bluuebunny/crossref_metadata_2025 huggingface dataset:
An inhomogeneous Poisson model of the spatial intensity of opioid overdoses, as represented by EMS naloxone use
Authors: Ryan Christopher W.
Published: January 2019

1

From 1999 to 2017, the age-adjusted annual death rate in the United States from opioid overdose has increased several-fold, to about 18.3 per 100,000 population. The federal government has declared opioid overdose a public health emergency. Spatially-aware analyses and surveillance may contribute to control of this growing problem.

As naloxone has only one clinical use—the treatment of opioid overdose—its administration by emergency medical services (EMS) personnel can serve as a surveillance indicator for opioid overdose. I previously demonstrated spatial clustering of naloxone-involved EMS calls, over and above that to be expected fromEMS calls in general. To better understand the nature of that clustering, I modelled the spatial distribution of naloxone-involved EMS calls in a three-county region in south-central New York State as an inhomogeneous Poisson process, using as predictors several census-tract-level sociodemographic variables and the point locations of convenience stores (minimarts). In Monte Carlo simulations, I examined how well the model explained the observed clustering.

Although it assumes no interaction between event locations, the inhomogeneous Poisson model was nevertheless able to explain much of the observed spatial clustering. The spatial intensity of EMS calls for opioid overdose, in events per square kilometer, was signficantly higher in census tracts with lower rates of owner-occupancy of housing. Neither the proportion of households in poverty nor the proportion of residents in the 20–44 age band were signficant predictors. Spatial intensity of overdose events decreased by about 10% for each kilometer of distance from the nearest minimart, but this was of borderline signfificance at conventional levels. These findings cast some doubt on the utility of real-time surveillance for apparent spatial clusters of opioid overdose and instead favor a longer-term, systemic strategy comprising efforts to improve neighborhood conditions.
Genomic, Ancestral and Networking Analyses of a High-Altitude Native American Ecuadorian Patient with Congenital Insensitivity to Pain with Anhidrosis
Authors: López-Cortés Andrés , Zambrano Ana Karina , Guevara-Ramírez Patricia , Echeverría Byron Albuja , Guerrero Santiago , Cabascango Eliana , Pérez-Villa Andy , Armendáriz-Castillo Isaac , García-Cárdenas Jennyfer , Yumiceba Verónica , Pérez-M Gabriela , Leone Paola E. , Paz-y-Miño César
Published: January 2019

Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder characterized by insensitivity to pain, inability to sweat and intellectual disability. CIPA is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) that encodes the high-affinity receptor of nerve growth factor (NGF). Patients with CIPA lack the primary afferents and sympathetic postganglionic neurons leading to lack of pain sensation and the presence of anhidrosis, respectively. Herein, we conducted a genomic analysis of 4,811 genes and 18,933 variants, including 54 mutations of NTRK1 in a high-altitude indigenous Ecuadorian patient with CIPA. As results, the patient presented 87.8% of Native American ancestry, 6.6% of African ancestry and 5.6% of European ancestry. The mutational analysis of the kinase domain of NTRK1 showed two pathogenic mutations, rs80356677 (Asp674Tyr) and rs763758904 (Arg602*). The genomic analysis showed 68 pathogenic and/or likely pathogenic variants in 45 genes, and two variants of uncertain significance in CACNA2D1 (rs370103843) and TRPC4 (rs80164537) genes involved in the pain matrix. The GO enrichment analysis showed 28 genes with relevant mutations involved in several biological processes, cellular components and molecular functions. In addition, the protein-protein interaction (PPi) networking analysis showed that NTRK1, SPTBN2 and GRM6 interact with several proteins of the pain matrix. In conclusion, this is the first time that a study associates genomic, ancestral and networking data in a high-altitude Native American Ecuadorian patient with consanguinity background in order to better understand CIPA pathogenesis.
Mitochondrial volume fraction controls translation of nuclear-encoded mitochondrial proteins
Authors: Tsuboi Tatsuhisa , Viana Matheus P. , Xu Fan , Yu Jingwen , Chanchani Raghav , Arceo Ximena G. , Tutucci Evelina , Choi Joonhyuk , Chen Yang S. , Singer Robert H. , Rafelski Susanne M. , Zid Brian M.
Published: January 2019

Mitochondria are dynamic in their size and morphology yet must also precisely control their protein composition according to cellular energy demand. This control is particularly complicated for mitochondria, as they must coordinate gene expression from both the nuclear and mitochondrial genome. We have found that cells are able to use this dynamic morphology to post-transcriptionally coordinate protein expression with the metabolic demands of the cell through enhanced mRNA localization to the mitochondria. As yeast switch to respiratory metabolism, they increase their mitochondrial volume fraction that is, the ratio of mitochondrial volume to intracellular volume which drives the localization of nuclear-encoded mitochondrial mRNAs to the surface of the mitochondria. Through artificial tethering experiments, we show that this mitochondrial localization is sufficient to increase protein production, whereas sequestering mRNAs away from the mitochondrial surface decreases protein production, and those cells are deficient in growth in respiratory conditions. Furthermore, we find that this mRNA sensitivity to mitochondrial volume fraction is driven by the speed of translation downstream of the mitochondrial targeting sequence (MTS), as local ribosome stalling through a stretch of polyprolines in the nascent peptide can drive constitutive localization of mRNAs to the mitochondria. This points to a mechanism by which organelle volume fraction provides feedback to regulate organelle-specific gene expression through mRNA localization while potentially circumventing the need to directly coordinate with the nuclear genome.
Elevation of FAM129A in neutrophils exposed to serum of patients with severe sepsis: in silico investigations during a hands on training workshop and follow on validation of protein expression in neutrophils
Authors: Roelands Jessica , Chiche Laurent , Marches Radu , Toufiq Mohammed , Kabeer Basirudeen Ahamed , Alfaki Mohamed Alkhair Ibrahim , Saadaoui Marwa , Lakshmanan Arun Prasath , Bangarusamy Dhinoth Kumar , Murugesan Selvasankar , Bedognetti Davide , Hendrickx Wouter , Khodor Souhaila Al , Terranegra Annalisa , Banchereau Jacques , Garand Mathieu , Chaussabel Damien , Rinchai Darawan
Published: January 2019

Steps involved in reductionist investigation approaches can be imitated using public transcriptome datasets as source of training material. In the present report trainees explored an apparent gap in biological knowledge for FAM129A (family with sequence similarity 129 member A). Elevated abundance of FAM129A transcripts were observed in a transcriptome dataset where neutrophils were exposed in vitro to plasma of patients with sepsis. However, no literature linking FAM129A and either neutrophils, sepsis or inflammation could be identified. Additional datasets were selected to independently validate this initial observation and further explore differential expression of FAM129A in the context of sepsis studies. Follow on investigations carried out at the bench confirmed restriction of the expression of FAM129A protein at the surface of circulating blood neutrophils and monocytes. A potential role for FAM129A in neutrophil survival was inferred from profiling of literature associated with FAM129A, which remains to be investigated in further follow on investigations.
Effects of transcranial alternating-current stimulation to secondary motor areas on cortical oscillations in stroke patients
Authors: Krawinkel Lutz A. , Bönstrup Marlene , Feldheim Jan F. , Schulz Robert , Backhaus Winifried , Schneider Till R. , Misselhorn Jonas , Cheng Bastian , Gerloff Christian
Published: January 2019

Background

There is growing evidence that secondary motor areas are relevant for recovery after motor stroke. Communication among brain areas occurs via synchronization of oscillatory activity which can potentially be modulated via transcranial alternating-current stimulation (tACS).

Hypothesis

We hypothesized that tACS to secondary motor areas of the stroke-lesioned hemisphere leads to modulation of task-related connectivity among primary and secondary motor areas, reflected in metrics of EEG coupling in the frequency domain.

Methods

We applied focal tACS at 1mA peak-to-peak intensity to ipsilesional ventral premotor cortex (PMv) and supplementary motor area (SMA) in chronic stroke patients while they moved their impaired hand. To probe effects of stimulation on cortical oscillations, several task-related EEG-based connectivity metrics (coherence, imaginary coherence, phase-locking value, mutual information) were assessed before and after each stimulation.

Results

Overall, we found significant but weak modulations of the motor network by tACS. Stimulation of PMv reduced task-related coupling between (i) both primary motor cortices (M1) (coherence, −0.0514±0.0665 (mean±SD, active stimulation) vs. 0.0085±0.0888 (sham), p=0.0029) and (ii) between ipsilesional M1 and contralesional PMv (coherence, - 0.0386±0.0703 vs. 0.0226±0.0694, p=0.0283; phase-locking value, −0.0363±0.0581 vs. 0.0036±0.0497, p=0.0097) compared with sham stimulation.

Conclusions

In this exploratory analysis, tACS to the ipsilesional PMv induced a weak decrease of task-related connectivity between ipsilesional M1 and contralesional M1 and PMv. As an excess of interhemispheric coupling is under discussion as maladaptive phenomenon of motor reorganization after stroke (e.g., bimodal balance-recovery model), tACS-induced reduction of coupling might be an interesting approach to assist re-normalization of the post-stroke motor network.
Bayesian Multiple Emitter Fitting using Reversible Jump Markov Chain Monte Carlo
Authors: Fazel Mohamadreza , Wester Michael J. , Mazloom-Farsibaf Hanieh , Meddens Marjolein B. M. , Eklund Alexandra , Schlichthaerle Thomas , Schueder Florian , Jungmann Ralf , Lidke Keith A.
Published: January 2019

In single molecule localization-based super-resolution imaging, high labeling density or the desire for greater data collection speed can lead to clusters of overlapping emitter images in the raw super-resolution image data. We describe a Bayesian inference approach to multiple-emitter fitting that uses Reversible Jump Markov Chain Monte Carlo to identify and localize the emitters in dense regions of data. This formalism can take advantage of any prior information, such as emitter intensity and density. The output is both a posterior probability distribution of emitter locations that includes uncertainty in the number of emitters and the background structure, and a set of coordinates and uncertainties from the most probable model.
Disentangling strictly self-serving mutations from win-win mutations in a mutualistic microbial community
Authors: Hart Samuel F. M. , Pineda Jose Mario Bello , Chen Chi-Chun , Green Robin , Shou Wenying
Published: January 2019

Mutualisms can be promoted by win-win mutations which directly benefit self (self-serving) and partner (partner-serving). Intuitively, partner-serving phenotype could be quantified as the benefit supply rate to partner by an individual. Here, we demonstrate the inadequacy of this thinking, and propose an alternative measure. Specifically, we evolved well-mixed mutualistic communities where two engineered yeast strains exchanged essential metabolites lysine and hypoxanthine. Among cells that consumed lysine and released hypoxanthine, a chromosome duplication mutation seemed win-win: it improved cell’s affinity for lysine, and increased hypoxanthine release rate per cell. However, increased release rate was due to increased cell size accompanied by increased lysine consumption per birth. Consequently this mutation is solely self-serving, since a fixed amount of intake lysine leads to an identical total hypoxanthine release rate - either by more numerous lower-releasing ancestors or fewer higher-releasing mutants. By extension, individuals with reduced benefit production rates may not be cheaters.
Glycosylation of gigaxonin regulates intermediate filaments: Novel molecular insights into giant axonal neuropathy
Authors: CHEN PO-HAN , Smith Timothy , Hu Jimin , Pan Samuel , Smith Alexander , Lu Annie , Chi Jen-Tsan , Boyce Michael
Published: January 2019

Gigaxonin (also known as KLHL16) is an E3 ligase adaptor protein that promotes the ubiquitination and degradation of intermediate filament (IF) proteins. Mutations in human gigaxonin cause the fatal neurodegenerative disease giant axonal neuropathy (GAN), in which IF proteins accumulate and aggregate in axons throughout the nervous system, impairing neuronal function and viability. Despite this pathophysiological significance, the upstream regulation and downstream effects of normal and aberrant gigaxonin function remain incompletely understood. Here, we report that gigaxonin is modified by O-linked-beta-N-acetylglucosamine (O-GlcNAc), a prevalent form of intracellular glycosylation, in a nutrient- and growth factor-dependent manner. Mass spectrometry analyses of human gigaxonin revealed nine candidate sites of O-GlcNAcylation, two of which - serine 272 and threonine 277 - are required for its ability to mediate IF turnover in novel gigaxonin-deficient human cell models that we created. Taken together, these results suggest that nutrient-responsive gigaxonin O-GlcNAcylation forms a regulatory link between metabolism and IF proteostasis. Our work may have significant implications for understanding the non-genetic modifiers of GAN phenotypes and for the optimization of gene therapy for this disease.
Graphene oxide affects soil bacterial and fungal diversity even at parts-per-trillion concentrations
Authors: Forstner Christian , Orton Thomas G. , Skarshewski Adam , Wang Peng , Kopittke Peter M. , Dennis Paul G.
Published: January 2019

Graphene oxide (GO) is an oxidized form of graphene that is relatively cheap and easy to produce. This has heralded its widespread use in a range of industries, with its likelihood of release into the environment increasing accordingly. In pure culture, GO has been shown to influence bacteria and fungi, but its effects on environmental microbial communities remain poorly characterized, despite the important ecosystem services that these organisms underpin. Here, we characterized the effects of GO and graphite, over time and at three concentrations (1 ng, 1 µg and 1 mg kg dry soil-1), on soil bacterial and fungal diversity using 16S rRNA and ITS2 gene amplicon sequencing. Graphite was included as a reference material as it is widely distributed in the environment. Neither GO or graphite had significant effects on the alpha diversity of microbial communities. The composition of bacterial and fungal communities, however, was significantly influenced by GO and graphite. These effects were equally apparent between doses and varied over time. Predicted KEGG pathways and fungal guild structures were not significantly influenced by the treatments. Our study demonstrates that GO can influence soil microbial diversity, even at parts-per-trillion concentration, which is equivalent to the rates of release predicted for similar nanomaterials such as carbon nanotubes.

Importance

Graphene oxide is a nanomaterial with broad and expanding industrial applications. Some evidence indicates that it can influence the growth of microorganisms, many of which support important ecosystem services, such as the provision of food and clean water. The amount of graphene oxide currently entering soils is not known but is likely to be similar to other nanomaterials, such as carbon nanotubes (i.e. parts-per-trillion to parts-per-billion per year). In this study, we demonstrate that graphene oxide added to soil at these concentrations (or higher) can alter the composition of bacterial and fungal communities. Nonetheless, we found that these changes were of similar magnitude to those associated with the addition of graphite, which is common and occurs naturally in soils. Further research is recommended to determine whether the changes in microbial community composition that we have shown can be induced by graphene oxide, have deleterious consequences for soil health.
Hera-T: an efficient and accurate approach for quantifying gene abundances from 10X-Chromium data with high rates of non-exonic reads
Authors: Tran Thang , Truong Thao , Vuong Hy , Pham Son
Published: January 2019

An important but rarely discussed phenomenon in single cell data generated by the 10X-Chromium protocol is that the fraction of non-exonic reads is very high. This number usually exceeds 30% of the total reads. Without aligning them to a complete genome reference, non-exonic reads can be erroneously aligned to the transcriptome reference with higher error rates. To tackle this problem, Cell Ranger chooses to firstly align reads against the whole genome, and at a later step, uses a genome annotation to select reads that align to the transcriptome. Despite its high running time and large memory consumption, Cell Ranger remains the most widely used tool to quantify 10XGenomics single cell RNA-Seq data for its accuracy.

In this work, we introduce Hera-T, a fast and accurate tool for estimating gene abundances in single cell data generated by the 10X-Chromium protocol. By devising a new strategy for aligning reads to both transcriptome and genome references, Hera-T reduces both running time and memory consumption from 10 to 100 folds while giving similar results compared to Cell Ranger’s. Hera-T also addresses some difficult splicing alignment scenarios that Cell Ranger fails to address, and therefore, obtains better accuracy compared to Cell Ranger. Excluding the reads in those scenarios, Hera-T and Cell Ranger results have correlation scores > 0.99.

For a single-cell data set with 49 million of reads, Cell Ranger took 3 hours (179 minutes) while Hera-T took 1.75 minutes; for another single-cell data set with 784 millions of reads, Cell Ranger took about 25 hours while Hera-T took 32 minutes. For those data sets, Cell Ranger completely used all 32 GB of memory while Hera-T consumed at most 8 GB. Hera-T package is available for download at: https://bioturing.com/product/hera-t
Seeded propagation of alpha-synuclein aggregation in mouse brain using protein misfolding cyclic amplification
Authors: Nicot Simon , Verchère Jérémy , Belondrade Maxime , Mayran Charly , Bétemps Dominique , Bougard Daisy , Baron Thierry
Published: January 2019

Alpha-synuclein (α-syn) protein aggregation is associated with several neurodegenerative disorders collectively referred to as synucleinopathies, including Parkinson disease. We used protein misfolding cyclic amplification (PMCA) to study α-syn aggregation in brain homogenates of wild-type or transgenic mice expressing normal (D line) or A53T mutant (M83 line) human α-syn. We found that sonication-incubation cycles of M83 mouse brain gradually produce large quantities of SDS-resistant α-syn aggregates, involving both human and mouse proteins. These PMCA products, containing partially proteinase K resistant α-syn species, are competent to accelerate the onset of neurological symptoms after intracerebral inoculation to young M83 mice and to seed aggregate formation of α-syn following PMCA, including in D and wild-type mouse brain substrates. Our data indicate that similar to prions, PMCA can reproduce some characteristics of α-syn aggregation and seeded-propagation in vitro in a complex milieu. This opens new opportunities for the molecular study of synucleinopathies.
Engineered reversal of function in glycolytic yeast promoters
Authors: Rajkumar Arun S. , Özdemir Emre , Lis Alicia V. , Schneider Konstantin , Jensen Michael K. , Keasling Jay D.
Published: January 2019

Promoters are key components of cell factory design, allowing precise expression of genes in a heterologous pathway. Several commonly-used promoters in yeast cell factories belong to glycolytic genes, highly expressed in actively-growing yeast when glucose is used as a carbon source. However, their expression can be suboptimal when alternate carbon sources are used, or if there is a need to decouple growth from production. Hence, there is a need for alternate promoters for different carbon sources and production schemes. In this work, we demonstrate a reversal of regulatory function in two glycolytic yeast promoters by replacing glycolytic regulatory elements with ones induced by the diauxic shift. We observe a shift in induction from glucose-rich to glucose-poor medium without loss of regulatory activity, and strong ethanol induction. Applications of these promoters were validated for expression of the vanillin biosynthetic pathway, reaching production of vanillin comparable to pathway designs using strong constitutive promoters.
“Risk Factors for Visceral Leishmaniasis in Selected High Endemic Areas of Morang District, Nepal”: A case control study
Authors: Mandal Punam Kumari , Wagle Rajendra Raj , Thakur Ajoy Kumar , Uranw Surendra
Published: January 2019

Visceral leishmaniasis is a major public health concern in Nepal. During the last few years, several KA outbreaks have been reported from Tarai region including Morang district. A case control study was conducted to assess the risk factors associated with VL in 5 endemic VDC of Morang district with 62 cases already treated from BPKIHS and Koshi zonal hospital and 248 controls selected randomly from the same village. Data collected using semi structured questionnaire from September to November 2013. This study revealed that people living in thatched house, sleeping in ground floor, ownership of animal, history of migration to India (Bihar and Jharkhand) and proximity to other KA cases within 50 m distance of household were strong risk factors for VL. Education remains protective (OR 0.39,95 % CI 0.19-0.79). The association with socioeconomic status showed clear dose – response effect. The odds for VL consistently decreased as the level of socioeconomic status increased (OR 4.26, 3.81). Strengthening surveillance system for early diagnosis and treatment, awareness programme and further extensive study is needed on risk factor, vector and control measures.

Author Summary

This study aims to explore the risk factors for visceral leishmaniasis. Based on findings there is a need to educate people in high-transmission areas how to realize, reduce or avoid environmental factors that favor the survival of the vector in the community. Similarly introduction of more exact surveillance tools in order to improve morbidity and mortality surveillance by health sector. People living in mud thatched houses need to be aware about cracks and crevices in the mud walls, their function as breeding places and how they can be controlled, for example by plastering with lime and mud․. However, a primary condition is that people need to understand the purpose of all these efforts in order to be motivated to put them into practice.
A Short Bout of High-intensity Exercise Alters Ipsilesional Motor Cortical Excitability Post-stroke
Authors: Li Xin , Charalambous Charalambos C. , Reisman Darcy S. , Morton Susanne M.
Published: January 2019

Background

Acute exercise can increase motor cortical excitability and enhance motor learning in healthy individuals, an effect known as exercise priming. Whether it has the same effects in people with stroke is unclear.

Objectives

The objective of this study was to investigate whether a short, clinically-feasible high-intensity exercise protocol can increase motor cortical excitability in non-exercised muscles of chronic stroke survivors.

Methods

Thirteen participants with chronic, unilateral stroke participated in two sessions, at least one week apart, in a crossover design. In each session, they underwent either high-intensity lower extremity exercise or quiet rest. Motor cortical excitability of the extensor carpi radialis muscles was measured bilaterally with transcranial magnetic stimulation before and immediately after either exercise or rest. Motor cortical excitability changes (post-exercise or rest measures normalized to pre-test measures) were compared between exercise vs. rest conditions.

Results

All participants were able to reach the target high-intensity exercise level. Blood lactate levels increased significantly after exercise (p < 0.001, d = 2.85). Resting motor evoked potentials from the lesioned hemisphere increased after exercise compared to the rest condition (p = 0.046, d = 2.76), but this was not the case for the non-lesioned hemisphere (p = 0.406, d = 0.25).

Conclusions

High-intensity exercise can increase lesioned hemisphere motor cortical excitability in a non-exercised muscle post-stroke. Our short and clinically-feasible exercise protocol shows promise as a potential priming method in stroke rehabilitation.
Phylogeny of Holarctic gall wasps of the genera Diplolepis and Periclistus (Hymenoptera: Cynipidae) based on DNA barcodes
Authors: Zhang Y. Miles , László Zoltán , Looney Chris , Dénes Avar-Lehel , Hanner Robert H. , Shorthouse Joseph D.
Published: January 2019

Rose gall wasps Diplolepis induce structurally distinct galls on wild roses, which provide gallers with food and shelter. These galls are attacked by a wide variety of micro-hymenopterans including another cynipid Periclistus that act as inquilines. Both Diplolepis and Periclistus are difficult to distinguish based on adult morphology, instead the structural appearance of galls is often used to distinguish species. Using the mitochondrial gene COI, we built phylogenies of both Diplolepis and Periclistus, while also estimating the ancestral host use of the inducers. Our phylogeny recovered the monophyly of Diplolepis, which have likely diverged from single-or multi-chambered leaf gallers to other plant organs. Periclistus exhibits a divide between the Palearctic and Nearctic clades, and ranges from specialists to generalists in terms of host specificity. The molecular results have largely supported the validity of species described in the literature, with notable exceptions in four species groups. While it is premature to enact any taxonomic changes without additional molecular markers, this incongruence between morphological and molecular data indicates these groups need taxonomic revision and gall morphology alone may be inadequate to delimit species.
Factorial Mendelian randomization: using genetic variants to assess interactions
Authors: Rees Jessica MB , Foley Christopher N , Burgess Stephen
Published: January 2019

Background

Factorial Mendelian randomization is the use of genetic variants to answer questions about interactions. Although the approach has been used in applied investigations, little methodological advice is available on how to design or perform a factorial Mendelian randomization analysis. Previous analyses have employed a 2 × 2 approach, using dichotomized genetic scores to divide the population into 4 subgroups as in a factorial randomized trial.

Methods

We describe two distinct contexts for factorial Mendelian randomization: investigating interactions between risk factors, and investigating interactions between pharmacological interventions on risk factors. We propose two-stage least squares methods using all available genetic variants and their interactions as instrumental variables, and using continuous genetic scores as instrumental variables rather than dichotomized scores. We illustrate our methods using data from UK Biobank to investigate the interaction between body mass index and alcohol consumption on systolic blood pressure.

Results

Simulated and real data show that efficiency is maximized using the full set of interactions between genetic variants as instruments. In the applied example, between four- and ten-fold improvement in efficiency is demonstrated over the 2 × 2 approach. Analyses using continuous genetic scores are more efficient than those using dichotomized scores. Efficiency is improved by finding genetic variants that divide the population at a natural break in the distribution of the risk factor, or else divide the population into more equal sized groups.

Conclusions

Previous factorial Mendelian randomization analyses may have been under-powered. Efficiency can be improved by using all genetic variants and their interactions as instrumental variables, rather than the 2 × 2 approach.

Key messages

Factorial Mendelian randomization is an extension of the Mendelian randomization paradigm to answer questions about interactions.

There are two contexts in which factorial Mendelian randomization can be used: for investigating interactions between risk factors, and interactions between pharmacological interventions on risk factors.

While most applications of factorial Mendelian randomization have dichotomized the population as in a 2 × 2 factorial randomized trial, this approach is generally inefficient for detecting statistical interactions.

In the first context, efficiency is maximized by including all genetic variants and their cross-terms as instrumental variables for the two risk factors and their product term.

In the second context, efficiency is maximized by using continuous genetic scores rather than dichotomized scores.
IFN-α and 5-Aza-2’-deoxycytidine enhance the anti-tumor efficacy of a dendritic- cell targeting MIP3a-Gp100-Trp2 DNA vaccine by affecting T-cell recruitment and tumor microenvironment gene expression
Authors: Gordy James T. , Luo Kun , Markham Richard B.
Published: January 2019

Background

The chemokine MIP-3α (CCL20) binds to CCR6 found on immature dendritic cells. DNA vaccines fusing MIP-3α to melanoma-associated antigens have shown improved efficacy and immunogenicity in the B16F10 model. To optimize the therapy, our laboratory has added agents designed to overcome immunoregulatory mechanisms of the tumor microenvironment. Here, we report that the combination of type-I interferon therapy (IFNα) with 5-Aza-2’-deoxycitidine (Aza) profoundly enhanced the therapeutic anti-melanoma efficacy of a MIP-3α-Gp100-Trp2 DNA vaccine.

Methods

The current studies utilize the B16F10 syngeneic mouse melanoma model. The vaccine is administered intramuscularly (i.m.) followed by i.m. electroporation. Vaccinations are given thrice at one-week intervals beginning day 5 with CpG adjuvant given two days later as noted. Aza is given i.p. at 1mg/kg on days 5 and 12. IFNα therapy is given in a series of one high followed by three low doses, beginning on days 5 and 12. Tumor sizes, growth, and survival were all assessed. Tumor microenvironment gene expression levels were explored by qRT-PCR. Tumor-infiltrating lymphocytes (TILs) were assessed by stimulating the purified lymphocyte fraction of tumors with vaccine antigens followed by intracellular cytokine staining flow cytometry.

Results

We demonstrate that the addition of IFNα and Aza treatments to mice vaccinated with the MIP-3α-Gp100-Trp2 vaccine has led to significantly reduced tumor burden and overall increases in mouse survival, increasing median survival by 39% over vaccine and 86% over controls. Importantly, this increase in efficacy was dependent on the presence of all three components: vaccine, IFNα, and Aza. The addition of Aza and IFNα to the vaccine increased T-cell tumor infiltration and altered the proportion of CD8+T-cells. Also, IFNα and vaccine induced durable changes in IFNα-stimulated gene transcription.

Conclusions

Efficient targeting of antigen to immature dendritic cells with a chemokine-fusion vaccine offers a potential alternative approach to classic and dendritic cell based vaccines currently undergoing clinical investigation. Combining this approach with IFNα and Aza combination treatment significantly improved vaccine efficacy, with efficacy correlating with changes in TILs and in IFNα -stimulated gene expression. Further potential therapy optimization currently undergoing investigation offers promise for this line of investigation to become a novel melanoma therapy.
Efficacy for Anemia and Changes in Serum Ferritin Levels by Long‐Term Oral Iron Administration in Hemodialysis Patients
Authors: Daimon Shoichiro
Published: January 2019

Oral iron preparations are useful for the treatment of anemia in hemodialysis patients; however, long‐term changes in the iron dynamics and effects of anemia are unknown. Serum ferritin levels and erythropoietin‐stimulating agent (ESA)/hemoglobin (Hb) ratios were investigated for 750 days in the following four groups: patients treated with sodium ferrous citrate (SF) (de novo 50 mg/day and 150 mg/day switched from 50 mg/day) and patients treated with 1500 mg/day of ferric citrate (FC) (de novo and switched from 50 mg/day of SF). Compared with the other groups, serum ferritin levels increased less apparently with de novo 50 mg/day SF. ESA/Hb ratios did not change in groups switched from 50 mg/day SF. Conversely, in groups with de novo iron, ESA/Hb ratios decreased and ultimately reached the same levels in all groups. Although more iron results in higher serum ferritin levels, 50 mg/day SF has an equivalent effect for anemia treatment.
Tramadol as an adjunct to intra‐articular local anaesthetic infiltration in knee arthroscopy: a systematic review and meta‐analysis
Authors: Ryan Thomas , Hodge Anthony , Holyoak Rhys , Vlok Ruan , Melhuish Thomas , Binks Matthew , Hurtado Glenn , White Leigh
Published: January 2019

Background

Arthroscopic knee surgery is a common technique used in Australia. Post‐operative pain is common and can lead to delayed discharge and impair early mobilization. Use of local anaesthesia can reduce pain while avoiding systemic side effects. This systematic review and meta‐analysis aimed to establish the use of tramadol as an adjunct to intra‐articular local anaesthetic infiltration in knee arthroscopy in the current literature.

Methods

Two independent reviewers performed a systematic search of four databases, where 24 articles were identified with six studies (four high‐quality and two low‐quality randomized controlled trials), with a total of 334 patients were included for analysis. RevMan 5.3 software (The Nordic Cochrane Centre, Copenhagen, Denmark) was used to perform the data analysis. The studies included focused on outcomes such as pain scores, breakthrough analgesia, total analgesia, time to discharge and adverse events related to the use of tramadol as an adjunctive therapy.

Results

This study found that using tramadol as an adjunct to intra‐articular local anaesthetic infiltration in arthroscopic knee surgery reduced post‐operative pain and increased time to breakthrough analgesia without an increase in side effects.

Conclusion

This meta‐analysis suggests that tramadol is an efficacious adjunct for use in intra‐articular local anaesthetic infiltration following arthroscopic knee surgery.
Establishment of a simple and rapid method to detect MECP2 duplications using digital polymerase chain reaction
Authors: Imaizumi Taichi , Yamamoto‐Shimojima Keiko , Yamamoto Hitoshi , Yamamoto Toshiyuki
Published: January 2019

Genomic copy number variations (CNVs) can be detected by chromosomal microarray testing. However, upon final diagnosis, other methods may be recommended for a validation method to confirm CNVs. Trio analyses or carrier detection in family members are also frequently required. Previously, fluorescence in situ hybridization and/or quantitative PCR have been used; however, these methods present limitations. The purpose of this study was to establish a simple and rapid method to detect genomic copy numbers. We utilized droplet digital PCR (dPCR) with an intercalation method. Thirteen patients, who were diagnosed with MECP2 duplications via chromosomal microarray testing, were enrolled in this study. Four of their female relatives, who were verified as carriers of MECP2 duplications, were also included. Genomic copy numbers of MECP2 and IRAK1 were analyzed in comparison with reference genes: XIST and AR on the X‐chromosome, and RPP30 and RPPH1 on the autosomal chromosomes. As a result, genomic copy numbers of MECP2 were rapidly and precisely detected by the dPCR system established in this study. This method can be widely applied as a diagnostic method to confirm CNVs on other chromosomal regions.
Twenty‐eight‐day follow‐up of patch test reactions to p‐phenylenediamine and p‐phenylenediamine dihydrochloride: A multicentre study on behalf of the European Environmental and Contact Dermatitis Research Group
Authors: Young Ewa , Andersen Klaus E. , Bruze Magnus , Giménez‐Arnau Ana , Ross‐Hansen Katrine , Johansen Jeanne D. , Madsen Jakob Torp , Zimerson Erik , Svedman Cecilia
Published: January 2019

Background

There is an ongoing discussion on whether routinely patch testing with p‐phenylenediamine (PPD) 1.0% pet. is safe, owing to the risk of patch test sensitization. Late‐appearing patch test reactions may reflect patch test sensitization, but may also be attributable to a low degree of pre‐existing sensitization.

Objectives

To follow the positive patch test reactions to PPD and its salt PPD dihydrochloride (PPD‐DHC) in order to characterize reaction patterns concerning time and dose in PPD‐sensitized individuals.

Methods

Volunteers with previous reactions to PPD 1.0% were included and patch tested with PPD and PPD‐DHC in equimolar dilution series. There were then seven follow‐up visits over a period of 28 days.

Results

Twenty‐six volunteers completed the study, of whom 23 of 26 (88%) reacted to PPD 1.0%, and 69% reacted to PPD 0.32%. Altogether, 42% and 27% reacted to the corresponding equimolar concentrations of PPD‐DHC. After day 7, no new reactions were observed to any concentration tested, either of PPD or of PPD‐DHC.

Conclusion

No late‐appearing reactions to PPD or PPD‐DHC were observed at any dose. There is a risk of missing contact allergy when the dose is decreased.
Stomoxys calcitrans, mechanical vector of virulent Besnoitia besnoiti from chronically infected cattle to susceptible rabbit
Authors: Sharif S. , Jacquiet P. , Prevot F. , Grisez C. , Raymond‐Letron I. , Semin M. O. , Geffré A. , Trumel C. , Franc M. , Bouhsira É. , Liénard E.
Published: January 2019

Cattle besnoitiosis caused by Besnoitia besnoiti (Eucoccidiorida: Sarcocystidae) is a re‐emerging disease in Europe. Its mechanical transmission by biting flies has not been investigated since the 1960s. The aim of this study was to re‐examine the ability of Stomoxys calcitrans (Diptera: Muscidae) to transmit virulent B. besnoiti bradyzoites from chronically infected cows to susceptible rabbits. Three batches of 300 stable flies were allowed to take an interrupted bloodmeal on chronically infected cows, followed by an immediate bloodmeal on three rabbits (Group B). A control group of rabbits and a group exposed to the bites of non‐infected S. calcitrans were included in the study. Blood quantitative polymerase chain reaction (qPCR) analyses, and clinical, serological and haematological surveys were performed in the three groups over 152 days until the rabbits were killed. Quantitative PCR analyses and histological examinations were performed in 24 tissue samples per rabbit. Only one rabbit in Group B exhibited clinical signs of the acute phase of besnoitiosis (hyperthermia, weight loss, regenerative anaemia and transient positive qPCR in blood) and was seroconverted. Parasite DNA was detected in four tissue samples from this rabbit, but no cysts were observed on histological examination. These findings indicate that S. calcitrans may act as a mechanical vector of B. besnoiti more efficiently than was previously considered.
Anatomical changes with needle length are correlated with leaf structural and physiological traits across fivePinusspecies
Authors: Wang Na , Palmroth Sari , Maier Christopher A. , Domec Jean‐Christophe , Oren Ram
Published: January 2019

The genusPinushas wide geographical range and includes species that are the most economically valued among forest trees worldwide. Pine needle length varies greatly among species, but the effects of needle length on anatomy, function, and coordination and trade‐offs among traits are poorly understood. We examined variation in leaf morphological, anatomical, mechanical, chemical, and physiological characteristics among five southern pine species:Pinus echinata,Pinus elliottii,Pinus palustris,Pinus taeda, andPinus virginiana. We found that increasing needle length contributed to a trade‐off between the relative fractions of support versus photosynthetic tissue (mesophyll) across species. From the shortest (7 cm) to the longest (36 cm) needles, mechanical tissue fraction increased by 50%, whereas needle dry density decreased by 21%, revealing multiple adjustments to a greater need for mechanical support in longer needles. We also found a fourfold increase in leaf hydraulic conductance over the range of needle length across species, associated with weaker upward trends in stomatal conductance and photosynthetic capacity. Our results suggest that the leaf size strongly influences their anatomical traits, which, in turn, are reflected in leaf mechanical support and physiological capacity.
Glutamate hypothesis in schizophrenia
Authors: Uno Yota , Coyle Joseph T.
Published: January 2019

Schizophrenia is a chronic and severe psychiatric disorder that has profound impact on an individual’s life and on society. Thus, developing more effective therapeutic interventions is essential. Over the past quarter‐century, an abundance of evidence from pharmacologic challenges, post‐mortem studies, brain imaging, and genetic studies supports the role of glutamatergic dysregulation in the pathophysiology of schizophrenia, and the results of recent randomized clinical trials based on this evidence have yielded promising results. In this article, we review the evidence that alterations in glutamatergic neurotransmission, especially focusing on the N‐methyl‐d‐aspartate receptor (NMDAR) function, may be a critical causative feature of schizophrenia, how this contributes to pathologic circuit function in the brain, and how these insights are revealing whole new avenues for treatment development that could reduce treatment‐resistant symptoms, which account for persistent disability.
Sobering challenges faced by the brewing industry in a warming world
Authors: Law Simon R.
Published: January 2019

Barley (Hordeum vulgare), a vital crop to the food and beverage industry, is highly vulnerable to unstable conditions on the climatic horizon. An article in this special issue of Physiologia Plantarum by Mahalingam and Bregitzer (2019) describes the impact that individual and combined stresses linked to climate change could have on the agronomic source of one of our favourite libations, as well as offering achievable solutions that will be needed if crop yield and quality are to be maintained.
Brown, Title IX and the impact of race and sex segregation on sports participation opportunities for Black females
Authors: Theune Felecia
Published: January 2019

Although neither the 1954 Brown v. Board of Education of Topeka, Kansas decision nor Title IX of the Education Amendments Act (1972) specifically mentions sports participation, both antidiscrimination laws have changed the landscape of high school and college sports by granting Blacks and females increased access to athletic opportunities previously reserved for Whites males. Although Brown and Title IX are popular topics among research scholars, studies rarely consider the unique experiences of Black females, who unlike Black males and White females, occupy at least two subordinate social locations due to their race and gender. This article goes beyond the usual single axis of inquiry and examines the intersection of Brown and Title IX and, thus, the intersection of race and sex for Black females who inhabit a sports world dominated by Whites and males. Using existing literature to assess the implementation and effectiveness of Brown and Title IX independently before exploring their sociohistorical linkages and integrated effect on access to sports participation opportunities, the author finds that Black women and girls have been left out of the game.
Canine CD4+ T‐cell lymphoma identified by flow cytometry exhibits a consistent histomorphology and gene expression profile
Authors: Harris Lauren J. , Hughes Kelly L. , Ehrhart E. J. , Labadie Julia D. , Yoshimoto Janna , Avery Anne C.
Published: January 2019

T‐cell lymphomas (TCL) are a diverse group of neoplasms with variable diagnostic features, pathophysiologies, therapeutic responses and clinical outcomes. In dogs, TCL includes indolent and aggressive tumours such as T‐zone lymphoma (TZL) and peripheral T‐cell lymphoma (PTCL), respectively. Delineation of molecular subtypes and investigation into underlying pathophysiologies of aggressive TCLs remains inadequate. We investigate the correlations between flow cytometry and histopathology of 73 cases of nodal TCL. The majority of cases (82.2%) were characterized as CD4+ TCL by flow cytometry. Fewer cases were classified as CD8+ TCL (6.8%) or CD4−CD8− TCL (11.0%). All cases, regardless of immunophenotype, exhibited conserved histologic features consistent with the WHO classification of PTCL. Histologic subsets of PTCL corresponding to immunophenotypic features were not identified. Neoplastic cell size determined by flow cytometry correlated significantly with mitotic rate. RNA‐seq was performed on a subset of CD4+ PTCL cases (n = 6) and compared with sorted control CD4+ T‐cells. The gene expression pattern of CD4+ PTCL was similar between all cases regardless of breed. PTCL was enriched in pathways representing G‐coupled protein receptor signalling, extracellular matrix remodelling and vascular development, immune signalling and mitotic activity. Furthermore, global gene expression changes were consistent with downregulation of PTEN signalling and upregulation of the MTOR‐PI3K‐ATK axis. In this study, we evaluated the correlations between flow cytometry, histopathology and gene expression within a large cohort of nodal TCLs. We further demonstrate the ability of flow cytometry to identify a subtype of T‐cell lymphoma, CD4+ PTCL, with a uniform histomorphology and gene expression profile.