State of the climate in 2018

In 2018, the dominant greenhouse gases released into Earth’s atmosphere—carbon dioxide, methane, and nitrous oxide—continued their increase. The annual global average carbon dioxide concentration at Earth’s surface was 407.4 ± 0.1 ppm, the highest in the modern instrumental record and in ice core records dating back 800 000 years. Combined, greenhouse gases and several halogenated gases contribute just over 3 W m−2 to radiative forcing and represent a nearly 43% increase since 1990. Carbon dioxide is responsible for about 65% of this radiative forcing. With a weak La Niña in early 2018 transitioning to a weak El Niño by the year’s end, the global surface (land and ocean) temperature was the fourth highest on record, with only 2015 through 2017 being warmer. Several European countries reported record high annual temperatures. There were also more high, and fewer low, temperature extremes than in nearly all of the 68-year extremes record. Madagascar recorded a record daily temperature of 40.5°C in Morondava in March, while South Korea set its record high of 41.0°C in August in Hongcheon. Nawabshah, Pakistan, recorded its highest temperature of 50.2°C, which may be a new daily world record for April. Globally, the annual lower troposphere temperature was third to seventh highest, depending on the dataset analyzed. The lower stratospheric temperature was approximately fifth lowest. The 2018 Arctic land surface temperature was 1.2°C above the 1981–2010 average, tying for third highest in the 118-year record, following 2016 and 2017. June’s Arctic snow cover extent was almost half of what it was 35 years ago. Across Greenland, however, regional summer temperatures were generally below or near average. Additionally, a satellite survey of 47 glaciers in Greenland indicated a net increase in area for the first time since records began in 1999. Increasing permafrost temperatures were reported at most observation sites in the Arctic, with the overall increase of 0.1°–0.2°C between 2017 and 2018 being comparable to the highest rate of warming ever observed in the region. On 17 March, Arctic sea ice extent marked the second smallest annual maximum in the 38-year record, larger than only 2017. The minimum extent in 2018 was reached on 19 September and again on 23 September, tying 2008 and 2010 for the sixth lowest extent on record. The 23 September date tied 1997 as the latest sea ice minimum date on record. First-year ice now dominates the ice cover, comprising 77% of the March 2018 ice pack compared to 55% during the 1980s. Because thinner, younger ice is more vulnerable to melting out in summer, this shift in sea ice age has contributed to the decreasing trend in minimum ice extent. Regionally, Bering Sea ice extent was at record lows for almost the entire 2017/18 ice season. For the Antarctic continent as a whole, 2018 was warmer than average. On the highest points of the Antarctic Plateau, the automatic weather station Relay (74°S) broke or tied six monthly temperature records throughout the year, with August breaking its record by nearly 8°C. However, cool conditions in the western Bellingshausen Sea and Amundsen Sea sector contributed to a low melt season overall for 2017/18. High SSTs contributed to low summer sea ice extent in the Ross and Weddell Seas in 2018, underpinning the second lowest Antarctic summer minimum sea ice extent on record. Despite conducive conditions for its formation, the ozone hole at its maximum extent in September was near the 2000–18 mean, likely due to an ongoing slow decline in stratospheric chlorine monoxide concentration. Across the oceans, globally averaged SST decreased slightly since the record El Niño year of 2016 but was still far above the climatological mean. On average, SST is increasing at a rate of 0.10° ± 0.01°C decade−1 since 1950. The warming appeared largest in the tropical Indian Ocean and smallest in the North Pacific. The deeper ocean continues to warm year after year. For the seventh consecutive year, global annual mean sea level became the highest in the 26-year record, rising to 81 mm above the 1993 average. As anticipated in a warming climate, the hydrological cycle over the ocean is accelerating: dry regions are becoming drier and wet regions rainier. Closer to the equator, 95 named tropical storms were observed during 2018, well above the 1981–2010 average of 82. Eleven tropical cyclones reached Saffir–Simpson scale Category 5 intensity. North Atlantic Major Hurricane Michael’s landfall intensity of 140 kt was the fourth strongest for any continental U.S. hurricane landfall in the 168-year record. Michael caused more than 30 fatalities and $25 billion (U.S. dollars) in damages. In the western North Pacific, Super Typhoon Mangkhut led to 160 fatalities and$6 billion (U.S. dollars) in damages across the Philippines, Hong Kong, Macau, mainland China, Guam, and the Northern Mariana Islands. Tropical Storm Son-Tinh was responsible for 170 fatalities in Vietnam and Laos. Nearly all the islands of Micronesia experienced at least moderate impacts from various tropical cyclones. Across land, many areas around the globe received copious precipitation, notable at different time scales. Rodrigues and Réunion Island near southern Africa each reported their third wettest year on record. In Hawaii, 1262 mm precipitation at Waipā Gardens (Kauai) on 14–15 April set a new U.S. record for 24-h precipitation. In Brazil, the city of Belo Horizonte received nearly 75 mm of rain in just 20 minutes, nearly half its monthly average. Globally, fire activity during 2018 was the lowest since the start of the record in 1997, with a combined burned area of about 500 million hectares. This reinforced the long-term downward trend in fire emissions driven by changes in land use in frequently burning savannas. However, wildfires burned 3.5 million hectares across the United States, well above the 2000–10 average of 2.7 million hectares. Combined, U.S. wildfire damages for the 2017 and 2018 wildfire seasons exceeded $40 billion (U.S. dollars)