Neutrino oscillations in a model with a source and detector

We study the oscillations of neutrinos in a model in which the neutrino is coupled to a localized, idealized source and detector. By varying the spatial and temporal resolution of the source and detector we are able to model the full range of source and detector types ranging from coherent to incoherent. We find that this approach is useful in understanding the interface between the Quantum Mechanical nature of neutrino oscillations on the one hand and the production and detection systems on the other hand. This method can easily be extended to study the oscillations of other particles such as the neutral K and B mesons. We find that this approach gives a reliable way to treat the various ambiguities which arise when one examines the oscillations from a wave packet point of view. We demonstrate that the conventional oscillation formula is correct in the relativistic limit and that several recent claims of an extra factor of 2 in the oscillation length are incorrect. We also demonstrate explicitly that the oscillations of neutrinos which have separated spatially may be "revived" by a long coherent measurement.Comment: 30 pages, 6 figures, Late

Targeted proteomic quantitation of NRF2 signaling and predictive biomarkers in HNSCC

The NFE2L2 (NRF2) oncogene and transcription factor drives a gene expression program that promotes cancer progression, metabolic reprogramming, immune evasion, and chemoradiation resistance. Patient stratification by NRF2 activity may guide treatment decisions to improve outcome. Here, we developed a mass spectrometry-based targeted proteomics assay based on internal standard-triggered parallel reaction monitoring to quantify 69 NRF2 pathway components and targets, as well as 21 proteins of broad clinical significance in head and neck squamous cell carcinoma (HNSCC). We improved an existing internal standard-triggered parallel reaction monitoring acquisition algorithm, called SureQuant, to increase throughput, sensitivity, and precision. Testing the optimized platform on 27 lung and upper aerodigestive cancer cell models revealed 35 NRF2 responsive proteins. In formalin-fixed paraffin-embedded HNSCCs, NRF2 signaling intensity positively correlated with NRF2-activating mutations and with SOX2 protein expression. Protein markers of T-cell infiltration correlated positively with one another and with human papilloma virus infection status. CDKN2A (p16) protein expression positively correlated with the human papilloma virus oncogenic E7 protein and confirmed the presence of translationally active virus. This work establishes a clinically actionable HNSCC protein biomarker assay capable of quantifying over 600 peptides from frozen or formalin-fixed paraffin-embedded archived tissues in under 90 min

Revealing Historic Invasion Patterns and Potential Invasion Sites for Two Non-Native Plant Species

The historical spatio-temporal distribution of invasive species is rarely documented, hampering efforts to understand invasion dynamics, especially at regional scales. Reconstructing historical invasions through use of herbarium records combined with spatial trend analysis and modeling can elucidate spreading patterns and identify susceptible habitats before invasion occurs. Two perennial species were chosen to contrast historic and potential phytogeographies: Japanese knotweed (Polygonum cuspidatum), introduced intentionally across the US; and mugwort (Artemisia vulgaris), introduced largely accidentally to coastal areas. Spatial analysis revealed that early in the invasion, both species have a stochastic distribution across the contiguous US, but east of the 90th meridian, which approximates the Mississippi River, quickly spread to adjacent counties in subsequent decades. In contrast, in locations west of the 90th meridian, many populations never spread outside the founding county, probably a result of encountering unfavorable environmental conditions. Regression analysis using variables categorized as environmental or anthropogenic accounted for 24% (Japanese knotweed) and 30% (mugwort) of the variation in the current distribution of each species. Results show very few counties with high habitat suitability (≥80%) remain un-invaded (5 for Japanese knotweed and 6 for mugwort), suggesting these perennials are reaching the limits of large-scale expansion. Despite differences in initial introduction loci and pathways, Japanese knotweed and mugwort demonstrate similar historic patterns of spread and show declining rates of regional expansion. Invasion mitigation efforts should be concentrated on areas identified as highly susceptible that border invaded regions, as both species demonstrate secondary expansion from introduction loci

Optimizing de novo genome assembly from PCR-amplified metagenomes

Background Metagenomics has transformed our understanding of microbial diversity across ecosystems, with recent advances enabling de novo assembly of genomes from metagenomes. These metagenome-assembled genomes are critical to provide ecological, evolutionary, and metabolic context for all the microbes and viruses yet to be cultivated. Metagenomes can now be generated from nanogram to subnanogram amounts of DNA. However, these libraries require several rounds of PCR amplification before sequencing, and recent data suggest these typically yield smaller and more fragmented assemblies than regular metagenomes. Methods Here we evaluate de novo assembly methods of 169 PCR-amplified metagenomes, including 25 for which an unamplified counterpart is available, to optimize specific assembly approaches for PCR-amplified libraries. We first evaluated coverage bias by mapping reads from PCR-amplified metagenomes onto reference contigs obtained from unamplified metagenomes of the same samples. Then, we compared different assembly pipelines in terms of assembly size (number of bp in contigs ≥ 10 kb) and error rates to evaluate which are the best suited for PCR-amplified metagenomes. Results Read mapping analyses revealed that the depth of coverage within individual genomes is significantly more uneven in PCR-amplified datasets versus unamplified metagenomes, with regions of high depth of coverage enriched in short inserts. This enrichment scales with the number of PCR cycles performed, and is presumably due to preferential amplification of short inserts. Standard assembly pipelines are confounded by this type of coverage unevenness, so we evaluated other assembly options to mitigate these issues. We found that a pipeline combining read deduplication and an assembly algorithm originally designed to recover genomes from libraries generated after whole genome amplification (single-cell SPAdes) frequently improved assembly of contigs ≥10 kb by 10 to 100-fold for low input metagenomes. Conclusions PCR-amplified metagenomes have enabled scientists to explore communities traditionally challenging to describe, including some with extremely low biomass or from which DNA is particularly difficult to extract. Here we show that a modified assembly pipeline can lead to an improved de novo genome assembly from PCR-amplified datasets, and enables a better genome recovery from low input metagenomes

The effect of starch-based biomaterials on leukocyte adhesion and activation in vitro

Leukocyte adhesion to biomaterials has long been recognised as a key element to determine their inflammatory potential. Results regarding leukocyte adhesion and activation are contradictory in some aspects of the material’s effect in determining these events. It is clear that together with the wettability or hydrophilicity/hydrophobicity, the roughness of a substrate has a major effect on leukocyte adhesion. Both the chemical and physical properties of a material influence the adsorbed proteins layer which in turn determines the adhesion of cells. In this work polymorphonuclear (PMN) cells and a mixed population of monocytes/macrophages and lymphocytes (mononuclear cells) were cultured separately with a range of starch-based materials and composites with hydroxyapatite (HA). A combination of both reflected light microscopy and scanning electron microscopy (SEM) was used in order to study the leukocyte morphology. The quantification of the enzyme lactate dehydrogenase (LDH) was used to determine the number of viable cells adhered to the polymers. Cell adhesion and activation was characterised by immunocytochemistry based on the expression of several adhesion molecules, crucial in the progress of an inflammatory response. This work supports previous in vitro studies with PMN and monocytes/macrophages, which demonstrated that there are several properties of the materials that can influence and determine their biological response. From our study, monocytes/macrophages and lymphocytes adhere in similar amounts to more hydrophobic (SPCL) and to moderately hydrophilic (SEVA-C) surfaces and do not preferentially adhere to rougher substrates (SCA). Contrarily, more hydrophilic surfaces (SCA) induced higher PMN adhesion and lower activation. In addition, the hydroxyapatite reinforcement induces changes in cell behaviour for some materials but not for others. The observed response to starch-based biodegradable polymers was not significantly different from the control materials. Thus, the results reported herein indicate the low potential of the starch-based biodegradable polymers to induce inflammation especially the HA reinforced composite materials

Exome Sequencing in Suspected Monogenic Dyslipidemias

Abstract BACKGROUND: -Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We utilized this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. METHODS AND RESULTS: -We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein (LDL) cholesterol (after candidate gene sequencing excluded known genetic causes for high LDL cholesterol families) or high-density lipoprotein (HDL) cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual in order to account for their burden of common genetic variants known to influence lipid levels. In nine families, we identified likely pathogenic variants in known lipid genes (ABCA1, APOB, APOE, LDLR, LIPA, and PCSK9); however, we were unable to identify obvious genetic etiologies in the remaining 32 families despite follow-up analyses. We identified three factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. CONCLUSIONS: -We identified the genetic basis of disease in nine of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies

Omega-3 fatty acids and genome-wide interaction analyses reveal DPP10-pulmonary function association

Rationale: Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have anti-inflammatory properties that could benefit adults with comprised pulmonary health. Objective: To investigate n-3 PUFA associations with spirometric measures of pulmonary function tests (PFTs) and determine underlying genetic susceptibility. Methods: Associations of n-3 PUFA biomarkers (a-linolenic acid, eicosapentaenoic acid, docosapentaenoic acid [DPA], and docosahexaenoic acid [DHA]) were evaluated with PFTs (FEV1, FVC, and FEV1/FVC) in meta-analyses across seven cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (N=16,134 of European or African ancestry). PFT-associated n-3 PUFAs were carried forward to genome-wide interaction analyses in the four largest cohorts (N=11,962) and replicated in one cohort (N=1,687). Cohort-specific results were combined using joint 2 degree-of-freedom (2df) meta-analyses of SNPassociations and their interactions with n-3PUFAs. Results: DPA and DHA were positively associated with FEV1 and FVC (P < 0.025), with evidence for effect modification by smoking and by sex. Genome-wide analyses identified a novel association of rs11693320-an intronic DPP10 SNP-with FVC when incorporating an interaction with DHA, and the finding was replicated (P-2df = 9.4 x 10(-9) across discovery and replication cohorts). The rs11693320-A allele (frequency, similar to 80%) was associated with lower FVC (P-SNP = 2.1 x 10(-9); beta(SNP) = 2161.0 ml), and the association was attenuated by higher DHA levels (P-SNPxDHA interaction = 2.1x10(-7); beta(SNPxDHA interaction) = 36.2 ml). Conclusions: We corroborated beneficial effects of n-3 PUFAs on pulmonary function. By modeling genome-wide n-3 PUFA interactions, we identified a novel DPP10 SNP association with FVC that was not detectable in much larger studies ignoring this interaction

Association Between Whole Blood-Derived Mitochondrial Dna Copy Number, Low-Density Lipoprotein Cholesterol, and Cardiovascular Disease Risk

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia)

Lifetime Doctor-Diagnosed Mental Health Conditions and Current Substance Use Among Gay and Bisexual Men Living in Vancouver, Canada

BackgroundStudies have found that gay, bisexual, and other men who have sex with men (GBM) have higher rates of mental health conditions and substance use than heterosexual men, but are limited by issues of representativeness.ObjectivesTo determine the prevalence and correlates of mental health disorders among GBM in Metro Vancouver, Canada.MethodsFrom 2012 to 2014, the Momentum Health Study recruited GBM (≥16 years) via respondent-driven sampling (RDS) to estimate population parameters. Computer-assisted self-interviews (CASI) collected demographic, psychosocial, and behavioral information, while nurse-administered structured interviews asked about mental health diagnoses and treatment. Multivariate logistic regression using manual backward selection was used to identify covariates for any lifetime doctor diagnosed: (1) alcohol/substance use disorder and (2) any other mental health disorder.ResultsOf 719 participants, 17.4% reported a substance use disorder and 35.2% reported any other mental health disorder; 24.0% of all GBM were currently receiving treatment. A lifetime substance use disorder diagnosis was negatively associated with being a student (AOR = 0.52, 95% CI [confidence interval]: 0.27-0.99) and an annual income ≥$30,000 CAD (AOR = 0.38, 95% CI: 0.21-0.67) and positively associated with HIV-positive serostatus (AOR = 2.54, 95% CI: 1.63-3.96), recent crystal methamphetamine use (AOR = 2.73, 95% CI: 1.69-4.40) and recent heroin use (AOR = 5.59, 95% CI: 2.39-13.12). Any other lifetime mental health disorder diagnosis was negatively associated with self-identifying as Latin American (AOR = 0.25, 95% CI: 0.08-0.81), being a refugee or visa holder (AOR = 0.18, 95% CI: 0.05-0.65), and living outside Vancouver (AOR = 0.52, 95% CI: 0.33-0.82), and positively associated with abnormal anxiety symptomology scores (AOR = 3.05, 95% CI: 2.06-4.51).ConclusionsMental health conditions and substance use, which have important implications for clinical and public health practice, were highly prevalent and co-occurring