On The Future Of Antidepressant Treatments: Targeting Neurotrophic Factors And Plasticity

For 60-plus years the explanatory model for Major Depressive Disorder (MDD) has been the monoamine theory, which states that low levels of monoamine neurotransmitters or alterations in their post-synaptic receptors are responsible for depressive symptoms. Drugs designed to elevate synaptic monoamine levels have remained the first line of pharmacotherapy prescribed by clinicians for MDD patients. However, these drugs have shortcomings. Despite evidence that current antidepressants elevate synaptic monoamine levels within hours of administration, these drugs require four to six weeks of daily administration before symptom relief appears. Furthermore, approximately half of patients taking typical antidepressants never achieve full symptom relief. The therapeutic lag time and low response rates associated with typical antidepressants suggests that elevation of monoaminergic activity may not be their true mechanism of antidepressant action and brings into question the validity of the monoamine theory. As a result, novel biological targets have been investigated for development of more reliable and faster-acting antidepressants. Recent work has shown that low doses of ketamine, a glutamatergic N-methyl-D-aspartate (NMDA) receptor antagonist, can provide depressive symptom relief within hours of administration. What is interesting about these findings is that ketamine works on a completely different biological system than typical antidepressants. Moreover, a number of non-drug treatments, such as electro-convulsive therapy, psychotherapies, and exercise have proven efficacious in treating depressive symptoms. Understanding the biological mechanisms that underlie all of these various treatment modalities may provide evidence for a more valid explanatory model of MDD. In a review of relevant literature examining biologic alterations produced by monoaminergic antidepressants, ketamine and other glutamatergic agents, psychotherapies, electroconvulsive shock therapy, or exercise a commonality was identified: all of the treatments promote the growth of new synapses (synaptogenesis) and the growth of new neurons (neurogenesis). This finding prompts support for the developing Stress-Neurogenic Theory of depression. This theory suggests depressive symptoms are due to chronic, unpredictable stressors which stimulate the production of stress hormones leading to cell death in major brain areas and treatment for depression is dependent upon stimulating the brain’s natural processes responsible for the growth of new connections and new cells in affected brain regions

History and Logic Model NASA Goddard Space Flight Center Instrument Project Division (IPD) Schedule and Cost Study

No abstract availabl

Fertility control as a means of controlling bovine tuberculosis in badger (Meles meles) populations in south-west England: predictions from a spatial stochastic simulation model

A spatial stochastic simulation model was used to assess the potential of fertility control, based on a yet-to-be-developed oral bait-delivered contraceptive directed at females, for the control of bovine tuberculosis in badger populations in south-west England. The contraceptive had a lifelong effect so that females rendered sterile in any particular year remained so for the rest of their lives. The efficacy of fertility control alone repeated annually for varying periods of time was compared with a single culling operation and integrated control involving an initial single cull followed by annually repeated fertility control. With fertility control alone, in no instance was the disease eradicated completely while a viable badger population (mean group size of at least one individual) was still maintained. Near eradication of the disease (less than 1% prevalence) combined with the survival of a minimum viable badger population was only achieved under a very limited set of conditions, either with high efficiency of control (95%) over a short time period (1-3 years) or a low efficiency of control (20%) over an intermediate time period (10-20 years). Under these conditions, it took more than 20 years for the disease to decline to such low levels. A single cull of 80% efficiency succeeded in near eradication of the disease (below 1% prevalence) after a period of 6-8 years, while still maintaining a viable badger population. Integrated strategies reduced disease prevalence more rapidly and to lower levels than culling alone, although the mean badger group size following the onset of control was smaller. Under certain integrated strategies, principally where a high initial cull (80%) was followed by fertility control over a short (1-3 year) time period, the disease could be completely eradicated while a viable badger population was maintained. However, even under the most favourable conditions of integrated control, it took on average more than 12 years following the onset of control for the disease to disappear completely from the badger population. These results show that whilst fertility control would not be a successful strategy for the control of bovine tuberculosis in badgers if used alone, it could be effective if used with culling as part of an integrated strategy. This type of integrated strategy is likely to be more effective in terms of disease eradication than a strategy employing culling alone. However, the high cost of developing a suitable fertility control agent, combined with the welfare and conservation implications, are significant factors which should be taken into account when considering its possible use as a means of controlling bovine tuberculosis in badger populations in the UK

NuSTAR detection of X-ray heating events in the quiet Sun

The explanation of the coronal heating problem potentially lies in the existence of nanoflares, numerous small-scale heating events occurring across the whole solar disk. In this Letter, we present the first imaging spectroscopy X-ray observations of three quiet Sun flares during the Nuclear Spectroscopic Telescope ARray (NuSTAR) solar campaigns on 2016 July 26 and 2017 March 21, concurrent with the Solar Dynamics Observatory/Atmospheric Imaging Assembly (SDO/AIA) observations. Two of the three events showed time lags of a few minutes between peak X-ray and extreme ultraviolet emissions. Isothermal fits with rather low temperatures in the range 3.2–4.1 MK and emission measures of (0.6–15) × 1044 cm−3 describe their spectra well, resulting in thermal energies in the range (2–6) × 1026 erg. NuSTAR spectra did not show any signs of a nonthermal or higher temperature component. However, as the estimated upper limits of (hidden) nonthermal energy are comparable to the thermal energy estimates, the lack of a nonthermal component in the observed spectra is not a constraining result. The estimated Geostationary Operational Environmental Satellite (GOES) classes from the fitted values of temperature and emission measure fall between 1/1000 and 1/100 A class level, making them eight orders of magnitude fainter in soft X-ray flux than the largest solar flares

NuSTAR hard X-ray observation of a sub-A class solar flare

We report a NuSTAR observation of a solar microflare, SOL2015-09-01T04. Although it was too faint to be observed by the GOES X-ray Sensor, we estimate the event to be an A0.1 class flare in brightness. This microflare, with only 5 counts per second per detector observed by RHESSI, is fainter than any hard X-ray (HXR) flare in the existing literature. The microflare occurred during a solar pointing by the highly sensitive NuSTAR astrophysical observatory, which used its direct focusing optics to produce detailed HXR microflare spectra and images. The microflare exhibits HXR properties commonly observed in larger flares, including a fast rise and more gradual decay, earlier peak time with higher energy, spatial dimensions similar to the RHESSI microflares, and a high-energy excess beyond an isothermal spectral component during the impulsive phase. The microflare is small in emission measure, temperature, and energy, though not in physical size; observations are consistent with an origin via the interaction of at least two magnetic loops. We estimate the increase in thermal energy at the time of the microflare to be 2.4x10^27 ergs. The observation suggests that flares do indeed scale down to extremely small energies and retain what we customarily think of as "flarelike" properties.Comment: Status: Accepted by the Astrophysical Journal, 2017 July 1

Allele-specific gene expression can underlie altered transcript abundance in zebrafish mutants.

In model organisms, RNA-sequencing (RNA-seq) is frequently used to assess the effect of genetic mutations on cellular and developmental processes. Typically, animals heterozygous for a mutation are crossed to produce offspring with different genotypes. Resultant embryos are grouped by genotype to compare homozygous mutant embryos to heterozygous and wild-type siblings. Genes that are differentially expressed between the groups are assumed to reveal insights into the pathways affected by the mutation. Here we show that in zebrafish, differentially expressed genes are often over-represented on the same chromosome as the mutation due to different levels of expression of alleles from different genetic backgrounds. Using an incross of haplotype-resolved wild-type fish, we found evidence of widespread allele-specific expression, which appears as differential expression when comparing embryos homozygous for a region of the genome to their siblings. When analysing mutant transcriptomes, this means that the differential expression of genes on the same chromosome as a mutation of interest may not be caused by that mutation. Typically, the genomic location of a differentially expressed gene is not considered when interpreting its importance with respect to the phenotype. This could lead to pathways being erroneously implicated or overlooked due to the noise of spurious differentially expressed genes on the same chromosome as the mutation. These observations have implications for the interpretation of RNA-seq experiments involving outbred animals and non-inbred model organisms

Allele-specific gene expression can underlie altered transcript abundance in zebrafish mutants.

In model organisms, RNA-sequencing (RNA-seq) is frequently used to assess the effect of genetic mutations on cellular and developmental processes. Typically, animals heterozygous for a mutation are crossed to produce offspring with different genotypes. Resultant embryos are grouped by genotype to compare homozygous mutant embryos to heterozygous and wild-type siblings. Genes that are differentially expressed between the groups are assumed to reveal insights into the pathways affected by the mutation. Here we show that in zebrafish, differentially expressed genes are often over-represented on the same chromosome as the mutation due to different levels of expression of alleles from different genetic backgrounds. Using an incross of haplotype-resolved wild-type fish, we found evidence of widespread allele-specific expression, which appears as differential expression when comparing embryos homozygous for a region of the genome to their siblings. When analysing mutant transcriptomes, this means that the differential expression of genes on the same chromosome as a mutation of interest may not be caused by that mutation. Typically, the genomic location of a differentially expressed gene is not considered when interpreting its importance with respect to the phenotype. This could lead to pathways being erroneously implicated or overlooked due to the noise of spurious differentially expressed genes on the same chromosome as the mutation. These observations have implications for the interpretation of RNA-seq experiments involving outbred animals and non-inbred model organisms

A Resolved Ring of Debris Dust around the Solar Analog HD 107146

We present resolved images of the dust continuum emission from the debris disk around the young (80-200 Myr) solar-type star HD 107146 with CARMA at λ = 1.3 mm and the CSO at λ = 350 μ. Both images show that the dust emission extends over an approximately 10" diameter region. The high-resolution (3") CARMA image further reveals that the dust is distributed in a partial ring with significant decrease in a flux inward of 97 AU. Two prominent emission peaks appear within the ring separated by ~140° in the position angle. The morphology of the dust emission is suggestive of dust captured into a mean motion resonance, which would imply the presence of a planet at an orbital radius of ~45-75 AU