Microglia in aging and Alzheimer’s disease: A comparative species review

Microglia are the primary immune cells of the central nervous system that help nourish and support neurons, clear debris, and respond to foreign stimuli. Greatly impacted by their environment, microglia go through rapid changes in cell shape, gene expression, and functional behavior during states of infection, trauma, and neurodegeneration. Aging also has a profound effect on microglia, leading to chronic inflammation and an increase in the brain’s susceptibility to neurodegenerative processes that occur in Alzheimer’s disease. Despite the scientific community’s growing knowledge in the field of neuroinflammation, the overall success rate of drug treatment for age-related and neurodegenerative diseases remains incredibly low. Potential reasons for the lack of translation from animal models to the clinic include the use of a single species model, an assumption of similarity in humans, and ignoring contradictory data or information from other species. To aid in the selection of validated and predictive animal models and to bridge the translational gap, this review evaluates similarities and differences among species in microglial activation and density, morphology and phenotype, cytokine expression, phagocytosis, and production of oxidative species in aging and Alzheimer’s disease

Relationship of Blood and Urinary Manganese Levels with Cognitive Function in Elderly Individuals in the United States by Race/Ethnicity, NHANES 2011–2014

Manganese (Mn) is an essential metal with a biphasic relationship with health outcomes. High-level exposure to Mn is associated with manganism, but few data explore the effects of chronic, lower-level Mn on cognitive function in adults. We sought to determine the relationship between blood/urinary manganese levels and cognitive function in elderly individuals using 2011–2014 data from the National Health and Nutrition Examination Survey (NHANES). Weighted multivariate regression models were used to determine correlations, adjusting for several covariates. Blood Mn was inversely associated with the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) immediate learning of new verbal information (p-value = 0.04), but lost significance after adjusting for medical history (p-value = 0.09). In addition, blood Mn was inversely associated with Animal Fluency scores after adjusting for all covariates. Urinary Mn was inversely associated with CERAD immediate learning after adjusting for all covariates (p-value = 0.01) and inversely associated with the Digit Symbol Substitution Test scores (p-value = 0.0002), but lost significance after adjusting for medical history (p-value = 0.13). Upon stratifying by race/ethnicity, other Races and Non-Hispanic (NH)-Blacks had significantly higher blood Mn levels when compared to NH-Whites. Collectively, these findings suggest that increased blood and urinary Mn levels are associated with poorer cognitive function in an elderly US population

Association of Pyrethroid Pesticide Exposure With Attention-Deficit/Hyperactivity Disorder in a Nationally Representative Sample of U.S. Children

Background Pyrethroid pesticides cause abnormalities in the dopamine system and produce an ADHD phenotype in animal models, with effects accentuated in males versus females. However, data regarding behavioral effects of pyrethroid exposure in children is limited. We examined the association between pyrethroid pesticide exposure and ADHD in a nationally representative sample of US children, and tested whether this association differs by sex. Methods Data are from 8–15 year old participants (N = 687) in the 2001–2002 National Health and Nutrition Examination Survey. Exposure was assessed using concurrent urinary levels of the pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA). ADHD was defined by either meeting Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition criteria on the Diagnostic Interview Schedule for Children (DISC) or caregiver report of a prior diagnosis. ADHD symptom counts were determined via the DISC. Multivariable logistic regression examined the link between pyrethroid exposure and ADHD, and poisson regression investigated the link between exposure and ADHD symptom counts. Results Children with urinary 3-PBA above the limit of detection (LOD) were twice as likely to have ADHD compared with those below the LOD (adjusted odds ratio [aOR] 2.42; 95 % confidence interval [CI] 1.06, 5.57). Hyperactive-impulsive symptoms increased by 50 % for every 10-fold increase in 3-PBA levels (adjusted count ratio 1.50; 95 % CI 1.03, 2.19); effects on inattention were not significant. We observed possible sex-specific effects: pyrethroid biomarkers were associated with increased odds of an ADHD diagnosis and number of ADHD symptoms for boys but not girls. Conclusions We found an association between increasing pyrethroid pesticide exposure and ADHD which may be stronger for hyperactive-impulsive symptoms compared to inattention and in boys compared to girls. Given the growing use of pyrethroid pesticides, these results may be of considerable public health import

Regional Motor Unit Firing Behaviors of Mono- and Bi-Articular Leg Extensor Muscles

Motor unit (MU) activation patterns provide vast insight into skeletal muscle contractions and may differ depending on architectural differences. Previous findings have suggested that MU activation patterns, specifically within the quadriceps group, are region-specific; this, along with the architectural differences between the quadriceps muscles, may further influence force production as reflected within the relationships between the firings. PURPOSE: To examine regional activation in proximal and distal regions of biarticular [rectus femoris (RF)] and monoarticular [vastus lateralis (VL)] knee extensors during submaximal isometric knee extensions. METHODS: On two separate randomized visits, eight lower-body resistance trained individuals, 6 males (n=6, age= 25.2 ±3.77) and 2 females (n=2, age= 21 ±1.4), performed submaximal isometric contractions at 30% and 70% of their maximal voluntary contractions (MVC) in a custom-built seat using an S-beam load-cell. Two separate 5-pin surface electromyography (EMG) sensors were used to record activation in the proximal and distal locations of either the VL or RF. Signals were recorded and decomposed into their constituent motor unit action potential (MUAP) trains, validated, and assessed for relative behavioral properties. For subsequent analysis of firing behaviors, the relationships (Slopes and intercepts) between motor unit action potential size (MUAPsize,) recruitment threshold (RT%), and mean firing rate (MFR) were calculated. Twelve separate two-way repeated measures analyses of variance (ANOVA) (location [proximal v distal] x muscle [VL v RF]) were used to compare slopes and intercepts of MFR vs. RT%, MUAPsize vs. RT%, and MFR vs. MUAPsize at both 30% and 70% MVC. RESULTS: There was a significant location x muscle interaction in the MFR v MUAPsize slopes during 30% MVC contraction (pCONCLUSION: The location by muscle interaction in the MFR v MUAPsize slopes during 30% MVC may indicate muscle fiber type distribution differences between sensor locations specifically, more type II fibers in the distal location of the VL

A Stellar Dynamical Measurement of the Black Hole Mass in the Maser Galaxy NGC 4258

We determine the mass of the black hole at the center of the spiral galaxy NGC 4258 by constructing axisymmetric dynamical models of the galaxy. These models are constrained by high spatial resolution imaging and long-slit spectroscopy of the nuclear region obtained with the {\em Hubble Space Telescope}, complemented by ground-based observations extending to larger radii. Our best mass estimate is \MBH = (3.3 \pm 0.2) \times 10^7 \MSun for a distance of 7.28 Mpc (statistical errors only). This is within 15% of (3.82\pm 0.01) \times 10^7 \MSun, the mass determined from the kinematics of water masers (rescaled to the same distance) assuming they are in Keplerian rotation in a warped disk. The construction of accurate dynamical models of NGC 4258 is somewhat compromised by an unresolved active nucleus and color gradients, the latter caused by variations in the stellar population and/or obscuring dust. These problems are not present in the $\sim 30$ other black hole mass determinations from stellar dynamics that have been published by us and other groups; thus, the relatively close agreement between the stellar dynamical mass and the maser mass in NGC 4258 enhances our confidence in the black hole masses determined in other galaxies from stellar dynamics using similar methods and data of comparable quality.Comment: 58 pages, submitted to ApJ. Some figures excluded due to size. The entire paper is at http://www.noao.edu/noao/staff/lauer/nuker_papers.htm

Sperm Toolbox-A selection of small molecules to study human spermatozoa

Male contraceptive options and infertility treatments are limited, and almost all innovation has been limited to updates to medically assisted reproduction protocols and methods. To accelerate the development of drugs that can either improve or inhibit fertility, we established a small molecule library as a toolbox for assay development and screening campaigns using human spermatozoa. We have profiled all compounds in the Sperm Toolbox in several automated high-throughput assays that measure stimulation or inhibition of sperm motility or the acrosome reaction. We have assayed motility under non-capacitating and capacitating conditions to distinguish between pathways operating under these different physiological states. We also assayed cell viability to ensure any effects on sperm function are specific. A key advantage of our studies is that all compounds are assayed together in the same experimental conditions, which allows quantitative comparisons of their effects in complementary functional assays. We have combined the resulting datasets to generate fingerprints of the Sperm Toolbox compounds on sperm function. The data are included in an on-line R-based app for convenient querying.</p

Timing of CGM initiation in pediatric diabetes: The CGM TIME Trial.

OBJECTIVE: To determine whether timing of CGM initiation offering low glucose suspend (LGS) affects CGM adherence in children and youth starting insulin pump therapy. METHODS: A 5-site RCT of pump-naïve subjects (aged 5-18 years) with type 1 diabetes (T1D) for at least 1 year compared simultaneous pump and CGM initiation offering LGS vs standard pump therapy with CGM initiation delayed for 6 months. Primary outcome was CGM adherence (hours per 28 days) (MiniMed™ Paradigm™ Veo™ system; CareLink Pro™ software) over 6 months after CGM initiation. Secondary outcome HbA1c was measured centrally. Linear mixed-models and ordinary least squares models were fitted to estimate effect of intervention, and covariates baseline age, T1D duration, HbA1c, gender, ethnicity, hypoglycemia history, clinical site, and association between CGM adherence and HbA1c. RESULTS: The trial randomized 144/152 (95%) eligible subjects. Baseline mean age was 11.5 ± 3.3(SD) years, T1D duration 3.4 ± 3.1 years, and HbA1c 7.9 ± 0.9%. Six months after CGM initiation, adjusted mean difference in CGM adherence was 62.4 hours per 28 days greater in the Simultaneous Group compared to Delayed Group (P = .007). There was no difference in mean HbA1c at 6 months. However, for each 100 hours of CGM use per 28-day period, HbA1c was 0.39% (95% CI 0.10%-0.69%) lower. Higher CGM adherence was associated with reduced time with glucose \u3e10 mmol/L (P \u3c .001). CONCLUSION: CGM adherence was higher after 6 months when initiated at same time as pump therapy compared to starting CGM 6 months after pump therapy. Greater CGM adherence was associated with improved HbA1c

The BTB-zinc finger transcription factor abrupt acts as an epithelial oncogene in drosophila melanogaster through maintaining a progenitor-like cell state

The capacity of tumour cells to maintain continual overgrowth potential has been linked to the commandeering of normal self-renewal pathways. Using an epithelial cancer model in Drosophila melanogaster, we carried out an overexpression screen for oncogenes capable of cooperating with the loss of the epithelial apico-basal cell polarity regulator, scribbled (scrib), and identified the cell fate regulator, Abrupt, a BTB-zinc finger protein. Abrupt overexpression alone is insufficient to transform cells, but in cooperation with scrib loss of function, Abrupt promotes the formation of massive tumours in the eye/antennal disc. The steroid hormone receptor coactivator, Taiman (a homologue of SRC3/AIB1), is known to associate with Abrupt, and Taiman overexpression also drives tumour formation in cooperation with the loss of Scrib. Expression arrays and ChIP-Seq indicates that Abrupt overexpression represses a large number of genes, including steroid hormone-response genes and multiple cell fate regulators, thereby maintaining cells within an epithelial progenitor-like state. The progenitor-like state is characterised by the failure to express the conserved Eyes absent/Dachshund regulatory complex in the eye disc, and in the antennal disc by the failure to express cell fate regulators that define the temporal elaboration of the appendage along the proximo-distal axis downstream of Distalless. Loss of scrib promotes cooperation with Abrupt through impaired Hippo signalling, which is required and sufficient for cooperative overgrowth with Abrupt, and JNK (Jun kinase) signalling, which is required for tumour cell migration/invasion but not overgrowth. These results thus identify a novel cooperating oncogene, identify mammalian family members of which are also known oncogenes, and demonstrate that epithelial tumours in Drosophila can be characterised by the maintenance of a progenitor-like state

BBLN-1 is essential for intermediate filament organization and apical membrane morphology

Epithelial tubes are essential components of metazoan organ systems that control the flow of fluids and the exchange of materials between body compartments and the outside environment. The size and shape of the central lumen confer important characteristics to tubular organs and need to be carefully controlled. Here, we identify the small coiled-coil protein BBLN-1 as a regulator of lumen morphology in the C. elegans intestine. Loss of BBLN-1 causes the formation of bubble-shaped invaginations of the apical membrane into the cytoplasm of intestinal cells and abnormal aggregation of the subapical intermediate filament (IF) network. BBLN-1 interacts with IF proteins and localizes to the IF network in an IF-dependent manner. The appearance of invaginations is a result of the abnormal IF aggregation, indicating a direct role for the IF network in maintaining lumen homeostasis. Finally, we identify bublin (BBLN) as the mammalian ortholog of BBLN-1. When expressed in the C. elegans intestine, BBLN recapitulates the localization pattern of BBLN-1 and can compensate for the loss of BBLN-1 in early larvae. In mouse intestinal organoids, BBLN localizes subapically, together with the IF protein keratin 8. Our results therefore may have implications for understanding the role of IFs in regulating epithelial tube morphology in mammals

The Panchromatic Hubble Andromeda Treasury II. Tracing the Inner M31 Halo with Blue Horizontal Branch Stars

We attempt to constrain the shape of M31's inner stellar halo by tracing the surface density of blue horizontal branch (BHB) stars at galactocentric distances ranging from 2 kpc to 35 kpc. Our measurements make use of resolved stellar photometry from a section of the Panchromatic Hubble Andromeda Treasury (PHAT) survey, supplemented by several archival Hubble Space Telescope observations. We find that the ratio of BHB to red giant stars is relatively constant outside of 10 kpc, suggesting that the BHB is as reliable a tracer of the halo population as the red giant branch. In the inner halo, we do not expect BHB stars to be produced by the high metallicity bulge and disk, making BHB stars a good candidate to be a reliable tracer of the stellar halo to much smaller galactocentric distances. If we assume a power-law profile r^(-\alpha) for the 2-D projected surface density BHB distribution, we obtain a high-quality fit with a 2-D power-law index of \alpha=2.6^{+0.3}_{-0.2} outside of 3 kpc, which flattens to \alpha<1.2 inside of 3 kpc. This slope is consistent with previous measurements but is anchored to a radial baseline that extends much farther inward. Finally, assuming azimuthal symmetry and a constant mass-to-light ratio, the best-fitting profile yields a total halo stellar mass of 2.1^{+1.7}_{-0.4} x 10^9 M_sun. These properties are comparable with both simulations of stellar halo formation formed by satellite disruption alone, and with simulations that include some in situ formation of halo stars.Comment: 15 pages, 1 table, 5 figures, accepted for publication in Ap