Carcinoids and Capsules: A Case Series Highlighting the Utility of Capsule Endoscopy in Patients With Small Bowel Carcinoids

Background: Neuroendocine tumors (NETs) or carcinoids arise at many different sites of the gastrointestinal tract. The small intestine is the most common site for NETs. Diagnosing small bowel carcinoids remains challenging given their non-specific presentations and the overall low incidence of small bowel tumors. Video capsule endoscopy (VCE) has significanly improved our ability to detect small bowel malignancies. We explore the value of VCE in the initial workup and management of a series of small bowel carcinoid patients. Methods: We retrospectively analyzed adult patients undergoing surgical management for small bowel lesions from July 2005 to September 2015 at a tertiary care center. Patient characteristics, presenting symptomatology, diagnostic workup and surgical management were analyzed among patients with histologically confirmed small bowel carcinoid tumors. Results: Our study identified 16 patients treated surgically for small bowel carcinoids. The majority of patients (87.5%) presented with either occult gastrointestinal bleeding or anemia. Most patients (87.5%) were initially evaluated with various endoscopic and imaging modalities before all ultimately undergoing surgery. Seventy-five percent of patients had a VCE, with 83.3% (10/12) having positive findings that correlated with intraoperative findings compared to 62.5% (5/8) with computed tomography scan, 21.4% (3/14) with colonoscopy, 44% (4/9) with deep enteroscopy, and 0% (0/9) with esophagogastroduodenoscopy (EGD). Conclusions: In the absence of any contraindications, VCE is an effective endoscopic modality in the diagnostic workup of small bowel NETs. Furthermore, positive VCE findings appear to highly correlate with surgical findings, thus suggesting a valuable role for VCE in the initial surgical assessment of patients with small bowel NETs

Epigenetic memory in induced pluripotent stem cells.

Somatic cell nuclear transfer and transcription-factor-based reprogramming revert adult cells to an embryonic state, and yield pluripotent stem cells that can generate all tissues. Through different mechanisms and kinetics, these two reprogramming methods reset genomic methylation, an epigenetic modification of DNA that influences gene expression, leading us to hypothesize that the resulting pluripotent stem cells might have different properties. Here we observe that low-passage induced pluripotent stem cells (iPSCs) derived by factor-based reprogramming of adult murine tissues harbour residual DNA methylation signatures characteristic of their somatic tissue of origin, which favours their differentiation along lineages related to the donor cell, while restricting alternative cell fates. Such an 'epigenetic memory' of the donor tissue could be reset by differentiation and serial reprogramming, or by treatment of iPSCs with chromatin-modifying drugs. In contrast, the differentiation and methylation of nuclear-transfer-derived pluripotent stem cells were more similar to classical embryonic stem cells than were iPSCs. Our data indicate that nuclear transfer is more effective at establishing the ground state of pluripotency than factor-based reprogramming, which can leave an epigenetic memory of the tissue of origin that may influence efforts at directed differentiation for applications in disease modelling or treatment

Copy number variant detection in inbred strains from short read sequence data

Summary: We have developed an algorithm to detect copy number variants (CNVs) in homozygous organisms, such as inbred laboratory strains of mice, from short read sequence data. Our novel approach exploits the fact that inbred mice are homozygous at virtually every position in the genome to detect CNVs using a hidden Markov model (HMM). This HMM uses both the density of sequence reads mapped to the genome, and the rate of apparent heterozygous single nucleotide polymorphisms, to determine genomic copy number. We tested our algorithm on short read sequence data generated from re-sequencing chromosome 17 of the mouse strains A/J and CAST/EiJ with the Illumina platform. In total, we identified 118 copy number variants (43 for A/J and 75 for CAST/EiJ). We investigated the performance of our algorithm through comparison to CNVs previously identified by array-comparative genomic hybridization (array CGH). We performed quantitative-PCR validation on a subset of the calls that differed from the array CGH data sets

Draft Aphaenogaster genomes expand our view of ant genome size variation across climate gradients

Given the abundance, broad distribution, and diversity of roles that ants play in many ecosystems, they are an ideal group to serve as ecosystem indicators of climatic change. At present, only a few whole-genome sequences of ants are available (19 of \u3e16,000 species), mostly from tropical and sub-tropical species. To address this limited sampling, we sequenced genomes of temperate-latitude species from the genus Aphaenogaster, a genus with important seed dispersers. In total, we sampled seven colonies of six species: Aphaenogaster ashmeadi, Aphaenogaster floridana, Aphaenogaster fulva, Aphaenogaster miamiana, Aphaenogaster picea, and Aphaenogaster rudis. The geographic ranges of these species collectively span eastern North America from southern Florida to southern Canada, which encompasses a latitudinal gradient in which many climatic variables are changing rapidly. For the six genomes, we assembled an average of 271,039 contigs into 47,337 scaffolds. The Aphaenogaster genomes displayed high levels of completeness with 96.1% to 97.6% of Hymenoptera BUSCOs completely represented, relative to currently sequenced ant genomes which ranged from 88.2% to 98.5%. Additionally, the mean genome size was 370.5 Mb, ranging from 310.3 to 429.7, which is comparable to that of other sequenced ant genomes (212.8-396.0 Mb) and flow cytometry estimates (210.7-690.4 Mb). In an analysis of currently sequenced ant genomes and the new Aphaenogaster sequences, we found that after controlling for both spatial autocorrelation and phylogenetics ant genome size was marginally correlated with sample site climate similarity. Of all examined climate variables, minimum temperature, and annual precipitation had the strongest correlations with genome size, with ants from locations with colder minimum temperatures and higher levels of precipitation having larger genomes. These results suggest that climate extremes could be a selective force acting on ant genomes and point to the need for more extensive sequencing of ant genomes

wuHMM: a robust algorithm to detect DNA copy number variation using long oligonucleotide microarray data

Copy number variants (CNVs) are currently defined as genomic sequences that are polymorphic in copy number and range in length from 1000 to several million base pairs. Among current array-based CNV detection platforms, long-oligonucleotide arrays promise the highest resolution. However, the performance of currently available analytical tools suffers when applied to these data because of the lower signal:noise ratio inherent in oligonucleotide-based hybridization assays. We have developed wuHMM, an algorithm for mapping CNVs from array comparative genomic hybridization (aCGH) platforms comprised of 385 000 to more than 3 million probes. wuHMM is unique in that it can utilize sequence divergence information to reduce the false positive rate (FPR). We apply wuHMM to 385K-aCGH, 2.1M-aCGH and 3.1M-aCGH experiments comparing the 129X1/SvJ and C57BL/6J inbred mouse genomes. We assess wuHMM's performance on the 385K platform by comparison to the higher resolution platforms and we independently validate 10 CNVs. The method requires no training data and is robust with respect to changes in algorithm parameters. At a FPR of <10%, the algorithm can detect CNVs with five probes on the 385K platform and three on the 2.1M and 3.1M platforms, resulting in effective resolutions of 24 kb, 2–5 kb and 1 kb, respectively

Heat tolerance predicts the importance of species interaction effects as the climate changes

Few studies have quantified the relative importance of direct effects of climate change on communities versus indirect effects that are mediated thorough species interactions, and the limited evidence is conflicting. Trait-based approaches have been popular in studies of climate change, but can they be used to estimate direct versus indirect effects? At the species level, thermal tolerance is a trait that is often used to predict winners and losers under scenarios of climate change. But thermal tolerance might also inform when species interactions are likely to be important because only subsets of species will be able to exploit the available warmer climatic niche space, and competition may intensify in the remaining, compressed cooler climatic niche space. Here, we explore the relative roles of the direct effects of temperature change and indirect effects of species interactions on forest ant communities that were heated as part of a large-scale climate manipulation at high-A nd low-latitude sites in eastern North America. Overall, we found mixed support for the importance of negative species interactions (competition), but found that the magnitude of these interaction effects was predictable based on the heat tolerance of the focal species. Forager abundance and nest site occupancy of heat-intolerant species were more often influenced by negative interactions with other species than by direct effects of temperature. Our findings suggest that measures of species-specific heat tolerance may roughly predict when species interactions will influence responses to global climate change

Thermal reactionomes reveal divergent responses to thermal extremes in warm and cool-climate ant species

Background: The distributions of species and their responses to climate change are in part determined by their thermal tolerances. However, little is known about how thermal tolerance evolves. To test whether evolutionary extension of thermal limits is accomplished through enhanced cellular stress response (enhanced response), constitutively elevated expression of protective genes (genetic assimilation) or a shift from damage resistance to passive mechanisms of thermal stability (tolerance), we conducted an analysis of the reactionome: the reaction norm for all genes in an organism\u27s transcriptome measured across an experimental gradient. We characterized thermal reactionomes of two common ant species in the eastern U.S, the northern cool-climate Aphaenogaster picea and the southern warm-climate Aphaenogaster carolinensis, across 12 temperatures that spanned their entire thermal breadth. Results: We found that at least 2 % of all genes changed expression with temperature. The majority of upregulation was specific to exposure to low temperatures. The cool-adapted A. picea induced expression of more genes in response to extreme temperatures than did A. carolinensis, consistent with the enhanced response hypothesis. In contrast, under high temperatures the warm-adapted A. carolinensis downregulated many of the genes upregulated in A. picea, and required more extreme temperatures to induce down-regulation in gene expression, consistent with the tolerance hypothesis. We found no evidence for a trade-off between constitutive and inducible gene expression as predicted by the genetic assimilation hypothesis. Conclusions: These results suggest that increases in upper thermal limits may require an evolutionary shift in response mechanism away from damage repair toward tolerance and prevention

Lock-in detection using a cryogenic low noise looped current preamplifier for the readout of resistive bolometers

We implemented a low noise current preamplifier for the readout of resistive bolometers. We tested the apparatus on thermometer resistances ranging from 10 Ohm to 500 Mohm. The use of current preamplifier overcomes constraints introduced by the readout time constant due to the thermometer resistance and the input capacitance. Using cold JFETs, this preamplifier board is shown to have very low noise: the Johnson noise of the source resistor (1 fA/Hz1/2) dominated in our noise measurements. We also implemented a lock-in chain using this preamplifier. Because of fast risetime, compensation of the phase shift may be unnecessary. If implemented, no tuning is necessary when the sensor impedance changes. Transients are very short, and thus low-passing or sampling of the signal is simplified. In case of spurious noise, the modulation frequency can be chosen in a much wider frequency range, without requiring a new calibration of the apparatus.Comment: 18 pages, 7 figures, Accepted in NIM