Network structure determines patterns of network reorganization during adult neurogenesis

New cells are generated throughout life and integrate into the hippocampus via the process of adult neurogenesis. Epileptogenic brain injury induces many structural changes in the hippocampus, including the death of interneurons and altered connectivity patterns. The pathological neurogenic niche is associated with aberrant neurogenesis, though the role of the network-level changes in development of epilepsy is not well understood. In this paper, we use computational simulations to investigate the effect of network environment on structural and functional outcomes of neurogenesis. We find that small-world networks with external stimulus are able to be augmented by activity-seeking neurons in a manner that enhances activity at the stimulated sites without altering the network as a whole. However, when inhibition is decreased or connectivity patterns are changed, new cells are both less responsive to stimulus and the new cells are more likely to drive the network into bursting dynamics. Our results suggest that network-level changes caused by epileptogenic injury can create an environment where neurogenic reorganization can induce or intensify epileptic dynamics and abnormal integration of new cells.Comment: 28 pages, 10 figure

The Circumgalactic Medium of Submillimeter Galaxies. II. Unobscured QSOs within Dusty Starbursts and QSO Sightlines with Impact Parameters below 100 Kiloparsec

We present Atacama Large Millimeter/submillimeter Array (ALMA) 870um observations of 29 bright Herschel sources near high-redshift QSOs. The observations confirm that 20 of the Herschel sources are submillimeter-bright galaxies (SMGs) and identify 16 new SMG-QSO pairs that are useful to studies of the circumgalactic medium (CGM) of SMGs. Eight out of the 20 SMGs are blends of multiple 870um sources. The angular separations for six of the Herschel-QSO pairs are less than 10", comparable to the sizes of the Herschel beam and the ALMA primary beam. We find that four of these six "pairs" are actually QSOs hosted by SMGs. No additional submillimeter companions are detected around these QSOs and the rest-frame ultraviolet spectra of the QSOs show no evidence of significant reddening. Black hole accretion and star formation contribute almost equally in bolometric luminosity in these galaxies. The SMGs hosting QSOs show similar source sizes, dust surface densities, and SFR surface densities as other SMGs in the sample. We find that the black holes are growing $\sim$3$\times$ faster than the galaxies when compared to the present-day black-hole-galaxy mass ratio, suggesting a QSO duty cycle of $\lesssim$30% in SMGs at z ~ 3. The remaining two Herschel-detected QSOs are undetected at 870um but each has an SMG "companion" only 9" and 12" away (71 and 95 kpc at z = 3). They could be either merging or projected pairs. If the former, they would represent a rare class of "wet-dry" mergers. If the latter, the QSOs would, for the first time, probe the CGM of SMGs at impact parameters below 100 kpc.Comment: ApJ accepte

DockoMatic - Automated Ligand Creation and Docking

Background: The application of computational modeling to rationally design drugs and characterize macro biomolecular receptors has proven increasingly useful due to the accessibility of computing clusters and clouds. AutoDock is a well-known and powerful software program used to model ligand to receptor binding interactions. In its current version, AutoDock requires significant amounts of user time to setup and run jobs, and collect results. This paper presents DockoMatic, a user friendly Graphical User Interface (GUI) application that eases and automates the creation and management of AutoDock jobs for high throughput screening of ligand to receptor interactions. Results: DockoMatic allows the user to invoke and manage AutoDock jobs on a single computer or cluster, including jobs for evaluating secondary ligand interactions. It also automates the process of collecting, summarizing, and viewing results. In addition, DockoMatic automates creation of peptide ligand .pdb files from strings of single-letter amino acid abbreviations. Conclusions: DockoMatic significantly reduces the complexity of managing multiple AutoDock jobs by facilitating ligand and AutoDock job creation and management

From network structure to network reorganization: implications for adult neurogenesis

Networks can be dynamical systems that undergo functional and structural reorganization. One example of such a process is adult hippocampal neurogenesis, in which new cells are continuously born and incorporate into the existing network of the dentate gyrus region of the hippocampus. Many of these introduced cells mature and become indistinguishable from established neurons, joining the existing network. Activity in the network environment is known to promote birth, survival and incorporation of new cells. However, after epileptogenic injury, changes to the connectivity structure around the neurogenic niche are known to correlate with aberrant neurogenesis. The possible role of network-level changes in the development of epilepsy is not well understood. In this paper, we use a computational model to investigate how the structural and functional outcomes of network reorganization, driven by addition of new cells during neurogenesis, depend on the original network structure. We find that there is a stable network topology that allows the network to incorporate new neurons in a manner that enhances activity of the persistently active region, but maintains global network properties. In networks having other connectivity structures, new cells can greatly alter the distribution of firing activity and destroy the initial activity patterns. We thus find that new cells are able to provide focused enhancement of network only for small-world networks with sufficient inhibition. Network-level deviations from this topology, such as those caused by epileptogenic injury, can set the network down a path that develops toward pathological dynamics and aberrant structural integration of new cells.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/85406/1/ph10_4_046008.pd

The Waiting And Mating Game: Condition Dependent Mate Sampling In Female Gray Treefrogs (Hyla Versicolor)

Strong sexual selection by receivers can lead to the evolution of elaborate courtship behaviors in signalers. However the process by which receivers sample signalers and execute mate choice under complex signaling conditions—and thus the realized strength of sexual section—is poorly understood. Moreover, receivers can vary in condition, which can further influence mate sampling strategies. Using wild female frogs we tested two hypotheses at the intersection of these important problems: that some of the individual variation in mate sampling is explained by (1) the reproductive urgency hypothesis, which predicts that receivers in a more urgent reproductive state will sample mates less and/or (2) the reproductive investment hypothesis, which predicts that receivers that have invested less in the current reproductive effort will sample mates less. Eastern gray treefrogs, Hyla versicolor, were collected in amplexus and repeatedly tested for phonotaxis behavior using a dynamic playback assay. To evaluate if hormonal mechanisms explained variation in the mate sampling, three steroid hormones, estradiol, progesterone, and corticosterone, were collected using a noninvasive water-borne hormone assay, validated for this species in the present study. Finally, we measured clutch size (investment) and the duration of time required for each female to oviposit after being reunited with their male mate (urgency). We found repeatability in many of the behaviors, including mate sampling. We found that females with higher concentrations estradiol and corticosterone made quicker choices, and that females with higher progesterone sampled mates more. We also found that female frogs in a more urgent reproductive state had lower concentrations of progesterone and estradiol, thereby providing the first evidence of a relationship between gonadal hormones and reproductive urgency. Collectively we found some support for the reproductive urgency but not the investment hypothesis. Thus, even though a female frog\u27s reproductive readiness is a highly transient life history stage, fine scale variation in her reproductive timeline could mitigate the strength of directional selection

Extreme environmental conditions reduce coral reef fish biodiversity and productivity

Tropical ectotherms are hypothesized to be vulnerable to environmental changes, but cascading effects of organismal tolerances on the assembly and functioning of reef fish communities are largely unknown. Here, we examine differences in organismal traits, assemblage structure, and productivity of cryptobenthic reef fishes between the world’s hottest, most extreme coral reefs in the southern Arabian Gulf and the nearby, but more environmentally benign, Gulf of Oman. We show that assemblages in the Arabian Gulf are half as diverse and less than 25% as abundant as in the Gulf of Oman, despite comparable benthic composition and live coral cover. This pattern appears to be driven by energetic deficiencies caused by responses to environmental extremes and distinct prey resource availability rather than absolute thermal tolerances. As a consequence, production, transfer, and replenishment of biomass through cryptobenthic fish assemblages is greatly reduced on Earth’s hottest coral reefs. Extreme environmental conditions, as predicted for the end of the 21st century, could thus disrupt the community structure and productivity of a critical functional group, independent of live coral loss

Dosing Regimen of Enrofloxacin Impacts Intestinal Pharmacokinetics and the Fecal Microbiota in Steers

Objective: The intestinal concentrations of antimicrobial drugs that select for resistance in fecal bacteria of cattle are poorly understood. Our objective was to associate active drug concentrations in the intestine of steers with changes in the resistance profile and composition of the fecal microbiome.Methods: Steers were administered either a single dose (12.5 mg/kg) or 3 multiple doses (5 mg/kg) of enrofloxacin subcutaneously every 24 h. Enrofloxacin and ciprofloxacin concentrations in intestinal fluid were measured over 96 h, and the abundance and MIC of E. coli in culture and the composition of the fecal microbiota by 16S rRNA gene sequencing were assessed over 192 h after initial treatment.Results: Active drug concentrations in the ileum and colon exceeded plasma and interstitial fluid concentrations, but were largely eliminated by 48 h after the last dose. The concentration of E. coli in the feces significantly decreased during peak drug concentrations, but returned to baseline by 96 h in both groups. The median MIC of E. coli isolates increased for 24 h in the single dose group, and for 48 h in the multiple dose group. The median MIC was higher in the multiple dose group when compared to the single dose group starting 12 h after the initial dose. The diversity of the fecal microbiota did not change in either treatment group, and taxa-specific changes were primarily seen in phyla commonly associated with the rumen.Conclusions: Both dosing regimens of enrofloxacin achieve high concentrations in the intestinal lumen, and the rapid elimination mitigates long-term impacts on fecal E. coli resistance and the microbiota

Nutrient limitation, bioenergetics and stoichiometry: A new model to predict elemental fluxes mediated by fishes

Energy flow and nutrient cycling dictate the functional role of organisms in ecosystems. Fishes are key vectors of carbon (C), nitrogen (N) and phosphorus (P) in aquatic systems, and the quantification of elemental fluxes is often achieved by coupling bioenergetics and stoichiometry. While nutrient limitation has been accounted for in several stoichiometric models, there is no current implementation that permits its incorporation into a bioenergetics approach to predict ingestion rates. This may lead to biased estimates of elemental fluxes.Here, we introduce a theoretical framework that combines stoichiometry and bioenergetics with explicit consideration of elemental limitations. We examine varying elemental limitations across different trophic groups and life stages through a case study of three trophically distinct reef fishes. Further, we empirically validate our model using an independent database of measured excretion rates.Our model adequately predicts elemental fluxes in the examined species and reveals species‐ and size‐specific limitations of C, N and P. In line with theoretical predictions, we demonstrate that the herbivore Zebrasoma scopas is limited by N and P, and all three fish species are limited by P in early life stages. Further, we show that failing to account for nutrient limitation can result in a greater than twofold underestimation of ingestion rates, which leads to severely biased excretion rates.Our model improved predictions of ingestion, excretion and egestion rates across all life stages, especially for fishes with diets low in N and/or P. Due to its broad applicability, its reliance on many parameters that are well‐defined and widely accessible, and its straightforward implementation via the accompanying r‐package fishflux, our model provides a user‐friendly path towards a better understanding of ecosystem‐wide nutrient cycling in the aquatic biome.A free Plain Language Summary can be found within the Supporting Information of this article.A free Plain Language Summary can be found within the Supporting Information of this article.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/162691/5/fec13618_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162691/4/fec13618-sup-0002-AppendixS1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162691/3/fec13618-sup-0001-Summary.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162691/2/fec13618-sup-0003-AppendixS2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/162691/1/fec13618.pd

Genomic Profiling of Childhood Tumor Patient-Derived Xenograft Models to Enable Rational Clinical Trial Design.

Accelerating cures for children with cancer remains an immediate challenge as a result of extensive oncogenic heterogeneity between and within histologies, distinct molecular mechanisms evolving between diagnosis and relapsed disease, and limited therapeutic options. To systematically prioritize and rationally test novel agents in preclinical murine models, researchers within the Pediatric Preclinical Testing Consortium are continuously developing patient-derived xenografts (PDXs)-many of which are refractory to current standard-of-care treatments-from high-risk childhood cancers. Here, we genomically characterize 261 PDX models from 37 unique pediatric cancers; demonstrate faithful recapitulation of histologies and subtypes; and refine our understanding of relapsed disease. In addition, we use expression signatures to classify tumors for TP53 and NF1 pathway inactivation. We anticipate that these data will serve as a resource for pediatric oncology drug development and will guide rational clinical trial design for children with cancer

TOI-561 b: A Low Density Ultra-Short Period "Rocky" Planet around a Metal-Poor Star

TOI-561 is a galactic thick disk star hosting an ultra-short period (0.45 day orbit) planet with a radius of 1.37 R$_{\oplus}$, making it one of the most metal-poor ([Fe/H] = -0.41) and oldest ($\sim$10 Gyr) sites where an Earth-sized planet has been found. We present new simultaneous radial velocity measurements (RVs) from Gemini-N/MAROON-X and Keck/HIRES, which we combined with literature RVs to derive a mass of M$_{b}$=2.24 $\pm$ 0.20 M$_{\oplus}$. We also used two new Sectors of TESS photometry to improve the radius determination, finding R$_{b}$=$1.37 \pm 0.04 R_\oplus$, and confirming that TOI-561 b is one of the lowest-density super-Earths measured to date ($\rho_b$= 4.8 $\pm$ 0.5 g/cm$^{3}$). This density is consistent with an iron-poor rocky composition reflective of the host star's iron and rock-building element abundances; however, it is also consistent with a low-density planet with a volatile envelope. The equilibrium temperature of the planet ($\sim$2300 K) suggests that this envelope would likely be composed of high mean molecular weight species, such as water vapor, carbon dioxide, or silicate vapor, and is likely not primordial. We also demonstrate that the composition determination is sensitive to the choice of stellar parameters, and that further measurements are needed to determine if TOI-561 b is a bare rocky planet, a rocky planet with an optically thin atmosphere, or a rare example of a non-primordial envelope on a planet with a radius smaller than 1.5 R$_{\oplus}$.Comment: Accepted to AJ on 11/28/202