Splice variants of DOMINO control Drosophila circadian behavior and pacemaker neuron maintenance.

Circadian clocks control daily rhythms in behavior and physiology. In Drosophila, the small ventral lateral neurons (sLNvs) expressing PIGMENT DISPERSING FACTOR (PDF) are the master pacemaker neurons generating locomotor rhythms. Despite the importance of sLNvs and PDF in circadian behavior, little is known about factors that control sLNvs maintenance and PDF accumulation. Here, we identify the Drosophila SWI2/SNF2 protein DOMINO (DOM) as a key regulator of circadian behavior. Depletion of DOM in circadian neurons eliminates morning anticipatory activity under light dark cycle and impairs behavioral rhythmicity in constant darkness. Interestingly, the two major splice variants of DOM, DOM-A and DOM-B have distinct circadian functions. DOM-A depletion mainly leads to arrhythmic behavior, while DOM-B knockdown lengthens circadian period without affecting the circadian rhythmicity. Both DOM-A and DOM-B bind to the promoter regions of key pacemaker genes period and timeless, and regulate their protein expression. However, we identify that only DOM-A is required for the maintenance of sLNvs and transcription of pdf. Lastly, constitutive activation of PDF-receptor signaling rescued the arrhythmia and period lengthening of DOM downregulation. Taken together, our findings reveal that two splice variants of DOM play distinct roles in circadian rhythms through regulating abundance of pacemaker proteins and sLNvs maintenance

Quantitative Analysis of the Fate of Gold Nanocages In Vitro and In Vivo after Uptake by U87-MG Tumor Cells

Not always equal: When a mother cell that contains Au nanocages divides, the nanoparticles are unequally distributed between the two daughter cells. This unequal distribution of nanoparticles as well as their clearance from the cells (see picture) is quantitatively analyzed both in vitro and in vivo using two-photon microscopy and photoacoustic microscopy, respectively

Mechanism and treatment for learning and memory deficits in mouse models of Noonan syndrome.

In Noonan syndrome (NS) 30-50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated mutations in Ptpn11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, show hippocampal-dependent impairments in spatial learning and deficits in hippocampal long-term potentiation (LTP). In addition, viral overexpression of an NS-associated allele PTPN11(D61G) in adult mouse hippocampus results in increased baseline excitatory synaptic function and deficits in LTP and spatial learning, which can be reversed by a mitogen-activated protein kinase kinase (MEK) inhibitor. Furthermore, brief treatment with lovastatin reduces activation of the GTPase Ras-extracellular signal-related kinase (Erk) pathway in the brain and normalizes deficits in LTP and learning in adult Ptpn11(D61G/+) mice. Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS

Development of a novel ozone- and photo-stable HyPer5 red fluorescent dye for array CGH and microarray gene expression analysis with consistent performance irrespective of environmental conditions

<p>Abstract</p> <p>Background</p> <p>Array-based comparative genomic hybridization (CGH) and gene expression profiling have become vital techniques for identifying molecular defects underlying genetic diseases. Regardless of the microarray platform, cyanine dyes (Cy3 and Cy5) are one of the most widely used fluorescent dye pairs for microarray analysis owing to their brightness and ease of incorporation, enabling high level of assay sensitivity. However, combining both dyes on arrays can become problematic during summer months when ozone levels rise to near 25 parts per billion (ppb). Under such conditions, Cy5 is known to rapidly degrade leading to loss of signal from either "homebrew" or commercial arrays. Cy5 can also suffer disproportionately from dye photobleaching resulting in distortion of (Cy5/Cy3) ratios used in copy number analysis. Our laboratory has been active in fluorescent dye research to find a suitable alternative to Cy5 that is stable to ozone and resistant to photo-bleaching. Here, we report on the development of such a dye, called HyPer5, and describe its' exceptional ozone and photostable properties on microarrays.</p> <p>Results</p> <p>Our results show HyPer5 signal to be stable to high ozone levels. Repeated exposure of mouse arrays hybridized with HyPer5-labeled cDNA to 300 ppb ozone at 5, 10 and 15 minute intervals resulted in no signal loss from the dye. In comparison, Cy5 arrays showed a dramatic 80% decrease in total signal during the same interval. Photobleaching experiments show HyPer5 to be resistant to light induced damage with 3- fold improvement in dye stability over Cy5. In high resolution array CGH experiments, HyPer5 is demonstrated to detect chromosomal aberrations at loci 2p21-16.3 and 15q26.3-26.2 from three patient sample using bacterial artificial chromosome (BAC) arrays. The photostability of HyPer5 is further documented by repeat array scanning without loss of detection. Additionally, HyPer5 arrays are shown to preserve sensitivity and data quality from gene expression experiments.</p> <p>Conclusion</p> <p>HyPer5 is a red fluorescent dye that behaves functionally similar to Cy5 except in stability to ozone and light. HyPer5 is demonstrated to be resistant to ozone at up to 300 ppb, levels significantly higher than commonly observed during summer months. Consequently, HyPer5 dye can be used in parallel with Cy3 under any environmental conditions in array experiments.</p

Trajectories of Body Mass Index Among Active-Duty U.S. Army Soldiers

Establishing the shape and determinants of trajectories of body mass index (BMI) among Soldiers is critical given the importance of weight management to military service requirements. To establish the shape and determinants of BMI trajectories among Soldiers, we aimed to (1) model the overall BMI trajectory of Soldiers, (2) find the most common trajectory groups among Soldiers, (3) investigate the relationship between BMI trajectories and sociodemographic and military-specific characteristics, and (4) determine if there were Soldiers with large fluctuations in BMI. The study population included all US Army Soldiers on active-duty between 2011 and 2014 who were age 17–62 (n = 827,126). With longitudinal data from the Stanford Military Data Repository, we used group-based trajectory modeling to identify the BMI trajectories of Soldiers and multinomial logistic regression to estimate associations between Soldier characteristics and trajectory membership. Four distinct BMI trajectory groups were found: increasing, decreasing, constant, and inconstant. The constant, increasing, and decreasing trajectories were similar in shape and percentage between men and women. The constant trajectory had the fewest Soldiers who exceeded weight standards or had duty limitations. The increasing trajectory was associated with marriage and fewer service years. The decreasing trajectory was associated with more service years and higher educational attainment. The inconstant trajectory differed in shape between men and women. Over 6% of men and 12% of women had fluctuations in BMI indicative of weight cycling. Understanding the characteristics associated with BMI trends may assist the Army in targeting resources aimed to improve Soldier health and combat readiness

High atmospheric carbon dioxide-dependent alleviation of salt stress is linked to RESPIRATORY BURST OXIDASE 1 (RBOH1)-dependent H2O2 production in tomato (Solanum lycopersicum)

Plants acclimate rapidly to stressful environmental conditions. Increasing atmospheric CO2 levels are predicted to influence tolerance to stresses such as soil salinity but the mechanisms are poorly understood. To resolve this issue, tomato (Solanum lycopersicum) plants were grown under ambient (380 μmol mol–1) or high (760 μmol mol–1) CO2 in the absence or presence of sodium chloride (100 mM). The higher atmospheric CO2 level induced the expression of RESPIRATORY BURST OXIDASE 1 (SlRBOH1) and enhanced H2O2 accumulation in the vascular cells of roots, stems, leaf petioles, and the leaf apoplast. Plants grown with higher CO2 levels showed improved salt tolerance, together with decreased leaf transpiration rates and lower sodium concentrations in the xylem sap, vascular tissues, and leaves. Silencing SlRBOH1 abolished high CO2 -induced salt tolerance and increased leaf transpiration rates, as well as enhancing Na+ accumulation in the plants. The higher atmospheric CO2 level increased the abundance of a subset of transcripts involved in Na+ homeostasis in the controls but not in the SlRBOH1-silenced plants. It is concluded that high atmospheric CO2 concentrations increase salt stress tolerance in an apoplastic H2O2 dependent manner, by suppressing transpiration and hence Na+ delivery from the roots to the shoots, leading to decreased leaf Na+ accumulation

A multidimensional model of mothers’ perceptions of parent alcohol socialization and adolescent alcohol misuse.

We assessed a multidimensional model of parent alcohol socialization in which key socialization factors were considered simultaneously to identify combinations of factors that increase or decrease risk for development of adolescent alcohol misuse. Of interest was the interplay between putative risk and protective factors, such as whether the typically detrimental effects on youth drinking of parenting practices tolerant of some adolescent alcohol use are mitigated by an effective overall approach to parenting and parental modeling of modest alcohol use. The sample included 1,530 adolescents and their mothers; adolescents’ mean age was 13.0 (SD = .99) at the initial assessment. Latent profile analysis was conducted of mothers’ reports of their attitude toward teen drinking, alcohol-specific parenting practices, parental alcohol use and problem use, and overall approach to parenting. The profiles were used to predict trajectories of adolescent alcohol misuse from early to middle adolescence. Four profiles were identified: two profiles reflected conservative alcohol-specific parenting practices and two reflected alcohol-tolerant practices, all in the context of other attributes. Alcohol misuse accelerated more rapidly from grade 6 through 10 in the two alcohol-tolerant compared with conservative profiles. Results suggest that maternal tolerance of some youth alcohol use, even in the presence of dimensions of an effective parenting style and low parental alcohol use and problem use, is not an effective strategy for reducing risky adolescent alcohol use

Endovascular Thrombectomy for Mild Strokes: How Low Should We Go? A Multicenter Cohort Study

Background and Purpose:Endovascular thrombectomy (EVT) is effective for acute ischemic stroke with large vessel occlusion (LVO) and NIHSS ≥6. However, EVT benefit for mild deficits LVOs (NIHSS Methods: A retrospective cohort of patients with anterior circulation LVO and NIHSSoutcome; mRS=0–2 was the secondary. Symptomatic intracerebral hemorrhage (sICH) was the safety outcome. Clinical outcomes were compared through a multivariable logistic regression after adjusting for age, presentation NIHSS, time-last-seen-normal-to-presentation, center, IV-alteplase, ASPECTS, and thrombus location. We then performed propensity score matching as a sensitivity analysis. Results were also stratified by thrombus location. Results: 214 patients (EVT-124, medical management-90) were included from 8 US and Spain centers between January/2012 and March/2017. The groups were similar in age, ASPECTS, IValteplase rate and time-last-seen-normal-to-presentation. There was no difference in mRS=0–1 between EVT and medical management (55.7% versus 54.4%, respectively, aOR=1.3, 95%CI=0.64–2.64, p=0.47). Similar results were seen for mRS=0–2 (63.3% EVT versus 67.8% medical management, aOR=0.9, 95%CI=0.43–1.88, p=0.77). In a propensity matching analysis, there was no treatment effect in 62 matched pairs (53.5%EVT, 48.4% medical management; OR=1.17, 95%CI=0.54–2.52, p=0.69). There was no statistically significant difference when stratified by any thrombus location; M1 approached significance (p=0.07). sICH rates were higher with thrombectomy (5.8% EVT versus 0% medical management, p=0.02). Conclusions: Our retrospective multicenter cohort study showed no improvement in excellent and independent functional outcomes in mild strokes (NIHS

Motivations, expectations, and experiences of expatriate academic staff on an international branch campus in China

This article explores the experiences of non-Chinese academic staff working on an international branch campus in China. The article presents findings from an interview study that explored the expectations of expatriate staff and what motivated them to want to work abroad. The second part of the article reports on whether and how these expectations and motivations were fulfilled. The findings suggest that, although staff found many benefits from working on the international branch campus, they were insufficiently prepared for the structural and cultural differences inherent in working as an academic in China. The authors argue that more of the academics’ initial expectations and motivations could have been realized if better staff induction and ongoing collective professional development had been in place. In particular, university-level discourse communicated through policy and marketing texts, which promoted the vision of one inclusive and diverse international university community, militated against attention being paid to the structural, political, and cultural differences inherent in working as an academic in China. The authors argue that professional development that acknowledges the differences, difficulties, and disjunctions that staff are likely to encounter in their work is important in building successful international branch campuses both at the level of the organization and of the individual