Extracellular free water and glutathione in first-episode psychosis-a multimodal investigation of an inflammatory model for psychosis.

Evidence has been accumulating for an immune-based component to the etiology of psychotic disorders. Advancements in diffusion magnetic resonance imaging (MRI) have enabled estimation of extracellular free water (FW), a putative biomarker of neuroinflammation. Furthermore, inflammatory processes may be associated with altered brain levels of metabolites, such as glutathione (GSH). Consequently, we sought to test the hypotheses that FW is increased and associated with decreased GSH in patients with first-episode schizophrenia (SZ) compared with healthy controls (HC). SZ (n = 36) and HC (n = 40) subjects underwent a multi-shell diffusion MRI scan on a Siemens 3T scanner. 1H-MR spectroscopy data were acquired using a GSH-optimized MEGA-PRESS editing sequence and GSH/creatine ratios were calculated for DLPFC (SZ: n = 33, HC: n = 37) and visual cortex (SZ: n = 29, HC: n = 35) voxels. Symptoms and functioning were measured using the SANS, SAPS, BPRS, and GSF/GRF. SZ demonstrated significantly elevated FW in whole-brain gray (p = .001) but not white matter (p = .060). There was no significant difference between groups in GSH in either voxel. However, there was a significant negative correlation between DLPFC GSH and both whole-brain and DLPFC-specific gray matter FW in SZ (r = -.48 and -.47, respectively; both p < .05), while this relationship was nonsignificant in HC and in both groups in the visual cortex. These data illustrate an important relationship between a metabolite known to be important for immune function-GSH-and the diffusion extracellular FW measure, which provides additional support for these measures as neuroinflammatory biomarkers that could potentially provide tractable treatment targets to guide pharmacological intervention

Differential neuroproteomic and systems biology analysis of spinal cord injury

Acute spinal cord injury (SCI) is a devastating condition with many consequences and no known effective treatment. Although it is quite easy to diagnose traumatic SCI, the assessment of injury severity and projection of disease progression or recovery are often challenging, as no consensus biomarkers have been clearly identified. Here rats were subjected to experimental moderate or severe thoracic SCI. At 24h and 7d postinjury, spinal cord segment caudal to injury center versus sham samples was harvested and subjected to differential proteomic analysis. Cationic/anionic-exchange chromatography, followed by 1D polyacrylamide gel electrophoresis, was used to reduce protein complexity. A reverse phase liquid chromatography-tandem mass spectrometry proteomic platform was then utilized to identify proteome changes associated with SCI. Twenty-two and 22 proteins were up-regulated at 24 h and 7 day after SCI, respectively; whereas 19 and 16 proteins are down-regulated at 24 h and 7 day after SCI, respectively, when compared with sham control. A subset of 12 proteins were identified as candidate SCI biomarkers - TF (Transferrin), FASN (Fatty acid synthase), NME1 (Nucleoside diphosphate kinase 1), STMN1 (Stathmin 1), EEF2 (Eukaryotic translation elongation factor 2), CTSD (Cathepsin D), ANXA1 (Annexin A1), ANXA2 (Annexin A2), PGM1 (Phosphoglucomutase 1), PEA15 (Phosphoprotein enriched in astrocytes 15), GOT2 (Glutamic-oxaloacetic transaminase 2), and TPI-1 (Triosephosphate isomerase 1), data are available via ProteomeXchange with identifier PXD003473. In addition, Transferrin, Cathepsin D, and TPI-1 and PEA15 were further verified in rat spinal cord tissue and/or CSF samples after SCI and in human CSF samples from moderate/severe SCI patients. Lastly, a systems biology approach was utilized to determine the critical biochemical pathways and interactome in the pathogenesis of SCI. Thus, SCI candidate biomarkers identified can be used to correlate with disease progression or to identify potential SCI therapeutic targets

The fate of cerium oxide nanoparticles in sediments and their routes of uptake in a freshwater worm

The relative importance of ingestion and transdermal uptake of nanomaterials is poorly understood, particularly in sediment dwelling organisms, where diet has the potential to contribute significantly to particle accumulation. In aquatic sediments, nanoparticles may partition to bind with the solid fraction of sediment, be freely mobile in the pore water or, for certain metal/metal oxides, undergo dissolution, each of which could influence the route of nanoparticle uptake. Here, we used the freshwater worm Lumbriculus variegatus as a model species. We took advantage of its unique feeding and non-feeding life-stages to assess the contribution of dietary and transdermal uptake in the bioaccumulation of cerium oxide nanoparticles (CeO2 NP) and soluble Ce(III)NO3. Distribution of cerium between the solid, colloidal and soluble fractions in the sediments was determined through sediment separations using micro and ultrafiltration techniques. We assessed particles of differing sizes (10, 28 and 615 nm CeO2) and stabilizing surfactants (10 nm electrostatic Citrate-CeO2 and steric stabilized PEG-CeO2). Soluble Ce(III)NO3, was found to accumulate readily across the skin of the worms whilst nanoparticles were not. Sediments reduced the uptake of CeIII by limiting the presence of dissolved species of cerium in the pore waters. Neither particle size nor the coatings studied altered the distribution of nanoparticles between solid and colloidal fractions of the sediment, with ∼99% associated to the solid phase. Any uptake of CeO2 nanoparticles into worms was only through ingestion. Stabilized 10 nm particles were retained even after gut clearance, indicating that these particles may translocate across the gut wall

A Synthesis of Human-related Avian Mortality in Canada

Many human activities in Canada kill wild birds, yet the relative magnitude of mortality from different sources and the consequent effects on bird populations have not been systematically evaluated. We synthesize recent estimates of avian mortality in Canada from a range of industrial and other human activities, to provide context for the estimates from individual sources presented in this special feature. We assessed the geographic, seasonal, and taxonomic variation in the magnitude of national-scale mortality and in population-level effects on species or groups across Canada, by combining these estimates into a stochastic model of stage-specific mortality. The range of estimates of avian mortality from each source covers several orders of magnitude, and, numerically, landbirds were the most affected group. In total, we estimate that approximately 269 million birds and 2 million nests are destroyed annually in Canada, the equivalent of over 186 million breeding individuals. Combined, cat predation and collisions with windows, vehicles, and transmission lines caused > 95% of all mortality; the highest industrial causes of mortality were the electrical power and agriculture sectors. Other mortality sources such as fisheries bycatch can have important local or species-specific impacts, but are relatively small at a national scale. Mortality rates differed across species and families within major bird groups, highlighting that mortality is not simply proportional to abundance. We also found that mortality is not evenly spread across the country; the largest mortality sources are coincident with human population distribution, while industrial sources are concentrated in southern Ontario, Alberta, and southwestern British Columbia. Many species are therefore likely to be vulnerable to cumulative effects of multiple human-related impacts. This assessment also confirms the high uncertainty in estimating human-related avian mortality in terms of species involved, potential for population-level effects, and the cumulative effects of mortality across the landscape. Effort is still required to improve these estimates, and to guide conservation efforts to minimize direct mortality caused by human activities on Canada's wild bird populations. As avian mortality represents only a portion of the overall impact to avifauna, indirect effects such as habitat fragmentation and alteration, site avoidance, disturbance, and related issues must also be carefully considered

Revising evidence of hurricane strikes on Abaco Island (the Bahamas) over the last 700 years

© The Author(s), 2020. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Winkler, T. S., van Hengstum, P. J., Donnelly, J. P., Wallace, E. J., Sullivan, R. M., MacDonald, D., & Albury, N. A. Revising evidence of hurricane strikes on Abaco Island (the Bahamas) over the last 700 years. Scientific Reports, 10(1), (2020): 16556, doi:10.1038/s41598-020-73132-x.The northern Bahamas have experienced more frequent intense-hurricane impacts than almost anywhere else in the Atlantic since 1850 CE. In 2019, category 5 (Saffir-Simpson scale) Hurricane Dorian demonstrated the destructive potential of these natural hazards. Problematically, determining whether high hurricane activity levels remained constant through time is difficult given the short observational record (< 170 years). We present a 700-year long, near-annually resolved stratigraphic record of hurricane passage near Thatchpoint Blue Hole (TPBH) on Abaco Island, The Bahamas. Using longer sediment cores (888 cm) and more reliable age-control, this study revises and temporally expands a previous study from TPBH that underestimated the sedimentation rate. TPBH records at least 13 ≥ category 2 hurricanes per century between 1500 to 1670 CE, which exceeds the 9 ≥ category 2 hurricanes per century within 50 km of TPBH since 1850 CE. The eastern United States also experienced frequent hurricanes from 1500 to 1670 CE, but frequency was depressed elsewhere in the Atlantic Ocean. This suggests that spatial heterogeneity in Atlantic hurricane activity since 1850 CE could have persisted throughout the last millennium. This heterogeneity is impacted by climatic and stochastic forcing, but additional high-resolution paleo-hurricane reconstructions are required to assess the mechanisms that impact regional variability.Field support was provided by Jody Albury and the staff of Friends of the Environment in Marsh Harbour, The Bahamas, and technical support was provided was provided by M. Horgan and S. Molodtsov. Funding for this project was provided by NSF Awards OCE-1356509, OCE-1356708, OCE-1854917, OCE-1903616, and ICER-1854980. The open access publishing fees for this article have been covered by the Texas A&M University Open Access to Knowledge Fund (OAKFund), supported by the University Libraries

Targeted next generation sequencing as a tool for precision medicine

Background: Targeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 (CYP) 2D6 gene, or to identify the promoter (TA)7 TAA repeat polymorphism UDP glucuronosyltransferase (UGT) 1A1∗28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response. Methods: A panel of capture probes was generated to assess 422 kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms. Results: Adequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1∗28. Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy. Conclusions: PGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine

Trypanocidal and leishmanicidal activity of six limonoids

Six limonoids [kotschyienone A and B (1, 2), 7-deacetylgedunin (3), 7-deacetyl-7-oxogedunin (4), andirobin (5) and methyl angolensate (6)] were investigated for their trypanocidal and leishmanicidal activities using bloodstream forms of Trypanosoma brucei and promastigotes of Leishmania major. Whereas all compounds showed anti-trypanosomal activity, only compounds 1–4 displayed anti-leishmanial activity. The 50% growth inhibition (GI 50) values for the trypanocidal and leishmanicidal activity of the compounds ranged between 2.5 and 14.9 μM. Kotschyienone A (1) was found to be the most active compound with a minimal inhibition concentration (MIC) value of 10 μM and GI 50 values between 2.5 and 2.9 μM. Only compounds 1 and 3 showed moderate cytotoxicity against HL-60 cells with MIC and GI 50 values of 100 μM and 31.5–46.2 μM, respectively. Compound 1 was also found to show activity against intracellular amastigotes of L. major with a GI 50 value of 1.5 μM. The results suggest that limonoids have potential as drug candidates for the development of new treatments against trypanosomiasis and leishmaniasis

A cross-sectional study on the deprivation and sex differences in health-related fitness measures in school children

This study aimed to investigate deprivation and sex differences in selected health-relatedfitness measures in 9-12-year-old children. Data were captured on 3,407 children (49.3% boys; aged 10.5 ± 0.6 years). Cardiorespiratory fitness(20 m multistage shuttle run test; 20 m MSRT), muscular strength (handgrip strength) and body mass index (BMI) were measured. Welsh Index of Multiple Deprivation (WIMD) scores were used to make quintile groups. A two-way Analysis of Variance examined differences in BMI z-score by sex and WIMD quintiles. Two-wayAnalysis of Covariances investigated the effect of sex and WIMD quintiles on grip strength and shuttles achieved in 20 m MSRT, adjusting for BMI z-score and maturation, repectively. Independent of sex, children in the middle quintile had a significantly higher mean BMI z-score (p = 0.029) than their least deprived counterparts. There was a significant increase in grip strength (p = 0.005) and20 m MSRT (boys p < 0.001; girls p = 0.028) between most and least deprived quintiles. Significant differences in 20 m MSRT score were more apparent with decreases in deprivation in boys.Overall, inequalities exist in health-related fitness by sex and deprivation. These results can be used to inform focused services to improve current and future health

Focus Group Study of Diverse Local Populations and Their Health Care Experiences in Northeastern Pennsylvania: Cross-Cultural Issues

This investigation was conducted through the support of the College Misericordia Diversity Institute and a grant from the Blue Ribbon Foundation of Blue Cross of Northeastern Pennsylvania. Focus group participants were 49 adults from seven minority populations residing in northeastern Pennsylvania’s Luzerne and Lackawanna counties. Data was collected by 11 focus group leaders who were members of a Blue Ribbon Grant Core Committee at College Misericordia in 2004. The seven populations studied were African Americans, Arabic Muslims, Asian-Chinese and Korean, Gay and Lesbian, Hispanic, Jewish, and Asian Indian. A 30-question survey was used to collect data during one to two hour focus group interviews. Through content analysis, six problematic issues faced by many of the participants were identified. All of the findings were validated by a review process. The six issues faced by the 7 groups were: 1) Economics, Education, and Employment Influence Life for Newcomers, 2) Customs and Traditions Sometimes Sacrificed- The Influence of American Culture, 3) Socialization Often Limited to Same Population Group, 4) Mixed Acceptance Level from Area Natives, 5) Bilingual Challenges Impede Optimal Inclusion, 6) Health Care Access Problems. The aforementioned cross-groups study is explored in this report. The study also yielded seven other reports (one for each diverse population) which provide a description of that particular focus group’s perspective on topics such as religion, food, family, customs, and health care (see Appendices A, B, C, D, E, F, and G). Findings of this study are being disseminated in a local effort to educate health care professionals. Future research will be needed to determine if progress is being made in fulfilling the health care needs of all diverse populations living in Luzerne and Lackawanna County, as well as other parts of northeastern Pennsylvania