Regional-Specific Effects of Ovarian Hormone Loss on Synaptic Plasticity in Adult Human APOE Targeted Replacement Mice

The human apolipoprotein ε4 allele (APOE4) has been implicated as one of the strongest genetic risk factors associated with Alzheimer’s disease (AD) and in influencing normal cognitive functioning. Previous studies have demonstrated that mice expressing human apoE4 display deficits in behavioral and neurophysiological outcomes compared to those with apoE3. Ovarian hormones have also been shown to be important in modulating synaptic processes underlying cognitive function, yet little is known about how their effects are influenced by apoE. In the current study, female adult human APOE targeted replacement (TR) mice were utilized to examine the effects of human APOE genotype and long-term ovarian hormone loss on synaptic plasticity in limbic regions by measuring dendritic spine density and electrophysiological function. No significant genotype differences were observed on any outcomes within intact mice. However, there was a significant main effect of genotype on total spine density in apical dendrites in the hippocampus, with post-hoc t-tests revealing a significant reduction in spine density in apoE3 ovariectomized (OVX) mice compared to sham operated mice. There was also a significant main effect of OVX on the magnitude of LTP, with post-hoc t-tests revealing a decrease in apoE3 OVX mice relative to sham. In contrast, apoE4 OVX mice showed increased synaptic activity relative to sham. In the lateral amygdala, there was a significant increase in total spine density in apoE4 OVX mice relative to sham. This increase in spine density was consistent with a significant increase in spontaneous excitatory activity in apoE4 OVX mice. These findings suggest that ovarian hormones differentially modulate synaptic integrity in an apoE-dependent manner within brain regions that are susceptible to neurophysiological dysfunction associated with AD

Factors that Influence Enrollment in Syringe Services Programs in Rural Areas: A Qualitative Study among Program Clients in Appalachian Kentucky

BACKGROUND: Enrolling sufficient number of people who inject drugs (PWID) into syringe services programs (SSP) is important to curtail outbreaks of drug-related harms. Still, little is known about barriers and facilitators to SSP enrollment in rural areas with no history of such programs. This study\u27s purpose was to develop a grounded theory of the role of the risk environment and individual characteristics of PWID in shaping SSP enrollment in rural Kentucky. METHODS: We conducted one-on-one semi-structured interviews with 41 clients of 5 SSPs that were established in rural counties in Appalachian Kentucky in 2017-2018. Interviews covered PWID needs, the process of becoming aware of SSPs, and barriers and facilitators to SSP enrollment. Applying constructivist grounded theory methods and guided by the Intersectional Risk Environment Framework (IREF), we applied open, axial and selective coding to develop the grounded theory. RESULTS: Stigma, a feature of IREF\u27s meso-level social domain, is the main factor hampering SSP enrollment. PWID hesitated to visit SSPs because of internalized stigma and because of anticipated stigma from police, friends, family and healthcare providers. Fear of stigma was often mitigated or amplified by a constellation of meso-level environmental factors related to healthcare (e.g., SSPs) and social (PWID networks) domains and by PWID\u27s individual characteristics. SSPs mitigated stigma as a barrier to enrollment by providing low threshold services in a friendly atmosphere, and by offering their clients program IDs to protect them from paraphernalia charges. SSP clients spread positive information about the program within PWID networks and helped their hesitant peers to enroll by accompanying them to SSPs. Individual characteristics, including child custody, employment or high social status, made certain PWID more susceptible to drug-related stigma and hence more likely to delay SSP enrollment. CONCLUSIONS: Features of the social and healthcare environments operating at the meso-level, as well as PWID\u27s individual characteristics, appear to enhance or mitigate the effect of stigma as a barrier to SSP enrollment. SSPs opening in locations with high stigma against PWID need to ensure low threshold and friendly services, protect their clients from police and mobilize PWID networks to promote enrollment

Guidelines for DNA recombination and repair studies: Cellular assays of DNA repair pathways

Understanding the plasticity of genomes has been greatly aided by assays for recombination, repair and mutagenesis. These assays have been developed in microbial systems that provide the advantages of genetic and molecular reporters that can readily be manipulated. Cellular assays comprise genetic, molecular, and cytological reporters. The assays are powerful tools but each comes with its particular advantages and limitations. Here the most commonly used assays are reviewed, discussed, and presented as the guidelines for future studies.European Research Council ERC2014-ADG669898 TARLOOPMinisterio de Economía y Competitividad BFU2016-75058-PJunta de Andalucía BIO123

A vision for hydrological prediction

IMproving PRedictions and management of hydrological EXtremes (IMPREX) was a European Union Horizon 2020 project that ran from September 2015 to September 2019. Its aim was to improve society’s ability to anticipate and respond to future extreme hydrological events in Europe across a variety of uses in the water-related sectors (flood forecasting, drought risk assessment, agriculture, navigation, hydropower, and water supply utilities). Through the engagement with stakeholders and continuous feedback between model outputs and water applications, progress was achieved in better understanding the way hydrological predictions can be useful to (and operationally incorporated into) problem solving in the water sector. The work and discussions carried out during the project nurtured further reflections towards a common vision for hydrological prediction. In this article, we summarize the main findings of the IMPREX project within a broader overview of hydrological prediction, providing a vision for improving such predictions. In so doing, we firstly present a synopsis of hydrological and weather forecasting, with a focus on medium-range to seasonal scales of prediction for increased preparedness. Second, the lessons learnt from IMPREX are discussed. The key findings are the gaps highlighted in the global observing system of the hydrological cycle, the degree of accuracy of hydrological models and the techniques of post-processing to correct biases, the origin of seasonal hydrological skill in Europe, and user requirements of hydrometeorological forecasts to ensure their appropriate use in decision-making models and practices. Lastly, a vision for how to improve these forecast systems/products in the future is expounded and these include advancing numerical weather and hydrological models, improved earth monitoring, and more frequent interaction between forecasters and users to tailor the forecasts to applications. We conclude that if these improvements can be implemented in the coming years, earth system and hydrological modelling will become more skilful, thus leading to socioeconomic benefits for the citizens of Europe and beyond

Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology Guideline

PURPOSE: To develop recommendations about endocrine therapy for women with hormone receptor (HR) -positive metastatic breast cancer (MBC). METHODS: The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of evidence from 2008 through 2015 to create recommendations informed by that evidence. Outcomes of interest included sequencing of hormonal agents, hormonal agents compared with chemotherapy, targeted biologic therapy, and treatment of premenopausal women. This guideline puts forth recommendations for endocrine therapy as treatment for women with HR-positive MBC. RECOMMENDATIONS: Sequential hormone therapy is the preferential treatment for most women with HR-positive MBC. Except in cases of immediately life-threatening disease, hormone therapy, alone or in combination, should be used as initial treatment. Patients whose tumors express any level of hormone receptors should be offered hormone therapy. Treatment recommendations should be based on type of adjuvant treatment, disease-free interval, and organ function. Tumor markers should not be the sole criteria for determining tumor progression; use of additional biomarkers remains experimental. Assessment of menopausal status is critical; ovarian suppression or ablation should be included in premenopausal women. For postmenopausal women, aromatase inhibitors (AIs) are the preferred first-line endocrine therapy, with or without the cyclin-dependent kinase inhibitor palbociclib. As second-line therapy, fulvestrant should be administered at 500 mg with a loading schedule and may be administered with palbociclib. The mammalian target of rapamycin inhibitor everolimus may be administered with exemestane to postmenopausal women with MBC whose disease progresses while receiving nonsteroidal AIs. Among patients with HR-positive, human epidermal growth factor receptor 2-positive MBC, human epidermal growth factor receptor 2-targeted therapy plus an AI can be effective for those who are not chemotherapy candidates

Improvement in children’s fine motor skills following a computerized typing intervention

Children spend a large proportion of their school day engaged in tasks that require manual dexterity. If children experience difficulties with their manual dexterity skills it can have a consequential effect on their academic achievement. The first aim of this paper was to explore whether an online interactive typing intervention could improve children’s scores on a standardised measure of manual dexterity. The second aim was to implement a serial reaction time tapping task as an index of children's finger movement learning, and to see whether performance on this task would improve after the intervention. Seventy-eight typically developing children aged between 8 and 10 were tested at their school on the pre-intervention Movement Assessment Battery for Children (2 nd edition; MABC-2) and tapping tasks. Twenty-eight of these children volunteered to be randomly allocated to the intervention or control group. Children in the intervention group had a choice of two online games to play at home over a period of four weeks, while the children in the control group were not given these games to play. The intervention and control groups were then re-tested on the MABC-2 manual dexterity and the tapping task. Children in the intervention group significantly improved their manual dexterity scores in the MABC-2 compared to the control group. On average, all children learnt the tapping sequence, however, there were no group differences and no effect of the intervention on the tapping task. These results have important implications for implementing a freely available, easy to administer, fun and interactive intervention to help children improve their manual dexterity skills

The high-energy Sun - probing the origins of particle acceleration on our nearest star

As a frequent and energetic particle accelerator, our Sun provides us with an excellent astrophysical laboratory for understanding the fundamental process of particle acceleration. The exploitation of radiative diagnostics from electrons has shown that acceleration operates on sub-second time scales in a complex magnetic environment, where direct electric fields, wave turbulence, and shock waves all must contribute, although precise details are severely lacking. Ions were assumed to be accelerated in a similar manner to electrons, but γ-ray imaging confirmed that emission sources are spatially separated from X-ray sources, suggesting distinctly different acceleration mechanisms. Current X-ray and γ-ray spectroscopy provides only a basic understanding of accelerated particle spectra and the total energy budgets are therefore poorly constrained. Additionally, the recent detection of relativistic ion signatures lasting many hours, without an electron counterpart, is an enigma. We propose a single platform to directly measure the physical conditions present in the energy release sites and the environment in which the particles propagate and deposit their energy. To address this fundamental issue, we set out a suite of dedicated instruments that will probe both electrons and ions simultaneously to observe; high (seconds) temporal resolution photon spectra (4 keV – 150 MeV) with simultaneous imaging (1 keV – 30 MeV), polarization measurements (5–1000 keV) and high spatial and temporal resolution imaging spectroscopy in the UV/EUV/SXR (soft X-ray) regimes. These instruments will observe the broad range of radiative signatures produced in the solar atmosphere by accelerated particles

Analyses of the yeast Rad51 recombinase A265V mutant reveal different in vivo roles of Swi2-like factors

The Saccharomyces cerevisiae Swi2-like factors Rad54 and Rdh54 play multifaceted roles in homologous recombination via their DNA translocase activity. Aside from promoting Rad51-mediated DNA strand invasion of a partner chromatid, Rad54 and Rdh54 can remove Rad51 from duplex DNA for intracellular recycling. Although the in vitro properties of the two proteins are similar, differences between the phenotypes of the null allele mutants suggest that they play different roles in vivo. Through the isolation of a novel RAD51 allele encoding a protein with reduced affinity for DNA, we provide evidence that Rad54 and Rdh54 have different in vivo interactions with Rad51. The mutant Rad51 forms a complex on duplex DNA that is more susceptible to dissociation by Rdh54. This Rad51 variant distinguishes the in vivo functions of Rad54 and Rdh54, leading to the conclusion that two translocases remove Rad51 from different substrates in vivo. Additionally, we show that a third Swi2-like factor, Uls1, contributes toward Rad51 clearance from chromatin in the absence of Rad54 and Rdh54, and define a hierarchy of action of the Swi2-like translocases for chromosome damage repair