During immature stages, adult-born neurons pass through critical periods for survival and plasticity. It is generally assumed that by 2 months of age adult-born neurons are mature and equivalent to ...the broader neuronal population, raising questions of how they might contribute to hippocampal function in old age when neurogenesis has declined. However, few have examined adult-born neurons beyond the critical period or directly compared them to neurons born in infancy. Here, we used a retrovirus to visualize functionally relevant morphological features of 2- to 24-week-old adult-born neurons in male rats. From 2 to 7 weeks, neurons grew and attained a relatively mature phenotype. However, several features of 7-week-old neurons suggested a later wave of growth: these neurons had larger nuclei, thicker dendrites, and more dendritic filopodia than all other groups. Indeed, between 7 and 24 weeks, adult-born neurons gained additional dendritic branches, formed a second primary dendrite, acquired more mushroom spines, and had enlarged mossy fiber presynaptic terminals. Compared with neonatal-born neurons, old adult-born neurons had greater spine density, larger presynaptic terminals, and more putative efferent filopodial contacts onto inhibitory neurons. By integrating rates of cell birth and growth across the life span, we estimate that adult neurogenesis ultimately produces half of the cells and the majority of spines in the dentate gyrus. Critically, protracted development contributes to the plasticity of the hippocampus through to the end of life, even after cell production declines. Persistent differences from neonatal-born neurons may additionally endow adult-born neurons with unique functions even after they have matured.
Neurogenesis occurs in the hippocampus throughout adult life and contributes to memory and emotion. It is generally assumed that new neurons have the greatest impact on behavior when they are immature and plastic. However, since neurogenesis declines dramatically with age, it is unclear how they might contribute to behavior later in life when cell proliferation has slowed. Here we find that newborn neurons mature over many months in rats and may end up with distinct morphological features compared with neurons born in infancy. Using a mathematical model, we estimate that a large fraction of neurons is added in adulthood. Moreover, their extended growth produces a reserve of plasticity that persists even after neurogenesis has declined to low rates.
Rationale
Benzodiazepines induce electroencephalography (EEG) changes in rodents and humans that are associated with distinct behavioral effects and have been proposed as quantitative biomarkers for ...GABA
A
receptor modulation. Specifically, central EEG beta and occipital EEG delta activity have been associated with anxiolysis and sedation, respectively. The extent to which nonhuman primates show the same dose- and topography-dependent effects remained unknown.
Objectives
We aimed at establishing a nonhuman primate model for the evaluation of benzodiazepine EEG pharmacology.
Methods
Four adult male rhesus monkeys were prepared with fully implantable telemetry devices that monitored activity, peripheral body temperature, and contained two EEG (central and occipital), one electromyography (EMG), and one electrooculography channel. We investigated daytime alprazolam-induced changes in EEG spectral power, sleep–wake states, EMG activity, locomotor activity, and body temperature. Alprazolam (0.01–1.8 mg/kg, i.m.) or vehicle was administered acutely, and telemetry recording was conducted for 1 h.
Results
Daytime alprazolam dose-dependently increased central EEG power (including beta activity), increased occipital EEG delta power, and decreased occipital EEG alpha, theta, and sigma power. There was an ~8-fold difference in the potency of alprazolam to increase central EEG beta vs. occipital EEG delta activity (based on relative EEG power). The highest dose, which increased both central EEG beta and occipital EEG delta relative power, induced sedative effects (increased time spent in N1 and N2 sleep stages) and decreased peripheral body temperature and locomotor activity.
Conclusions
Alprazolam induces dose- and topography-dependent EEG changes in rhesus monkeys and provides a valuable model for studying benzodiazepine pharmacology.
"Doctor, What Happens After My Meniscectomy?" Smith, John-Rudolph H; Houck, Darby A; Kraeutler, Matthew J ...
Journal of bone and joint surgery. American volume,
2019-November-6, Letnik:
101, Številka:
21
Journal Article
Compounds that inhibit glutathione peroxidase 4 (GPX4) hold promise as cancer therapeutics in their ability to induce a form of nonapoptotic cell death called ferroptosis. Our research identified 24, ...a structural analog of the potent GPX4 inhibitor RSL3, that has much better plasma stability (t 1/2 > 5 h in mouse plasma). The bioavailability of 24 provided efficacious plasma drug concentrations with IP dosing, thus enabling in vivo studies to assess tolerability and efficacy. An efficacy study in mouse using a GPX4-sensitive tumor model found that doses of 24 up to 50 mg/kg were tolerated for 20 days but had no effect on tumor growth, although partial target engagement was observed in tumor homogenate.
We report here genome sequences and comparative analyses of three closely related parasitoid wasps: Nasonia vitripennis, N giraulti, and N. longicomis. Parasitoids are important regulators of ...arthropod populations, including major agricultural pests and disease vectors, and Nasonia is an emerging genetic model particularly for evolutionary and developmental genetics. Key findings include the identification of a functional DNA methylation tool kit; hymenopteran-specifk genes including diverse venoms; lateral gene transfers among Pox viruses, WolbacMa, and Nasonia; and the rapid evolution of genes involved in nuclearmitochondrial interactions that are implicated in spedation. Newly developed genome resources advance Nasonia for genetic research, accelerate mapping and cloning of quantitative trait loci, and will ultimately provide tools and knowledge for further increasing the utility of parasitoids as pest insect-control agents.
To examine the dose-response relationship between oral lutein supplementation and serum lutein concentrations in persons aged 60 years and older, with or without age-related macular degeneration ...(AMD).
Forty-five participants with no AMD, large drusen, or advanced AMD, were randomized to receive one of three doses (2.5, 5, or 10 mg) of lutein for 6 months and to be observed for 6 additional months after the cessation of lutein supplementation.
The mean age of the participants (33 women) was 71 years (range: 60-91). The serum lutein concentrations of each dose group were similar before supplementation, increased at 1 month, and peaked by 3 months. Median serum concentrations of the 2.5-, 5-, and 10-mg groups from baseline to month 6 increased from 18.7 to 35.1 microg/dL (2-fold increase), from 17.8 to 59.2 microg/dL (2.9-fold increase), and from 15.1 to 66.8 microg/dL (4-fold increase), respectively (all P < 0.001). The increases in lutein serum concentrations did not vary with AMD disease severity (P = 0.98). No toxicity was observed with any dose of lutein. No significant changes were detected in visual acuity or visual field tests.
Increasing doses of lutein supplements significantly increased the serum levels of lutein and zeaxanthin, and doses up to 10 mg were safely administered. A long-term large clinical trial is necessary to investigate the safety and efficacy of lutein in reducing the risk of the development of advanced AMD.
To describe the mortality risks by fine strata of gestational age and birthweight among 230 679 live births in nine low- and middle-income countries (LMICs) from 2000 to 2017.
Descriptive ...multi-country secondary data analysis.
Nine LMICs in sub-Saharan Africa, Southern and Eastern Asia, and Latin America.
Liveborn infants from 15 population-based cohorts.
Subnational, population-based studies with high-quality birth outcome data were invited to join the Vulnerable Newborn Measurement Collaboration. All studies included birthweight, gestational age measured by ultrasound or last menstrual period, infant sex and neonatal survival. We defined adequate birthweight as 2500-3999 g (reference category), macrosomia as ≥4000 g, moderate low as 1500-2499 g and very low birthweight as <1500 g. We analysed fine strata classifications of preterm, term and post-term: ≥42
, 39
-41
(reference category), 37
-38
, 34
-36
,34
-36
,32
-33
, 30
-31
, 28
-29
and less than 28 weeks.
Median and interquartile ranges by study for neonatal mortality rates (NMR) and relative risks (RR). We also performed meta-analysis for the relative mortality risks with 95% confidence intervals (CIs) by the fine categories, stratified by regional study setting (sub-Saharan Africa and Southern Asia) and study-level NMR (≤25 versus >25 neonatal deaths per 1000 live births).
We found a dose-response relationship between lower gestational ages and birthweights with increasing neonatal mortality risks. The highest NMR and RR were among preterm babies born at <28 weeks (median NMR 359.2 per 1000 live births; RR 18.0, 95% CI 8.6-37.6) and very low birthweight (462.8 per 1000 live births; RR 43.4, 95% CI 29.5-63.9). We found no statistically significant neonatal mortality risk for macrosomia (RR 1.1, 95% CI 0.6-3.0) but a statistically significant risk for all preterm babies, post-term babies (RR 1.3, 95% CI 1.1-1.5) and babies born at 37
-38
weeks (RR 1.2, 95% CI 1.0-1.4). There were no statistically significant differences by region or underlying neonatal mortality.
In addition to tracking vulnerable newborn types, monitoring finer categories of birthweight and gestational age will allow for better understanding of the predictors, interventions and health outcomes for vulnerable newborns. It is imperative that all newborns from live births and stillbirths have an accurate recorded weight and gestational age to track maternal and neonatal health and optimise prevention and care of vulnerable newborns.
Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar ...degeneration (FTLD).
We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (
) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal ('asymptomatic non-converters') and those who became symptomatic ('asymptomatic converters') using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL).
We studied 394 participants (non-carriers=143,
=117,
=62,
=72). In
, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In
higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=-0.16 (-0.22, -0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (β=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR
=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007).
Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.
•Reservoir thermal energy storage (RTES) is a type of underground energy storage.•RTES systems store hot or cold water for later use (seasonally or longer).•A reservoir is a permeable zone that is ...poorly connected with freshwater aquifers.•Flexible tools are developed to evaluate and design RTES geothermal resources.•For Portland, Oregon, RTES could heat or cool large business/industrial districts.
Tools to evaluate reservoir thermal energy storage (RTES; heat storage in slow-moving or stagnant geochemically evolved permeable zones in strata that underlie well-connected regional aquifers) are developed and applied to the Columbia River Basalt Group (CRBG) beneath the Portland Basin, Oregon, USA. The performance of RTES for heat storage and recovery in the Portland Basin is strongly dependent on the operational schedule of heat injection and extraction. We examined the effects of the operational schedule, based on an annual solar hot water supply pattern and a building heating demand model, using heat and fluid flow simulations with SUTRA. We show RTES to be feasible for supply of heating energy for a large combined research/teaching building on the Oregon Health and Science University South Waterfront expansion, an area of planned future development. Initially, heat is consumed to increase the reservoir temperature, and conductive heat loss is high due to high temperature gradients between the reservoir and surrounding rock. Conductive heat loss continues into the future, but the rate of heat loss decreases, and heat recovery efficiency of the RTES system increases over time. Simulations demonstrate the effects of varying heat-delivery rate and temperature on the heat production history of the reservoir. If 100% of building heating needs are to be supplied by combined solar/RTES, then the solar system must be sized to meet building needs plus long-term thermal losses (i.e., conductive losses once the system is heated to pseudo-steady state) from the RTES system. If the solar heating system barely meets these criteria, then during early years, less than 100% of the building demand will be supplied until the reservoir is fully-heated. The duration of supplying less than 100% of building demand can be greatly shortened by pre-heating the reservoir before building heating operations or by adding extra heat from external sources during early years. Analytic solutions are developed to evaluate efficacy and to help design RTES systems (e.g., well-spacing, thermal source sizing, etc.). A map of thermal energy storage capacity is produced for the CRBG beneath the Portland Basin. The simulated building has an annual heat load of ∼1.9 GWh, and the total annual storage capacity of the Portland Basin is estimated to be 43,400 GWh assuming seasonal storage of heat yields water from which 10 °C can be extracted via heat exchange, indicating a tremendous heating capacity of the CRBG.
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