Publications by authors named "Jason Hill"

106 Publications

High-Throughput UHPLC/MS/MS-Based Metabolic Profiling Using a Vacuum Jacketed Column.

Anal Chem 2021 Jul 19. Epub 2021 Jul 19.

Computational & Systems Medicine, Imperial College, Exhibition Rd, London SW7 2AZ, U.K.

In UHPLC, frictional heating from the eluent flowing through the column at pressures of ca. 10-15 Kpsi causes radial diffusion via temperature differences between the center of the column and its walls. Longitudinal dispersion also occurs due to temperature gradients between the inlet and outlet. These effects cause band broadening but can be mitigated via a combination of vacuum jacketed stainless steel tubing, reduced column end nut mass, and a constant temperature in the column from heating the inlet fitting. Here, vacuum jacketed column (VJC) technology, employing a novel column housing located on the source of the mass spectrometer and minimized tubing from the column outlet to the electrospray probe, was applied to profiling metabolites in urine. For a 75 s reversed-phase gradient separation, the average peak widths for endogenous compounds in urine were 1.2 and 0.6 s for conventional LC/MS and VJC systems, respectively. The peak tailing factor was reduced from 1.25 to 1.13 when using the VJC system compared to conventional UHPLC, and the peak capacity increased from 65 to 120, with a 25% increase in features detected in urine. The increased resolving power of the VJC system reduced co-elution, simplifying MS and MS/MS spectra, providing a more confident metabolite identification. The increased LC performance also gave more intense MS peaks, with a 10-120% increase in response, improving the quality of the MS data and detection limits. Reducing the LC gradient duration to 37 s gave peak widths of ca. 0.4 s and a peak capacity of 84.
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http://dx.doi.org/10.1021/acs.analchem.1c01982DOI Listing
July 2021

Management of Adults with Acute Oesophageal Soft Food Bolus and Foreign Body Obstructions at Two New Zealand District Health Boards.

Clin Exp Gastroenterol 2021 4;14:237-247. Epub 2021 Jun 4.

Department of Gastroenterology, Waitemata District Health Board, Auckland, New Zealand.

Aim: 1. Investigate the characteristics of adult patients presenting with acute oesophageal soft food bolus obstruction (SFBO) and impacted foreign body (IFB) at two New Zealand district health boards (DHBs). 2. Review current management against international guidelines for SFBO and IFB.

Methods: A multicentre retrospective search of the Provation endoscopy database identified patients presenting with acute oesophageal obstruction. Utilising electronic patient records, key data points including patient demographics, risk factors, pre-endoscopic medical therapies utilised, diagnostic radiological investigations performed and endoscopic complications were identified. Key timepoints and delays in the patient's hospital journey from oesophageal obstruction to therapeutic endoscopy were recorded. The probability of failing to undergo therapeutic endoscopy for SFBO within the timeframes advised in clinical guidelines as a result of a delay in referral to the endoscopy service was calculated.

Results: Over a cumulative 10.5-year period of data collection, 227 oesophago-gastro-duodenoscopies were performed: 195 SFBO, 16 IFB, 16 no obstruction identified. Median patient age was 57 (15-95) years. 143 male and 84 female patients. Radiographs were performed in 50.9% of uncomplicated SFBO. Pre-endoscopy medical therapies were administered in 41.4% of the cases. Median time delay from onset of obstruction to therapeutic endoscopy varied: SFBO 19h 0min, complete obstruction 17h 45min, impacted batteries 1h 15min, and presumed sharp objects 6h 0min. Three patients presenting with a soft food bolus obstruction failed to undergo therapeutic endoscopy due to a delay in referral to the endoscopy service, probability 0.034 (95% CI 0.012, 0.095). Two patients died of complications secondary to oesophageal obstruction.

Discussion: Oesophageal obstruction is a common gastroenterological presentation. At two large centres in New Zealand, patients waited considerably longer than the recommended timeframe from obstruction to therapeutic endoscopy. Contributing factors included patient-related delays to presentation, hospital system-related factors and delays in referral for endoscopy contributed to by unnecessary pre-endoscopic medical therapies and radiographic investigations. Education about oesophageal obstruction together with robust local guidelines have potential to reduce delays and length of hospital stay, as well as reduce patient discomfort and complications.
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http://dx.doi.org/10.2147/CEG.S300240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189695PMC
June 2021

Air quality-related health damages of food.

Proc Natl Acad Sci U S A 2021 May;118(20)

Department of Bioproducts and Biosystems Engineering, University of Minnesota, St. Paul, MN 55108;

Agriculture is a major contributor to air pollution, the largest environmental risk factor for mortality in the United States and worldwide. It is largely unknown, however, how individual foods or entire diets affect human health via poor air quality. We show how food production negatively impacts human health by increasing atmospheric fine particulate matter (PM), and we identify ways to reduce these negative impacts of agriculture. We quantify the air quality-related health damages attributable to 95 agricultural commodities and 67 final food products, which encompass >99% of agricultural production in the United States. Agricultural production in the United States results in 17,900 annual air quality-related deaths, 15,900 of which are from food production. Of those, 80% are attributable to animal-based foods, both directly from animal production and indirectly from growing animal feed. On-farm interventions can reduce PM-related mortality by 50%, including improved livestock waste management and fertilizer application practices that reduce emissions of ammonia, a secondary PM precursor, and improved crop and animal production practices that reduce primary PM emissions from tillage, field burning, livestock dust, and machinery. Dietary shifts toward more plant-based foods that maintain protein intake and other nutritional needs could reduce agricultural air quality-related mortality by 68 to 83%. In sum, improved livestock and fertilization practices, and dietary shifts could greatly decrease the health impacts of agriculture caused by its contribution to reduced air quality.
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http://dx.doi.org/10.1073/pnas.2013637118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8158015PMC
May 2021

PM polluters disproportionately and systemically affect people of color in the United States.

Sci Adv 2021 Apr 28;7(18). Epub 2021 Apr 28.

Department of Civil and Environmental Engineering, University of Washington, Seattle, WA 98195, USA.

Racial-ethnic minorities in the United States are exposed to disproportionately high levels of ambient fine particulate air pollution (PM), the largest environmental cause of human mortality. However, it is unknown which emission sources drive this disparity and whether differences exist by emission sector, geography, or demographics. Quantifying the PM exposure caused by each emitter type, we show that nearly all major emission categories-consistently across states, urban and rural areas, income levels, and exposure levels-contribute to the systemic PM exposure disparity experienced by people of color. We identify the most inequitable emission source types by state and city, thereby highlighting potential opportunities for addressing this persistent environmental inequity.
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http://dx.doi.org/10.1126/sciadv.abf4491DOI Listing
April 2021

The impact of FLT3 mutation clearance and treatment response after gilteritinib therapy on overall survival in patients with FLT3 mutation-positive relapsed/refractory acute myeloid leukemia.

Cancer Med 2021 02 19;10(3):797-805. Epub 2020 Dec 19.

Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.

The FLT3 inhibitor gilteritinib has clinical activity in patients with FLT3-mutated (FLT3 ) relapsed/refractory (R/R) acute myeloid leukemia (AML). The impact of FLT3 mutation clearance and the achievement of composite complete remission (CRc) and complete remission/complete remission with partial hematologic recovery (CR/CRh) on overall survival (OS) in patients with FLT3 R/R AML treated with single-agent gilteritinib in a phase 1/2 trial were evaluated. Using next-generation sequencing, a FLT3-ITD variant allele frequency of ≤10 was used to define FLT3-ITD clearance in patients with no morphologic leukemia (ie, CRc). A total of 108 patients with FLT3-ITD-positive (FLT3-ITD+) R/R AML were analyzed; 95 of these patients had received ≥80-mg/day gilteritinib. Ten of the 95 patients had FLT3-ITD clearance; eight of these 10 patients achieved CRc and were considered negative for measurable residual disease. There was a trend toward longer OS in patients who attained CRc with FLT3-ITD clearance (131.4 weeks) versus those who achieved CRc and did not have FLT3-ITD clearance (n = 41; 43.3 weeks; HR = 0.416; p = 0.066). Among patients treated with ≥80-mg/day gilteritinib who achieved CR/CRh (n = 24), seven had FLT3-ITD clearance. Among patients who received 120-mg/day gilteritinib, those who achieved CR/CRh had a longer median OS (70.6 weeks) and higher 52-week survival probability (66.7%) than patients who did not achieve CR/CRh (n = 71; median OS, 41.7 weeks; 52-week survival probability, 20.2%). Overall, these data suggest that gilteritinib can induce deep molecular responses in patients with FLT3-ITD+ R/R AML, and in the setting of CRc or CR/CRh, these responses may be associated with prolonged survival.
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http://dx.doi.org/10.1002/cam4.3652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897940PMC
February 2021

Global food system emissions could preclude achieving the 1.5° and 2°C climate change targets.

Science 2020 11;370(6517):705-708

Department of Bioproducts and Biosystems Engineering, University of Minnesota, St. Paul, MN, USA.

The Paris Agreement's goal of limiting the increase in global temperature to 1.5° or 2°C above preindustrial levels requires rapid reductions in greenhouse gas emissions. Although reducing emissions from fossil fuels is essential for meeting this goal, other sources of emissions may also preclude its attainment. We show that even if fossil fuel emissions were immediately halted, current trends in global food systems would prevent the achievement of the 1.5°C target and, by the end of the century, threaten the achievement of the 2°C target. Meeting the 1.5°C target requires rapid and ambitious changes to food systems as well as to all nonfood sectors. The 2°C target could be achieved with less-ambitious changes to food systems, but only if fossil fuel and other nonfood emissions are eliminated soon.
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http://dx.doi.org/10.1126/science.aba7357DOI Listing
November 2020

Frequency of venous thromboembolism in 6513 patients with COVID-19: a retrospective study.

Blood Adv 2020 11;4(21):5373-5377

Department of Hospital Medicine, Ochsner Health, New Orleans, LA.

Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) appear to be at increased risk for venous thromboembolism (VTE), especially if they become critically ill with COVID-19. Some centers have reported very high rates of thrombosis despite anticoagulant prophylaxis. The electronic health record (EHR) of a New Orleans-based health system was searched for all patients with polymerase chain reaction-confirmed SARS-CoV-2 infection who were either admitted to hospital or treated and discharged from an emergency department between 1 March 2020 and 1 May 2020. From this cohort, patients with confirmed VTE (either during or after their hospital encounter) were identified by administrative query of the EHR.: Between 1 March 2020 and 1 May 2020, 6153 patients with COVID-19 were identified; 2748 of these patients were admitted, while 3405 received care exclusively through the emergency department. In total, 637 patients required mechanical ventilation and 206 required renal replacement therapy. Within the hospitalized cohort, the overall mortality rate was 24.5% and VTE occurred in 86 patients (3.1%). In the 637 patients who required mechanical ventilation at some point during their hospital stay, 45 developed VTE (7.2%). After a median follow-up of 14.6 days, VTE had been diagnosed in 3 of the 2075 admitted who were discharged alive (0.14%). Among 6153 patients with COVID-19 who were hospitalized or treated in emergency departments, we did not find evidence of unusually high VTE risk. Pending further evidence from prospective, controlled trials, our findings support a traditional approach to primary VTE prevention in patients with COVID-19.
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http://dx.doi.org/10.1182/bloodadvances.2020003083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656921PMC
November 2020

Fossil Energy Use, Climate Change Impacts, and Air Quality-Related Human Health Damages of Conventional and Diversified Cropping Systems in Iowa, USA.

Environ Sci Technol 2020 09 25;54(18):11002-11014. Epub 2020 Aug 25.

Department of Bioproducts and Biosystems Engineering, University of Minnesota, St. Paul, Minnesota 55108, United States.

Cropping system diversification can reduce the negative environmental impacts of agricultural production, including soil erosion and nutrient discharge. Less is known about how diversification affects energy use, climate change, and air quality, when considering farm operations and supply chain activities. We conducted a life cycle study using measurements from a nine-year Iowa field experiment to estimate fossil energy (FE) use, greenhouse gas (GHG) emissions, PM-related emissions, human health impacts, and other agronomic and economic metrics of contrasting crop rotation systems and herbicide regimes. Rotation systems consisted of 2-year corn-soybean, 3-year corn-soybean-oat/clover, and 4-year corn-soybean-oat/alfalfa-alfalfa systems. Each was managed with conventional and low-herbicide treatments. FE consumption was 56% and 64% lower in the 3-year and 4-year rotations than in the 2-year rotation, and GHG emissions were 54% and 64% lower. Diversification reduced combined monetized damages from GHG and PM-related emissions by 42% and 57%. Herbicide treatment had no significant impact on environmental outcomes, while corn and soybean yields and whole-rotation economic returns improved significantly under diversification. Results suggest that diversification via shifting from conventional corn-soybean rotations to longer rotations with small grain and forage crops substantially reduced FE use, GHG emissions, and air quality damages, without compromising economic or agronomic performance.
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http://dx.doi.org/10.1021/acs.est.9b06929DOI Listing
September 2020

Gilteritinib is a clinically active FLT3 inhibitor with broad activity against FLT3 kinase domain mutations.

Blood Adv 2020 02;4(3):514-524

Division of Hematology-Oncology, Department of Medicine, University of California, San Francisco, San Francisco, CA.

Gilteritinib is the first FMS-like tyrosine kinase 3 (FLT3) tyrosine kinase inhibitor (TKI) approved as monotherapy in acute myeloid leukemia with FLT3 internal tandem duplication and D835/I836 tyrosine kinase domain (TKD) mutations. Sequencing studies in patients have uncovered less common, noncanonical (NC) mutations in FLT3 and have implicated secondary TKD mutations in FLT3 TKI resistance. We report that gilteritinib is active against FLT3 NC and TKI resistance-causing mutations in vitro. A mutagenesis screen identified FLT3 F691L, Y693C/N, and G697S as mutations that confer moderate resistance to gilteritinib in vitro. Analysis of patients treated with gilteritinib revealed that 2/9 patients with preexisting NC FLT3 mutations responded and that secondary TKD mutations are acquired in a minority (5/31) of patients treated with gilteritinib. Four of 5 patients developed F691L mutations (all treated at <200 mg). These studies suggest that gilteritinib has broad activity against FLT3 mutations and limited vulnerability to resistance-causing FLT3 TKD mutations, particularly when used at higher doses.
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http://dx.doi.org/10.1182/bloodadvances.2019000919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013266PMC
February 2020

A transposable element insertion is associated with an alternative life history strategy.

Nat Commun 2019 12 17;10(1):5757. Epub 2019 Dec 17.

Department of Zoology, Stockholm University, S106 91, Stockholm, Sweden.

Tradeoffs affect resource allocation during development and result in fitness consequences that drive the evolution of life history strategies. Yet despite their importance, we know little about the mechanisms underlying life history tradeoffs. Many species of Colias butterflies exhibit an alternative life history strategy (ALHS) where females divert resources from wing pigment synthesis to reproductive and somatic development. Due to this reallocation, a wing color polymorphism is associated with the ALHS: either yellow/orange or white. Here we map the locus associated with this ALHS in Colias crocea to a transposable element insertion located downstream of the Colias homolog of BarH-1, a homeobox transcription factor. Using CRISPR/Cas9 gene editing, antibody staining, and electron microscopy we find white-specific expression of BarH-1 suppresses the formation of pigment granules in wing scales and gives rise to white wing color. Lipid and transcriptome analyses reveal physiological differences associated with the ALHS. Together, these findings characterize a mechanism for a female-limited ALHS.
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http://dx.doi.org/10.1038/s41467-019-13596-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917731PMC
December 2019

Utility of linear and nonlinear models for retention prediction in liquid chromatography.

J Chromatogr A 2020 Feb 9;1613:460690. Epub 2019 Nov 9.

Waters Corporation, 34 Maple Street, Milford, MA 01757, USA.

Linear solvation strength model in reversed-phase liquid chromatography assumes linear relationship between ln k and Φ. In this work we show that this assumption is true only in narrow range of mobile phase strength. The ln k versus Φ relationship could be more accurately described by three-parametric non-linear model in a wide range of eluent strength. We investigated the consequences of non-linearity on retention prediction accuracy and analyte retention behavior in reversed-phase chromatography. When the ln k versus Φ is measured in narrow range of mobile phase strength (ΔΦ ~ 0.1-0.2) both linear and nonlinear models provide comparable retention prediction results. We propose that the linear trend of ln k versus Φ relationship is obtained in the range flanking the elution factor k (value of retention factor at the column end). We calculated and plotted changes of retention factor of analytes along the column. The visualization illustrates the ranges of retention factor values participating in separation during gradient. For typical gradient slopes employed in liquid chromatography practice and small molecules the elution factor k value is between 2 and 8. As a simplified generalization for typical gradient slopes we propose using linear ln k versus Φ trend in the k range between 1 and 30. The spreadsheet was utilized to compare the retention prediction accuracy of linear and non-linear retention models. When fitting ln k versus Φ trend in k range 1-30 the simple linear model is in good agreement with nonlinear model with retention time prediction error 0.3-4.7% (for gradient slope 0.013-0.260).
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http://dx.doi.org/10.1016/j.chroma.2019.460690DOI Listing
February 2020

Multiple health and environmental impacts of foods.

Proc Natl Acad Sci U S A 2019 11 28;116(46):23357-23362. Epub 2019 Oct 28.

Department of Ecology, Evolution, and Behavior, University of Minnesota, St. Paul, MN 55108;

Food choices are shifting globally in ways that are negatively affecting both human health and the environment. Here we consider how consuming an additional serving per day of each of 15 foods is associated with 5 health outcomes in adults and 5 aspects of agriculturally driven environmental degradation. We find that while there is substantial variation in the health outcomes of different foods, foods associated with a larger reduction in disease risk for one health outcome are often associated with larger reductions in disease risk for other health outcomes. Likewise, foods with lower impacts on one metric of environmental harm tend to have lower impacts on others. Additionally, of the foods associated with improved health (whole grain cereals, fruits, vegetables, legumes, nuts, olive oil, and fish), all except fish have among the lowest environmental impacts, and fish has markedly lower impacts than red meats and processed meats. Foods associated with the largest negative environmental impacts-unprocessed and processed red meat-are consistently associated with the largest increases in disease risk. Thus, dietary transitions toward greater consumption of healthier foods would generally improve environmental sustainability, although processed foods high in sugars harm health but can have relatively low environmental impacts. These findings could help consumers, policy makers, and food companies to better understand the multiple health and environmental implications of food choices.
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http://dx.doi.org/10.1073/pnas.1906908116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859310PMC
November 2019

A chromosome-level assembly of the Atlantic herring genome-detection of a supergene and other signals of selection.

Genome Res 2019 11 24;29(11):1919-1928. Epub 2019 Oct 24.

Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, SE-75123 Uppsala, Sweden.

The Atlantic herring is a model species for exploring the genetic basis for ecological adaptation, due to its huge population size and extremely low genetic differentiation at selectively neutral loci. However, such studies have so far been hampered because of a highly fragmented genome assembly. Here, we deliver a chromosome-level genome assembly based on a hybrid approach combining a de novo Pacific Biosciences (PacBio) assembly with Hi-C-supported scaffolding. The assembly comprises 26 autosomes with sizes ranging from 12.4 to 33.1 Mb and a total size, in chromosomes, of 726 Mb, which has been corroborated by a high-resolution linkage map. A comparison between the herring genome assembly with other high-quality assemblies from bony fishes revealed few inter-chromosomal but frequent intra-chromosomal rearrangements. The improved assembly facilitates analysis of previously intractable large-scale structural variation, allowing, for example, the detection of a 7.8-Mb inversion on Chromosome 12 underlying ecological adaptation. This supergene shows strong genetic differentiation between populations. The chromosome-based assembly also markedly improves the interpretation of previously detected signals of selection, allowing us to reveal hundreds of independent loci associated with ecological adaptation.
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http://dx.doi.org/10.1101/gr.253435.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836730PMC
November 2019

Exploring a Pool-seq-only approach for gaining population genomic insights in nonmodel species.

Ecol Evol 2019 Oct 26;9(19):11448-11463. Epub 2019 Sep 26.

Division of Population Genetics Department of Zoology Stockholm University Stockholm Sweden.

Developing genomic insights is challenging in nonmodel species for which resources are often scarce and prohibitively costly. Here, we explore the potential of a recently established approach using Pool-seq data to generate a de novo genome assembly for mining exons, upon which Pool-seq data are used to estimate population divergence and diversity. We do this for two pairs of sympatric populations of brown trout (): one naturally sympatric set of populations and another pair of populations introduced to a common environment. We validate our approach by comparing the results to those from markers previously used to describe the populations (allozymes and individual-based single nucleotide polymorphisms [SNPs]) and from mapping the Pool-seq data to a reference genome of the closely related Atlantic salmon (). We find that genomic differentiation ( ) between the two introduced populations exceeds that of the naturally sympatric populations (  = 0.13 and 0.03 between the introduced and the naturally sympatric populations, respectively), in concordance with estimates from the previously used SNPs. The same level of population divergence is found for the two genome assemblies, but estimates of average nucleotide diversity differ (  ≈ 0.002 and  ≈ 0.001 when mapping to and , respectively), although the relationships between population values are largely consistent. This discrepancy might be attributed to biases when mapping to a haploid condensed assembly made of highly fragmented read data compared to using a high-quality reference assembly from a divergent species. We conclude that the Pool-seq-only approach can be suitable for detecting and quantifying genome-wide population differentiation, and for comparing genomic diversity in populations of nonmodel species where reference genomes are lacking.
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http://dx.doi.org/10.1002/ece3.5646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802065PMC
October 2019

A Somatostatin Receptor Subtype-3 (SST) Peptide Agonist Shows Antitumor Effects in Experimental Models of Nonfunctioning Pituitary Tumors.

Clin Cancer Res 2020 02 17;26(4):957-969. Epub 2019 Oct 17.

Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Cordoba, Spain.

Purpose: Somatostatin analogues (SSA) are efficacious and safe treatments for a variety of neuroendocrine tumors, especially pituitary neuroendocrine tumors (PitNET). Their therapeutic effects are mainly mediated by somatostatin receptors SST and SST. Most SSAs, such as octreotide/lanreotide/pasireotide, are either nonselective or activate mainly SST. However, nonfunctioning pituitary tumors (NFPTs), the most common PitNET type, mainly express SST and finding peptides that activate this particular somatostatin receptor has been very challenging. Therefore, the main objective of this study was to identify SST-agonists and characterize their effects on experimental NFPT models.

Experimental Design: Binding to SSTs and cAMP level determinations were used to screen a peptide library and identify SST-agonists. Key functional parameters (cell viability/caspase activity/chromogranin-A secretion/mRNA expression/intracellular signaling pathways) were assessed on NFPT primary cell cultures in response to SST-agonists. Tumor growth was assessed in a preclinical PitNET mouse model treated with a SST-agonist.

Results: We successfully identified the first SST-agonist peptides. SST-agonists lowered cell viability and chromogranin-A secretion, increased apoptosis , and reduced tumor growth in a preclinical PitNET model. As expected, inhibition of cell viability in response to SST-agonists defined two NFPT populations: responsive and unresponsive, wherein responsive NFPTs expressed more SST than unresponsive NFPTs and exhibited a profound reduction of MAPK, PI3K-AKT/mTOR, and JAK/STAT signaling pathways upon SST-agonist treatments. Concurrently, silencing increased cell viability in a subset of NFPTs.

Conclusions: This study demonstrates that SST-agonists activate signaling mechanisms that reduce NFPT cell viability and inhibit pituitary tumor growth in experimental models that expresses SST, suggesting that targeting this receptor could be an efficacious treatment for NFPTs.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2154DOI Listing
February 2020

Optimization of Oxygen Dynamics, UV-A Delivery, and Drug Formulation for Accelerated Epi-On Corneal Crosslinking.

Curr Eye Res 2020 04 2;45(4):450-458. Epub 2019 Oct 2.

Research & Development, Avedro, Inc, Waltham, MA, USA.

: Corneal collagen crosslinking (CXL) through an intact epithelium (epi-on) at high irradiance could potentially improve patient comfort, visual recovery, and clinical workflow compared to conventional epi-off CXL. However, intact epithelium limits stromal delivery of the oxygen, photosensitizer, and ultraviolet-A (UV-A) radiation needed to drive CXL. This study evaluated three different epi-on CXL protocols compared to positive and negative controls, specifically focusing on the impact of supplemental oxygen. Endpoints included stromal oxygen levels, stiffness of crosslinked tissue, and acute flattening of whole eyes.: porcine eyes were held in a custom environmental chamber. Intrastromal oxygen levels were continuously measured before, during, and after UV illumination by a fiberoptic probe inserted into a laser-cut flap. Accelerated, high irradiance, epi-on CXL protocols using riboflavin formulated with benzalkonium chloride (BAC) were studied, with and without supplemental oxygen. These were compared to an alternate, low irradiance, epi-on protocol using riboflavin formulated with sodium iodide. Both negative (no CXL) and positive (epi-off modified Dresden protocol) controls were performed. Post-CXL elastic modulus was measured using extensiometry and anterior tangential curvature was measured using a Scheimpflug tomographer.: Protocols including supplemental oxygen resulted in an approximately 5-fold increase in stromal oxygen levels prior to CXL. During epi-on, high-irradiance UV-A delivery under hyperoxic conditions, an aerobic state was maintained. Conversely, under normoxic conditions, stromal oxygen rapidly depleted to 0-5% for all other protocols. The combination of supplemental oxygen, BAC formulation, and high-irradiance UV-A resulted in the largest biomechanical changes and most pronounced flattening effects of the three epi-on protocols.: analysis of stromal oxygen levels, corneal stiffness, and acute anterior curvature change indicates that simultaneous optimization of the oxygen environment, riboflavin formulation, and UV-A protocol can significantly increase the effects of corneal collagen crosslinking.
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http://dx.doi.org/10.1080/02713683.2019.1669663DOI Listing
April 2020

Recurrent convergent evolution at amino acid residue 261 in fish rhodopsin.

Proc Natl Acad Sci U S A 2019 09 26;116(37):18473-18478. Epub 2019 Aug 26.

Department of Medical Biochemistry and Microbiology, Uppsala University, SE-751 23 Uppsala, Sweden;

The evolutionary process that occurs when a species colonizes a new environment provides an opportunity to explore the mechanisms underlying genetic adaptation, which is essential knowledge for understanding evolution and the maintenance of biodiversity. Atlantic herring has an estimated total breeding stock of about 1 trillion (10) and has colonized the brackish Baltic Sea within the last 10,000 y. Minute genetic differentiation between Atlantic and Baltic herring populations at selectively neutral loci combined with this rapid adaptation to a new environment facilitated the identification of hundreds of loci underlying ecological adaptation. A major question in the field of evolutionary biology is to what extent such an adaptive process involves selection of novel mutations with large effects or genetic changes at many loci, each with a small effect on phenotype (i.e., selection on standing genetic variation). Here we show that a missense mutation in (Phe261Tyr) is an adaptation to the red-shifted Baltic Sea light environment. The transition from phenylalanine to tyrosine differs only by the presence of a hydroxyl moiety in the latter, but this results in an up to 10-nm red-shifted light absorbance of the receptor. Remarkably, an examination of the rhodopsin sequences from 2,056 species of fish revealed that the same missense mutation has occurred independently and been selected for during at least 20 transitions between light environments across all fish. Our results provide a spectacular example of convergent evolution and how a single amino acid change can have a major effect on ecological adaptation.
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http://dx.doi.org/10.1073/pnas.1908332116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744887PMC
September 2019

Mismatch between sample diluent and eluent: Maintaining integrity of gradient peaks using in silico approaches.

J Chromatogr A 2019 Dec 6;1608:460414. Epub 2019 Aug 6.

Waters Corporation, 34 Maple Street, Milford, MA 01757, USA.

The mismatch of elution strength between the sample diluent and the eluent causes undesirable peak deformations for large sample volumes in gradient liquid chromatography. The solution to that problem consists in diluting the sample solution in a weak solvent. But the minimum dilution factor has to be determined by the user given some performance objectives. In silico approaches are applied in this work to find such adequate dilution factors. Two calculations methods are proposed for the prediction of peak distortions. The first comprehensive method is based on solving numerically the mass balance equations for all the analytes and the strong solvent. An excellent agreement between the experimental and the calculated gradient chromatograms is observed (sample diluent: acetonitrile/water, 50/50, v/v; injection volume: 15 μL; linear gradient: 5%-95% acetonitrile during 3 min) for five compounds (acetanilide, coumarin, benzoin, bi-naphthol, and dibutylphthalate) injected into a 2.1 × 50 mm column packed with 1.7 μm XBridge-C particles. This first method happens to be highly time-consuming and impractical for common users. Experimental work and calculation times are then minimized by applying a second method based on the basics of retention and dispersion of injected pulses. Despite being less accurate than the first method, the agreement between the experimental and calculated peak width remains physically meaningful allowing the experimenter to rapidly guess the required sample dilution factor for any combination of injected volume and strong solvent concentration in the sample solution.
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http://dx.doi.org/10.1016/j.chroma.2019.460414DOI Listing
December 2019

Unprecedented reorganization of holocentric chromosomes provides insights into the enigma of lepidopteran chromosome evolution.

Sci Adv 2019 06 12;5(6):eaau3648. Epub 2019 Jun 12.

Population Genetics, Department of Zoology, Stockholm University, Stockholm, Sweden.

Chromosome evolution presents an enigma in the mega-diverse Lepidoptera. Most species exhibit constrained chromosome evolution with nearly identical haploid chromosome counts and chromosome-level gene collinearity among species more than 140 million years divergent. However, a few species possess radically inflated chromosomal counts due to extensive fission and fusion events. To address this enigma of constraint in the face of an exceptional ability to change, we investigated an unprecedented reorganization of the standard lepidopteran chromosome structure in the green-veined white butterfly (). We find that gene content in has been extensively rearranged in large collinear blocks, which until now have been masked by a haploid chromosome number close to the lepidopteran average. We observe that ancient chromosome ends have been maintained and collinear blocks are enriched for functionally related genes suggesting both a mechanism and a possible role for selection in determining the boundaries of these genome-wide rearrangements.
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http://dx.doi.org/10.1126/sciadv.aau3648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6561736PMC
June 2019

Fine-scale damage estimates of particulate matter air pollution reveal opportunities for location-specific mitigation of emissions.

Proc Natl Acad Sci U S A 2019 04 8;116(18):8775-8780. Epub 2019 Apr 8.

Department of Civil and Environmental Engineering, University of Washington, Seattle, WA 98195.

Fine particulate matter (PM) air pollution has been recognized as a major source of mortality in the United States for at least 25 years, yet much remains unknown about which sources are the most harmful, let alone how best to target policies to mitigate them. Such efforts can be improved by employing high-resolution geographically explicit methods for quantifying human health impacts of emissions of PM and its precursors. Here, we provide a detailed examination of the health and economic impacts of PM pollution in the United States by linking emission sources with resulting pollution concentrations. We estimate that anthropogenic PM was responsible for 107,000 premature deaths in 2011, at a cost to society of $886 billion. Of these deaths, 57% were associated with pollution caused by energy consumption [e.g., transportation (28%) and electricity generation (14%)]; another 15% with pollution caused by agricultural activities. A small fraction of emissions, concentrated in or near densely populated areas, plays an outsized role in damaging human health with the most damaging 10% of total emissions accounting for 40% of total damages. We find that 33% of damages occur within 8 km of emission sources, but 25% occur more than 256 km away, emphasizing the importance of tracking both local and long-range impacts. Our paper highlights the importance of a fine-scale approach as marginal damages can vary by over an order of magnitude within a single county. Information presented here can assist mitigation efforts by identifying those sources with the greatest health effects.
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http://dx.doi.org/10.1073/pnas.1816102116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500143PMC
April 2019

Inequity in consumption of goods and services adds to racial-ethnic disparities in air pollution exposure.

Proc Natl Acad Sci U S A 2019 03 11;116(13):6001-6006. Epub 2019 Mar 11.

Department of Bioproducts and Biosystems Engineering, University of Minnesota, St. Paul, MN 55108

Fine particulate matter (PM) air pollution exposure is the largest environmental health risk factor in the United States. Here, we link PM exposure to the human activities responsible for PM pollution. We use these results to explore "pollution inequity": the difference between the environmental health damage caused by a racial-ethnic group and the damage that group experiences. We show that, in the United States, PM exposure is disproportionately caused by consumption of goods and services mainly by the non-Hispanic white majority, but disproportionately inhaled by black and Hispanic minorities. On average, non-Hispanic whites experience a "pollution advantage": They experience ∼17% less air pollution exposure than is caused by their consumption. Blacks and Hispanics on average bear a "pollution burden" of 56% and 63% excess exposure, respectively, relative to the exposure caused by their consumption. The total disparity is caused as much by how much people consume as by how much pollution they breathe. Differences in the types of goods and services consumed by each group are less important. PM exposures declined ∼50% during 2002-2015 for all three racial-ethnic groups, but pollution inequity has remained high.
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http://dx.doi.org/10.1073/pnas.1818859116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442600PMC
March 2019

Migratory patterns and connectivity of two North American grassland bird species.

Ecol Evol 2019 Jan 26;9(1):680-692. Epub 2018 Dec 26.

Vermont Center for Ecostudies Norwich Vermont.

Effective management and conservation of migratory bird populations require knowledge and incorporation of their movement patterns and space use throughout the annual cycle. To investigate the little-known migratory patterns of two grassland bird species, we deployed 180 light-level geolocators on Grasshopper Sparrows () and 29 Argos-GPS tags on Eastern Meadowlarks () at Konza Prairie, Kansas, USA, and six US Department of Defense (DoD) installations distributed across the species' breeding ranges. We analyzed location data from 34 light-level geolocators and five Argos-GPS tags attached for 1 year to Grasshopper Sparrows and Eastern Meadowlarks, respectively. Grasshopper Sparrows were present on the breeding grounds from mid-April through early October, substantially longer than previously estimated, and migrated on average ~2,500 km over ~30 days. Grasshopper Sparrows exhibited strong migratory connectivity only at a continental scale. The North American Great Lakes region likely serves as a migratory divide for Midwest and East Coast Grasshopper Sparrows; Midwest populations (Kansas, Wisconsin, and North Dakota;  = 13) largely wintered in Texas or Mexico, whereas East Coast populations (Maryland and Massachusetts,  = 20) wintered in the northern Caribbean or Florida. Our data from Eastern Meadowlarks provided evidence for a diversity of stationary and short- and long-distance migration strategies. By providing the most extensive examination of the nonbreeding movement ecology for these two North American grassland bird species to date, we refine information gaps and provide key insight for their management and conservation.
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http://dx.doi.org/10.1002/ece3.4795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6342103PMC
January 2019

Cropping System Diversity Effects on Nutrient Discharge, Soil Erosion, and Agronomic Performance.

Environ Sci Technol 2019 02 15;53(3):1344-1352. Epub 2019 Jan 15.

Department of Agronomy , Iowa State University , Ames , Iowa 50011 , United States.

Nutrient, herbicide, and sediment loading from agricultural fields cause environmental and economic damage. Nutrient leaching and runoff pollution can lead to eutrophication and impaired drinking water resources, while soil erosion reduces water quality and agronomic productivity. Increased cropping system diversification has been proposed to address these problems. We used the ArcSWAT model and long-term Iowa field experimental measurements to estimate eutrophication and erosion impacts of three crop rotation systems under two weed management regimes. Rotations were comprised of 2-year corn-soybean, 3-year corn-soybean-oat/clover, and 4-year corn-soybean-oat/alfalfa-alfalfa systems. All were managed with conventional or low herbicide applications. Total N and P runoff losses were up to 39% and 30% lower, respectively, in the more diverse systems than the 2-year corn-soybean system, but NO-N leaching losses were unaffected by cropping system. Diversification reduced erosion losses up to 60%. The 3- and 4-year systems maintained or increased crop yields and net returns relative to the 2-year conventional system. Reductions in herbicide use intensity generally did not affect nutrient and sediment losses nor crop yields and profitability. These results indicate that diversifying the corn-soybean rotation that dominates the central United States could reduce water nutrient contamination and soil erosion while maintaining farm productivity and profitability.
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http://dx.doi.org/10.1021/acs.est.8b02193DOI Listing
February 2019

The molecular genetic basis of herbivory between butterflies and their host plants.

Nat Ecol Evol 2018 09 3;2(9):1418-1427. Epub 2018 Aug 3.

Department of Ecology and Evolution, University of Chicago, Chicago, IL, USA.

Interactions between herbivorous insects and their host plants are a central component of terrestrial food webs and a critical topic in agriculture, where a substantial fraction of potential crop yield is lost annually to pests. Important insights into plant-insect interactions have come from research on specific plant defences and insect detoxification mechanisms. Yet, much remains unknown about the molecular mechanisms that mediate plant-insect interactions. Here we use multiple genome-wide approaches to map the molecular basis of herbivory from both plant and insect perspectives, focusing on butterflies and their larval host plants. Parallel genome-wide association studies in the cabbage white butterfly, Pieris rapae, and its host plant, Arabidopsis thaliana, pinpointed a small number of butterfly and plant genes that influenced herbivory. These genes, along with much of the genome, were regulated in a dynamic way over the time course of the feeding interaction. Comparative analyses, including diverse butterfly/plant systems, showed a variety of genome-wide responses to herbivory, as well as a core set of highly conserved genes in butterflies as well as their host plants. These results greatly expand our understanding of the genomic causes and evolutionary consequences of ecological interactions across two of nature's most diverse taxa, butterflies and flowering plants.
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http://dx.doi.org/10.1038/s41559-018-0629-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6149523PMC
September 2018

Microevolutionary selection dynamics acting on immune genes of the green-veined white butterfly, Pieris napi.

Mol Ecol 2018 07 4;27(13):2807-2822. Epub 2018 Jun 4.

Department of Zoology, Stockholm University, Stockholm, Sweden.

Insects rely on their innate immune system to successfully mediate complex interactions with their microbiota, as well as the microbes present in the environment. Previous work has shown that components of the canonical immune gene repertoire evolve rapidly and have evolutionary characteristics originating from interactions with fast-evolving microorganisms. Although these interactions are likely to vary among populations, there is a poor understanding of the microevolutionary dynamics of immune genes, especially in non-Dipteran insects. Here, we use the full set of canonical insect immune genes to investigate microevolutionary dynamics acting on these genes between and among populations by comparing three allopatric populations of the green-veined white butterfly, Pieris napi (Linné; Lepidoptera, Pieridae). Immune genes showed increased genetic diversity compared to genes from the rest of the genome and various functional categories exhibited different types of signatures of selection, at different evolutionary scales, presenting a complex pattern of selection dynamics. Signatures of balancing selection were identified in 10 genes, and 17 genes appear to be under positive selection. Genes involved with the cellular arm of the immune response as well as the Toll pathway appear to be enriched among our outlier loci, regardless of functional category. This suggests that the targets of selection might focus upon an entire pathway, rather than functional subsets across pathways. Our microevolutionary results are similar to previously observed macroevolutionary patterns from diverse taxa, suggesting that either the immune system is robust to dramatic differences in life history and microbial communities, or that diverse microbes exert similar selection pressures.
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http://dx.doi.org/10.1111/mec.14722DOI Listing
July 2018

A next-generation sequencing-based assay for minimal residual disease assessment in AML patients with -ITD mutations.

Blood Adv 2018 04;2(8):825-831

Invivoscribe, Inc, San Diego, CA.

Internal tandem duplications in (ITDs) are common in acute myeloid leukemia (AML) and confer a poor prognosis. A sensitive and specific assay for the detection of minimal residual disease (MRD) in ITD mutated AML could guide therapy decisions. Existing assays for MRD in ITD AML have not been particularly useful because of limited sensitivity. We developed a sensitive and specific MRD assay for ITD mutations using next-generation sequencing. The initial validation of this assay was performed by spiking fixed amounts of mutant DNA into wild-type DNA to establish a sensitivity of detection equivalent to ≥1 ITD-containing cell in 10 000, with a minimum input of 100 000 cell equivalents of DNA. We subsequently validated the assay in bone marrow samples from patients with ITD AML in remission. Finally, we analyzed bone marrow samples from 80 patients with ITD relapsed/refractory AML participating in a trial of a novel FLT3 inhibitor, gilteritinib, and demonstrated a relationship between the mutation burden, as detected by the assay, and overall survival. This novel MRD assay is specific and 2 orders of magnitude more sensitive than currently available polymerase chain reaction- or next-generation sequencing-based ITD assays. The assay is being prospectively validated in ongoing randomized clinical trials.
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http://dx.doi.org/10.1182/bloodadvances.2018015925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5916006PMC
April 2018

A systematic investigation of sample diluents in modern supercritical fluid chromatography.

J Chromatogr A 2017 Aug 3;1511:122-131. Epub 2017 Jul 3.

School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, CMU - Rue Michel Servet 1, 1211 Geneva 4, Switzerland. Electronic address:

This paper focuses on the possibility to inject large volumes (up to 10μL) in ultra-high performance supercritical fluid chromatography (UHPSFC) under generic gradient conditions. Several injection and method parameters have been individually evaluated (i.e. analyte concentration, injection volume, initial percentage of co-solvent in the gradient, nature of the weak needle wash solvent, nature of the sample diluent, nature of the column and of the analyte). The most critical parameters were further investigated using in a multivariate approach. The overall results suggested that several aprotic solvents including methyl tert-butyl ether (MTBE), dichloromethane, acetonitrile or cyclopentyl methyl ether (CPME) were well adapted for the injection of large volume in UHPSFC, while MeOH was generally the worst alternative. However, the nature of the stationary phase also had a strong impact and some of these diluents did not perform equally on each column. This was due to the existence of a competition in the adsorption of the analyte and the diluent on the stationary phase. This observation introduced the idea that the sample diluent should not only be chosen according to the analyte but also to the column chemistry to limit the interactions between the diluent and the ligands. Other important characteristics of the "ideal" SFC sample diluent were finally highlighted. Aprotic solvents with low viscosity are preferable to avoid strong solvent effects and viscous fingering, respectively. In the end, the authors suggest that the choice of the sample diluent should be part of the method development, as a function of the analyte and the selected stationary phase.
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http://dx.doi.org/10.1016/j.chroma.2017.06.075DOI Listing
August 2017

Structural complexity and molecular heterogeneity of a butterfly ejaculate reflect a complex history of selection.

Proc Natl Acad Sci U S A 2017 07 19;114(27):E5406-E5413. Epub 2017 Jun 19.

Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15260;

Male ejaculates are often structurally complex, and this complexity is likely to influence key reproductive interactions between males and females. However, despite its potential evolutionary significance, the molecular underpinnings of ejaculate structural complexity have received little empirical attention. To address this knowledge gap, we sought to understand the biochemical and functional properties of the structurally complex ejaculates of butterflies. Males in this species produce large ejaculates called spermatophores composed of an outer envelope, an inner matrix, and a bolus of sperm. Females are thought to benefit from the nutrition contained in the soluble inner matrix through increases in longevity and fecundity. However, the indigestible outer envelope of the spermatophore delays female remating, allowing males to monopolize paternity for longer. Here, we show that these two nonsperm-containing spermatophore regions, the inner matrix and the outer envelope, differ in their protein composition and functional properties. We also reveal how these divergent protein mixtures are separately stored in the male reproductive tract and sequentially transferred to the female reproductive tract during spermatophore assembly. Intriguingly, we discovered large quantities of female-derived proteases in both spermatophore regions shortly after mating, which may contribute to spermatophore digestion and hence, female control over remating rate. Finally, we report evidence of past selection on these spermatophore proteins and female proteases, indicating a complex evolutionary history. Our findings illustrate how structural complexity of ejaculates may allow functionally and/or spatially associated suites of proteins to respond rapidly to divergent selective pressures, such as sexual conflict or reproductive cooperation.
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http://dx.doi.org/10.1073/pnas.1707680114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502654PMC
July 2017
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