Exile Vol. XL No. 1

38th Year Title Page by Carrie Horner \u2797 i Epigraph by Ezra Pound ii Table of Contents iii-iv Vertigo by Lisa Stillman \u2795 1 Departing Flight by Morgan Roper \u2794 2 Untitled by Lizzie Loud \u2795 3 Marietta by Craig McDonough \u2794 4 Interlaken by Kira A . Pollack \u2794 5 Why Nature Surprises Us by Josh Endicott \u2796 6-7 Untitled by Colin Mack \u2794 7 My Father by Matt Wanat \u2795 8 Legs In The Dust by Alison Stevens \u2795 9-11 Untitled by Lilly Streett \u2794 12 of cigarettes, saltwater and death... by Tricia B. Swearingen \u2794 13 Serendipity by Lizzie Lout \u2795 14 Untitled by Lilly Streett \u2794 15 Summer by Allison Lemieux \u2795 16 And the Rain Fell by Jeremy Aufrance \u2795 17-18 Main Street by Elise Gargarella \u2795 19 Füssen by Morgan Roper \u2794 20 Lightning on the Snow by Matt Wanat \u2795 21 A discussion of 12 year-old murders, of course by Jeremy Aufrance \u2795 22 Get your hands off my hat by Jamie Oliver \u2794 23 The Hero by Sara Sterling Ely \u2796 24-26 Punker Dave by Trevett Allen \u2795 27 still looking for the perfect line by ryan shafer \u2794 28-29 Untitled by Lizzie Loud \u2795 30 Civil War by Katherine Anne Campo \u2794 31 Disposable belief by ryan shafer \u2794 32-33 Schizophrenic Sylvia by Maria Mohiuddin \u2795 34 Excerpts from Revolutions, a novel by Marcu McLaughlin \u2794 35-36 Untitled by Keith Chapman \u2795 37 The Survivors by Kira A. Pollack \u2794 38 Days of Prophecy by Trey Dunham \u2794 39 Untitled by Carrie Horner \u2797 40 What to do by Christopher Harnish \u2794 41 Familiar Stranger by Lisa Stillman \u2795 42-46 Untitled by John Salter \u2797 47 On Meeting Emma by Allison Lemieux \u2795 48 Nude Figure by James Oliver \u2794 49 Tathagata by Leslie Dana Wells \u2794 50 On Fences and My Dogs by Christopher Harnish \u2794 51 Editorial Board 52 Cover, Kira Pollack \u2794 -iv Editorial decision is shared equally among the Editorial Board. -5

Exile Vol. XL No. 2

38th Year Title Page by Carrie Horner \u2797 i Epigraph by Ezra Pound ii Table of Contents iii-iv Remembering Sundays by Allison Lemieux \u2795 1 Untitled by James Oliver \u2794 2 \u2778 Beige Chevy Malibu by Craig J. McDonough \u2794 3-4 Brushtown Road by Lelei Jennings \u2795 5 In Memoriam: River Phoenix, 1970-93 by Kirstin Rogers \u2794 6 Untitled by Kira Pollack \u2794 7 Checkmate by Kevin Nix \u2794 8 Anywhere in Ohio by Jen Hanysh \u2795 9 Untitled by Nicky Taylor \u2794 10 Under Your Influence by Katherine Anne Campo \u2794 11 Tulips by Tricia B. Swearingen \u2794 12 Untitled by Keith Chapman \u2795 12 December Storm by Erin Lott \u2796 13-19 On Meeting Phil Levine After a Reading at Denison University April 6, 1993 by Christopher Harnish \u2794 20 The 422 Bypass by Joel Husenits \u2795 21 Untitled by Ken Tyburski \u2794 22 Shakespeare\u27s Foreskin by Carey Christie \u2795 23 The Thaw by Chris Iven \u2794 24 The Rockbridge County Fair by Morgan Roper \u2794 25 Let it Drop Through by Carey Christie \u2795 26-27 Aladdin\u27s by Paul Rinkes \u2794 28-29 Untitled by Aileen Jones \u2794 30 The Tango by Hope Layne Morgan \u2794 31 Icarus by Carey Christine \u2795 32-33 fad by Jeremy Aufrance \u2795 34 Untitled by James Oliver \u2794 35 Desert Villanelle by Christopher Harnish \u2794 36 The Skull by Nicky Taylor \u2794 37 Rodeo Bar by Carl Jeffrey Boon \u2796 38 I, Mordred by Carey Christie \u2795 39-43 Between Centuries by Leslie Dana Wells \u2794 44-45 Untitled by Carrie Horner \u2797 45 Untitled by Alex Emmons \u2796 46 Coleridge\u27s Curse by Allison Lemieux \u2795 47 Untitled by Jenny Baker \u2794 48 five by Jeremy Aufrance \u2795 49 Untitled by James Oliver \u2794 50 Lobster Boy by Kirstin Rogers \u2794 51 Fire on the Mountain by Christopher Harnish \u2794 52-53 Yosemite by Morgan Roper \u2794 54 Untitled by Carrie Horner \u2797 54 Untitled by Ken Tyburski \u2794 55 Sleepless Nights Fades to Credits by Allison Lemieux \u2794 56 Dancing Days by Julie McDonald \u2794 57 Immobile by Adrienne Fair \u2796 58-59 Untitled by Kira Pollack \u2794 60 Dorm Fire by Lisa Marie Antonille \u2795 Untitled by Carrie Horner \u2797 61 The Book by Matt Wanat \u2795 62-63 Distance by Carl Jeffrey Boon \u2796 64 Untitled by Jenny Baker \u2794 65 Cover by Ken Tyburski \u2794 Editorial decision is shared equally among the Editorial Board. -6

Learning a peptide-protein binding affinity predictor with kernel ridge regression

We propose a specialized string kernel for small bio-molecules, peptides and pseudo-sequences of binding interfaces. The kernel incorporates physico-chemical properties of amino acids and elegantly generalize eight kernels, such as the Oligo, the Weighted Degree, the Blended Spectrum, and the Radial Basis Function. We provide a low complexity dynamic programming algorithm for the exact computation of the kernel and a linear time algorithm for it's approximation. Combined with kernel ridge regression and SupCK, a novel binding pocket kernel, the proposed kernel yields biologically relevant and good prediction accuracy on the PepX database. For the first time, a machine learning predictor is capable of accurately predicting the binding affinity of any peptide to any protein. The method was also applied to both single-target and pan-specific Major Histocompatibility Complex class II benchmark datasets and three Quantitative Structure Affinity Model benchmark datasets. On all benchmarks, our method significantly (p-value < 0.057) outperforms the current state-of-the-art methods at predicting peptide-protein binding affinities. The proposed approach is flexible and can be applied to predict any quantitative biological activity. The method should be of value to a large segment of the research community with the potential to accelerate peptide-based drug and vaccine development.Comment: 22 pages, 4 figures, 5 table

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The Human Cell Atlas White Paper

The Human Cell Atlas (HCA) will be made up of comprehensive reference maps of all human cells - the fundamental units of life - as a basis for understanding fundamental human biological processes and diagnosing, monitoring, and treating disease. It will help scientists understand how genetic variants impact disease risk, define drug toxicities, discover better therapies, and advance regenerative medicine. A resource of such ambition and scale should be built in stages, increasing in size, breadth, and resolution as technologies develop and understanding deepens. We will therefore pursue Phase 1 as a suite of flagship projects in key tissues, systems, and organs. We will bring together experts in biology, medicine, genomics, technology development and computation (including data analysis, software engineering, and visualization). We will also need standardized experimental and computational methods that will allow us to compare diverse cell and tissue types - and samples across human communities - in consistent ways, ensuring that the resulting resource is truly global. This document, the first version of the HCA White Paper, was written by experts in the field with feedback and suggestions from the HCA community, gathered during recent international meetings. The White Paper, released at the close of this yearlong planning process, will be a living document that evolves as the HCA community provides additional feedback, as technological and computational advances are made, and as lessons are learned during the construction of the atlas

A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Purpose Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned. Methods Data from the first 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to frequency, genotype, and mode of inheritance and reinterpreted. Results We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes, or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance, or high frequency). Conclusion The “ClinVar low-hanging fruit” analysis represents an effective, fast, and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Temporal Patterns in The Risk of Chronic Health Conditions in Survivors of Childhood Cancer Diagnosed 1970-99: a report from the Childhood Cancer Survivor Study cohort.

BACKGROUND: Treatments for childhood cancer have evolved over the past 50 years, with the goal of maximising the proportion of patients who achieve long-term survival, while minimising the adverse effects of therapy. We aimed to assess incidence patterns of serious chronic health conditions in long-term survivors of childhood cancer across three decades of diagnosis and treatment. METHODS: We used data from the Childhood Cancer Survivor Study, a retrospective cohort with longitudinal follow-up of 5-year survivors of common childhood cancers (leukaemia, tumours of the CNS, Hodgkin lymphoma, non-Hodgkin lymphoma, Wilms tumour, neuroblastoma, soft tissue sarcoma, or bone tumours) who were diagnosed before the age of 21 years and from 1970 to 1999 in North America. We examined the cumulative incidence of severe to fatal chronic health conditions occurring up to 20 years post-diagnosis among survivors, compared by diagnosis decade. We used multivariable regression models to estimate hazard ratios per diagnosis decade, and we added treatment variables to assess whether treatment changes attenuated associations between diagnosis decade and chronic disease risk. FINDINGS: Among 23 601 survivors with a median follow-up of 21 years (IQR 15-25), the 20-year cumulative incidence of at least one grade 3-5 chronic condition decreased significantly from 33·2% (95% CI 32·0-34·3) in those diagnosed 1970-79 to 29·3% (28·4-30·2; p\u3c0·0001) in 1980-89, and 27·5% (26·4-28·6; p=0·012 vs 1980-89) in 1990-99. By comparison, the 20-year cumulative incidence of at least one grade 3-5 condition in 5051 siblings was 4·6% (95% CI 3·9-5·2). The 15-year cumulative incidence of at least one grade 3-5 condition was lower for survivors diagnosed 1990-99 compared with those diagnosed 1970-79 for Hodgkin lymphoma (17·7% [95% CI 15·0-20·5] vs 26·4% [23·8-29·1]; p\u3c0·0001), non-Hodgkin lymphoma (16·9% [14·0-19·7] vs 23·8% [19·9-27·7]; p=0.0053), astrocytoma (30·5% [27·8-33·2] vs 47·3% [42·9-51·7]; p\u3c0·0001), Wilms tumour (11·9% [9·5-14·3] vs 17·6% [14·3-20·8]; p=0·034), soft tissue sarcoma (28·3% [23·5-33·1] vs 36·5% [31·5-41·4]; p=0·021), and osteosarcoma (65·6% [60·6-70·6] vs 87·5% [84·1-91·0]; p\u3c0·0001). By contrast, the 15-year cumulative incidence of at least one grade 3-5 condition was higher (1990-99 vs 1970-79) for medulloblastoma or primitive neuroectodermal tumour (58·9% [54·4-63·3] vs 42·9% [34·9-50·9]; p=0·00060), and neuroblastoma (25·0% [21·8-28·2] vs 18·0% [14·5-21·6]; p=0·0045). Results were consistent with changes in treatment as a significant mediator of the association between diagnosis decade and risk of grade 3-5 chronic conditions for astrocytoma (HR per decade without treatment in the model = 0·77, 95% CI 0·64-0·92; HR with treatment in the model=0·89, 95% CI 0·72-1·11; p=0·0085) and Hodgkin lymphoma (HR without treatment=0·75, 95% CI 0·65-0·85; HR with treatment=0·91, 95% CI 0·73-1·12; p=0·024). Temporal decreases in 15-year cumulative incidence comparing survivors diagnosed 1970-79 to survivors diagnosed 1990-99 were noted for endocrinopathies (5·9% [5·3-6·4] vs 2·8% [2·5-3·2]; p\u3c0·0001), subsequent malignant neoplasms (2·7% [2·3-3·1] vs 1·9% [1·6-2·2]; p=0·0033), musculoskeletal conditions (5·8% [5·2-6·4] vs 3·3% [2·9-3·6]; p\u3c0·0001), and gastrointestinal conditions (2·3% [2·0-2·7] vs 1·5% [1·3-1·8]; p=0·00037), while hearing loss increased (3·0% [2·6-3·5] vs 5·7% [5·2-6·1]; p\u3c0·0001). INTERPRETATION: Our results suggest that more recently treated survivors of childhood cancer had improvements in health outcomes, consistent with efforts over the same time period to modify childhood cancer treatment regimens to maximise overall survival, while reducing risk of long-term adverse events. Continuing advances in cancer therapy offer promise of further reducing the risk of long-term adverse events in childhood cancer survivors. However, achieving long-term survival for childhood cancer continues to come at a cost for many survivors, emphasising the importance of long-term follow-up care for this population. FUNDING: National Cancer Institute and the American Lebanese-Syrian Associated Charities