Pancreatic cancer patient survival correlates with DNA methylation of pancreas development genes.

DNA methylation is an epigenetic mark associated with regulation of transcription and genome structure. These markers have been investigated in a variety of cancer settings for their utility in differentiating normal tissue from tumor tissue. Here, we examine the direct correlation between DNA methylation and patient survival. We find that changes in the DNA methylation of key pancreatic developmental genes are strongly associated with patient survival

ESTABLISHING THE DISCRIMINATIVE STIMULUS PROPERTIES OF THE ATYPICAL ANTIPSYCHOTIC AMISULPRIDE IN C57BL/6 MICE

Abstract ESTABLISHING THE DISCRIMINATIVE STIMULUS PROPERTIES OF THE ATYPICAL ANTIPSYCHOTIC AMISULPRIDE IN C57BL/6 MICE Antipsychotic medications are used to treat schizophrenia. The present study used the drug discrimination paradigm to measure the subjective effects of the atypical antipsychotic amisulpride and to examine the underlying neuropharmacological mechanisms responsible for the discriminative stimulus property of the drug. Male C57BL/6 mice were trained to discriminate 10 mg/kg (-)S amisulpride from vehicle in a two-lever drug discrimination task. A dose effect curve for (-)S amisulpride yielded an ED50 = 1.77 mg/kg 95% CI [1.28, 2.45 mg/kg]. Substitution testing was conducted for the isomer (+)R amisulpride, racemic (±)SR amisulpride, the atypical antipsychotics clozapine, aripiprazole and the typical antipsychotic haloperidol. There was partial substitution for (+)R amisulpride, and full substitution for (±)SR amisulpride with a significant rightward shift in the dose effect curves. Clozapine, aripiprazole, and haloperidol failed to fully substitute with significant rate suppression at the higher doses. These results demonstrated that (-)S amisulpride has a unique discriminative stimulus that differs from other antipsychotic drugs

CHARACTERIZATION OF THE DISCRIMINATIVE STIMULUS PROPERTIES OF THE ATYPICAL ANTIPSYCHOTIC AMISULPRIDE IN C57BL/6 MICE

Amisulpride, a benzamide derivative, is an atypical antipsychotic drug used to treat both schizophrenia and depression. Amisulpride is a selective antagonist at dopamine D2 and D3 receptors and at serotonin 5-HT2B and 5-HT7 receptors and displays an atypical clinical profile with reduced extrapyramidal motor effects. The drug has a chiral center and is a mixture of two optical isomers: (S)-amisulpride and (R)-amisulpride. The present study used a two-lever drug discrimination assay to allow a direct comparison between amisulpride and its two isomers. Additionally, substitution testing was conducted with the typical antipsychotics, atypical antipsychotics, antidepressants, the anxiolytic chlordiazepoxide, several benzamide derivatives, and selective ligands with receptor mechanisms relevant to amisulpride. C57BL/6 mice were trained to discriminate 10 mg/kg rac-amisulpride from vehicle in a two-lever drug discrimination task for food reinforcement in an average of 35.7 sessions (range 6-89). The amisulpride dose-response curve (0.078 – 10.0 mg/kg) yielded an ED50 = 0.64 mg/kg, 95% CI [.47, 0.84 mg/kg]. The isomers fully substituted for amisulpride with a significant left-ward shift in the dose-response curve for (S)-amisulpride as compared to rac-amisulpride and (R)-amisulpride. The benzamide derivatives sulpiride and the (S)-sulpiride isomer fully substituted for amisulpride; tiapride produced partial substitution (76.4% DLR); none of the other tested drugs substituted for rac-amisulpride’s discriminative stimulus. These results showed that the rac-amisulpride stimulus was readily acquired in C57BL/6 mice, and that it has a unique and robust discriminative stimulus that is dose-dependent, time-dependent and stereoselective and is not shared with other antipsychotic or antidepressant drugs

Cosmogenic C-14 in Antarctic and non-Antarctic meteorites and lunar samples

We were able to develop measurements of C-14 in meteorites as a useful tool for estimates of terrestrial age. Prior to this accomplishment, only a few measurements of C-14 terrestrial ages had been made. The sample sizes were larger, and there had been no systematic study of the various parameters affecting production of C-14, such as depth dependence, and the production cross sections for C-14 from spallation amounted to a few data points. Presently, C-14 ages are an accepted terrestrial age estimate in the meteorite community, whereas before this work the few data available were difficult to interpret. We have obtained terrestrial ages not only on groups of meteorites from different geographic areas but also information on unique meteorites from particularly interesting groups, such as meteorites originating from the Moon, or SNC meteorites, which many researchers believe are derived from Mars

Biochemical and Genetic Characterization of PspE and GlpE, Two Single-domain Sulfurtransferases of Escherichia coli

The pspE and glpE genes of Escherichia coli encode periplasmic and cytoplasmic single-domain rhodaneses, respectively, that catalyzes sulfur transfer from thiosulfate to thiophilic acceptors. Strains deficient in either or both genes were constructed. Comparison of rhodanese activity in these strains revealed that PspE provides 85% of total rhodanese activity, with GlpE contributing most of the remainder. PspE activity was four times higher during growth on glycerol versus glucose, and was not induced by conditions that induce expression of the psp regulon. The glpE/pspE mutants displayed no apparent growth phenotypes, indicating that neither gene is required for biosynthesis of essential sulfur-containing molecules. PspE was purified by using cation exchange chromatography. Two distinct active peaks were eluted and differed in the degree of stable covalent modification, as assessed by mass spectrometry. The peak eluting earliest contained the equivalent mass of two additional sulfur atoms, whereas the second peak contained mainly one additional sulfur. Kinetic properties of purified PspE were consistent with catalysis occurring via a double-displacement mechanism via an enzyme-sulfur intermediate involving the active site cysteine. Kms for SSO32- and CN- were 2.7 mM and 32 mM, respectively, and kcat was 64s-1. The enzyme also catalyzed transfer of sulfur from thiosulfate to dithiothreitol, ultimately releasing sulfide

Towards HCP-style macaque connectomes: 24-channel 3T multi-array coil, MRI sequences and preprocessing

Macaque monkeys are an important animal model where invasive investigations can lead to a better understanding of the cortical organization of primates including humans. However, the tools and methods for noninvasive image acquisition (e.g. MRI RF coils and pulse sequence protocols) and image data preprocessing have lagged behind those developed for humans. To resolve the structural and functional characteristics of the smaller macaque brain, high spatial, temporal, and angular resolutions combined with high signal-to-noise ratio are required to ensure good image quality. To address these challenges, we developed a macaque 24-channel receive coil for 3-T MRI with parallel imaging capabilities. This coil enables adaptation of the Human Connectome Project (HCP) image acquisition protocols to the in-vivo macaque brain. In addition, we adapted HCP preprocessing methods to the macaque brain, including spatial minimal preprocessing of structural, functional MRI (fMRI), and diffusion MRI (dMRI). The coil provides the necessary high signal-to-noise ratio and high efficiency in data acquisition, allowing four- and five-fold accelerations for dMRI and fMRI. Automated FreeSurfer segmentation of cortex, reconstruction of cortical surface, removal of artefacts and nuisance signals in fMRI, and distortion correction of dMRI all performed well, and the overall quality of basic neurobiological measures was comparable with those for the HCP. Analyses of functional connectivity in fMRI revealed high sensitivity as compared with those from publicly shared datasets. Tractography-based connectivity estimates correlated with tracer connectivity similarly to that achieved using ex-vivo dMRI. The resulting HCP-style in vivo macaque MRI data show considerable promise for analyzing cortical architecture and functional and structural connectivity using advanced methods that have previously only been available in studies of the human brain

Using diffusion tractography to predict cortical connection strength and distance: a quantitative comparison with tracers in the monkey

Tractography based on diffusion MRI offers the promise of characterizing many aspects of long-distance connectivity in the brain, but requires quantitative validation to assess its strengths and limitations. Here, we evaluate tractography's ability to estimate the presence and strength of connections between areas of macaque neocortex by comparing its results with published data from retrograde tracer injections. Probabilistic tractography was performed on high-quality postmortem diffusion imaging scans from two Old World monkey brains. Tractography connection weights were estimated using a fractional scaling method based on normalized streamline density. We found a correlation between log-transformed tractography and tracer connection weights of r = 0.59, twice that reported in a recent study on the macaque. Using a novel method to estimate interareal connection lengths from tractography streamlines, we regressed out the distance dependence of connection strength and found that the correlation between tractography and tracers remains positive, albeit substantially reduced. Altogether, these observations provide a valuable, data-driven perspective on both the strengths and limitations of tractography for analyzing interareal corticocortical connectivity in nonhuman primates and a framework for assessing future tractography methodological refinements objectively

COVID Witness to Hope: Catholic Schools Respond to COVID-19

The twin uncertainties of the pandemic and the economic downturn have taken a toll on our Catholic schools. Yet reports across the country are that Catholic schools have been very successful in remote learning. Although there are well-documented efforts to define the values of Catholic schools, these values are not fully known and there is still not a well-crafted national value proposition for Catholic schools. As the context surrounding Catholic schools has changed, it has become imperative that Catholic schools coalesce around a new value proposition during uncertain times. What follows is an attempt by a group of dedicated Catholic school stakeholders determined to change the narrative. As our schools have pivoted to new forms of delivery and connections, this ad hoc group represents the same type of creative efforts to form a community. As a committee, we identified five themes of hope that can continue to guide the work and witness of our Catholic schools: prayer, partnership with families, personalization, persistence, and planning. In the following sections, we provide a rationale and overview of each theme. We also include relevant testimonials of diverse stakeholders to illuminate each theme and give voice to the hope across our school communities