bluuebunny/crossref_metadata_2025_split huggingface dataset:
A highly contiguous genome assembly of the bat hawkmoth Hyles vespertilio (Lepidoptera: Sphingidae)
Authors: Pippel Martin , Jebb David , Patzold Franziska , Winkler Sylke , Vogel Heiko , Myers Gene , Hiller Michael , Hundsdoerfer Anna K 
Published: January 2020

Abstract

Background
Adapted to different ecological niches, moth species belonging to the Hyles genus exhibit a spectacular diversity of larval color patterns. These species diverged ~7.5 million years ago, making this rather young genus an interesting system to study a wide range of questions including the process of speciation, ecological adaptation, and adaptive radiation.

Results
Here we present a high-quality genome assembly of the bat hawkmoth Hyles vespertilio, the first reference genome of a member of the Hyles genus. We generated 51× Pacific Biosciences long reads with an average read length of 8.9 kb. Pacific Biosciences reads longer than 4 kb were assembled into contigs, resulting in a 651.4-Mb assembly consisting of 530 contigs with an N50 value of 7.5 Mb. The circular mitochondrial contig has a length of 15,303 bp. The H. vespertilio genome is very repeat-rich and exhibits a higher repeat content (50.3%) than other Bombycoidea species such as Bombyx mori (45.7%) and Manduca sexta (27.5%). We developed a comprehensive gene annotation workflow to obtain consensus gene models from different evidence including gene projections, protein homology, transcriptome data, and ab initio predictions. The resulting gene annotation is highly complete with 94.5% of BUSCO genes being completely present, which is higher than the BUSCO completeness of the B. mori (92.2%) and M. sexta (90%) annotations.

Conclusions
Our gene annotation strategy has general applicability to other genomes, and the H. vespertilio genome provides a valuable molecular resource to study a range of questions in this genus, including phylogeny, incomplete lineage sorting, speciation, and hybridization. A genome browser displaying the genome, alignments, and annotations is available at https://genome-public.pks.mpg.de/cgi-bin/hgTracks?db=HLhylVes1.
Compartment and hub definitions tune metabolic networks for metabolomic interpretations
Authors: Waller T Cameron , Berg Jordan A , Lex Alexander , Chapman Brian E , Rutter Jared 
Published: January 2020

Abstract

Background
Metabolic networks represent all chemical reactions that occur between molecular metabolites in an organism's cells. They offer biological context in which to integrate, analyze, and interpret omic measurements, but their large scale and extensive connectivity present unique challenges. While it is practical to simplify these networks by placing constraints on compartments and hubs, it is unclear how these simplifications alter the structure of metabolic networks and the interpretation of metabolomic experiments.

Results
We curated and adapted the latest systemic model of human metabolism and developed customizable tools to define metabolic networks with and without compartmentalization in subcellular organelles and with or without inclusion of prolific metabolite hubs. Compartmentalization made networks larger, less dense, and more modular, whereas hubs made networks larger, more dense, and less modular. When present, these hubs also dominated shortest paths in the network, yet their exclusion exposed the subtler prominence of other metabolites that are typically more relevant to metabolomic experiments. We applied the non-compartmental network without metabolite hubs in a retrospective, exploratory analysis of metabolomic measurements from 5 studies on human tissues. Network clusters identified individual reactions that might experience differential regulation between experimental conditions, several of which were not apparent in the original publications.

Conclusions
Exclusion of specific metabolite hubs exposes modularity in both compartmental and non-compartmental metabolic networks, improving detection of relevant clusters in omic measurements. Better computational detection of metabolic network clusters in large data sets has potential to identify differential regulation of individual genes, transcripts, and proteins.
Negative evidence for a role of APH1B T27I variant in Alzheimer’s disease
Authors: Zhang Xulun , Zhang Can , Prokopenko Dmitry , Liang Yingxia , Han Weinong , Tanzi Rudolph E , Sisodia Sangram S 
Published: January 2020

Abstract
γ-secretase is a macromolecular complex that catalyzes intramembranous hydrolysis of more than 100 membrane-bound substrates. The complex is composed of presenilin (PS1 or PS2), anterior pharynx defect-1 (APH-1), nicastrin (NCT) and PEN-2 and early-onset; autosomal dominant forms of Alzheimer’s disease (AD) are caused by inheritance of mutations of PS. No mutations in genes encoding NCT, or PEN-2 have been identified to date that cause AD. In this regard, a large genetic meta-analysis of four cohorts consisting of more than 600 000 individuals identified a common missense variant, rs117618017 in the APH1B gene that results in a T27I mutation, as a novel genome-wide significant locus. In order to confirm the findings that rs117618017 is associated with risk of AD, we performed a genetic screen from deep whole genome sequencing of the large NIMH family-based Alzheimer’s Disease (AD) dataset. In parallel, we sought to uncover potential molecular mechanism(s) by which APH-1B T27I might be associated with AD by generating stable HEK293 cell lines, wherein endogenous APH-1A and APH-1B expression was silenced and into which either the wild type APH-1B or the APH-1B T27I variant was stably expressed. We then tested the impact of expressing either the wild type APH-1B or the APH-1B T27I variant on γ-secretase processing of human APP, the murine Notch derivative mNΔE and human neuregulin-1. We now report that we fail to confirm the association of rs1047552 with AD in our cohort and that cells expressing the APH-1B T27I variant show no discernable impact on the γ-secretase processing of established substrates compared with cells expressing wild-type APH-1B.
P097 FAVORABLE SAFETY PROFILE FOR AMISELIMOD, A SELECTIVE S1P RECEPTOR MODULATOR, IN CROHN’S DISEASE
Authors: D’Haens Geert R A M , Slatkin Neal , Israel Robert , Heimanson Zeev 
Published: January 2020

Abstract

Background
Sphingosine 1-phosphate (S1P) receptor modulators are being developed to treat autoimmune-mediated diseases, including ulcerative colitis (UC) and Crohn’s disease (CD). Amiselimod (AMS), a second-generation S1P receptor modulator, was developed to reduce bradycardia associated with other S1P receptor modulators, including fingolimod.

Methods
This multicenter, randomized, double-blind, parallel group, placebo (PBO)-controlled (DBPC) phase 2a clinical trial in adults with moderate to severe active CD evaluated the safety and efficacy of oral AMS 0.4 mg/d for 14 wks, followed by open-label extension (OLE) of AMS for ≤36 wks. Patients were required to have used corticosteroids, immunosuppressants, or anti-TNF-α agents for CD treatment. The primary efficacy endpoint was a 100-point drop at wk 12 in the Crohn’s Disease Activity Index.

Results
Of the 78 patients randomized 1:1 to receive AMS (n=40) or PBO (n=38), 78% [n=61] completed the DBPC phase. Of those continuing into the OLE, 26 (AMS/AMS [n=14]; PBO/AMS [n=12]) completed it. AMS 0.4 mg for 12 wks did not have a significant effect on clinical disease activity (CDA) in CD. At least 1 treatment-related adverse event (TRAE) was reported by 31% receiving AMS and 24% receiving PBO; the most frequently reported TREAs for AMS were skin and subcutaneous tissue disorders (10%), infections and infestations, musculoskeletal and connective tissue disorders, nervous system disorders, and cardiac disorders (all 8%). Five serious AEs (SAEs) led to treatment discontinuation (1 in the PBO group; 4 in the AMS group). In the OLE, more PBO/AMS patients (40%) vs AMS/AMS (33%) reported TRAEs; most frequent TRAEs for AMS/AMS were blood and lymphatic system disorders (14%) and investigations (14%). Of 13 SAEs reported by 9 patients, 2 treatment-related SAEs (1 in the PBO/AMS group) led to treatment discontinuation. In the DBPC study, cardiac disorders, all mild, were reported in 3 in the AMS group vs 1 in the PBO group; in the OLE, cardiac disorders were reported by 1 in the AMS group and 1 in the PBO group. There were no clinically significant reports of bradycardia, ventricular tachycardia, or atrioventricular block in the AMS group in either study. In the DBPC study, macular edema (ME) was confirmed in 1 AMS patient (mild/nonserious); none were reported in the OLE. There were no deaths, opportunistic infections, clinically significant negative laboratory or abnormal ECG findings after AMS treatment.

Conclusions
Oral AMS 0.4 mg was generally well tolerated, with no new safety concerns identified. Other than 1 patient with mild ME, there were no other findings related to the known AMS risk profile. While AMS did not have an effect on CDA in previously treated CD, this favorable safety profile, including no clinically significant reports of bradycardia, is promising for treatment of other autoimmune-mediated diseases, including UC.
P098 FROM OLD BUMP TO BONE INFECTION: A CASE OF BRODIE’S ABSCESS IN A CROHN’S PATIENT
Authors: Marston John , Chapman J C , Hamer Diana 
Published: January 2020

Abstract

Introduction
Brodie’s abscess is an uncommon variant of subacute osteomyelitis leading to a contained infectious focus within a bone. It classically occurs in young people with a history of trauma to the affected bone. We present a case of a Brodie’s abscess in a 52-year-old Crohn’s patient on dual immunosuppressive therapy.

Case Description
A 52 year old man with Crohn’s disease managed with adalimumab and methotrexate presented to an orthopedist with worsening left hip and thigh pain and fevers over the week prior. He reported a remote sports-related injury to the same region with mild pain intermittently over the subsequent years. MRI of the left pelvis showed an enhancing lesion of the anterior superior iliac spine with cortical erosion. He was admitted and started on broad spectrum antibiotics, and his immunosuppressive agents were held. CT-guided biopsy of the lesion returned as abscess, and culture of the lesion grew methicillin-sensitive staphylococcus aureus. The abscess was debrided in the OR and he completed a 6-week course of culture-guided antibiotic therapy.

Discussion
To our knowledge this is the first reported case of Brodie’s abscess associated with Crohn’s disease and dual immunosuppressive therapy. Opportunistic pathogens are most often associated with anti-TNFα therapy, though there is also evidence other bacterial infections are more frequent in these patients, particularly salmonellosis, listeriosis, and pneumococcal disease. Patients on anti-TNFα therapy appear to be at highest risk for serious infections in the first six months after initiation, but it is unclear if there is a persistent or cumulative risk with long-term therapy. The underlying mechanism of immunosuppression in anti-TNFα therapy is thought to be multifactorial, impacting both innate and adaptive immunity. Data suggests increased risk of infection in rheumatoid arthritis patients taking methotrexate. Only observational data exists regarding infection risk in Crohn’s patients on methotrexate, but it is reasonable to infer that it may have played a role in our patient’s presentation. Bone trauma seems to be associated with the development of Brodie’s abscess, and our patient reported a long history of chronic left hip and thigh pain due to a remote sports-related injury to that region. The source of his infection was most likely transient bacteremia, which seeded this nidus in his anterior superior iliac spine. While causation cannot be determined, this interesting case serves as reminder to prescribers of dual immunosuppressive therapy to be cognizant of infectious complications outside of those commonly attributed.
P099 LEUKOCYTOCLASTIC VASCULITIS AFTER USTEKINUMAB INDUCTION IN CROHN’S DISEASE: A CASE SERIES AND SYSTEMATIC REVIEW
Authors: Chugh Rishika , Proctor Deborah , Little Alicia , Myung Peggy , Imaeda Suguru , Al-Bawardy Badr 
Published: January 2020

Abstract
Ustekinumab (UST) is an effective treatment for Crohn’s disease (CD). Here we present two cases of leukocytoclastic vasculitis (LCV) in CD patients after UST induction therapy with a review of the literature.
Patient #1: A 26 year old woman with a 14 year history of Crohn’s ileocolitis. She was previously treated with 6-mercaptopurine, infliximab, and vedolizumab without durable response. She ultimately underwent a left hemicolectomy due to development of a sigmoid stricture and was started on UST postoperatively. Thirty-six days after her initial UST intravenous (IV) infusion of 390 milligrams (mg) she developed new partially blanching, erythematous, non-tender, non-pruritic macules and papules over the right medial thigh, which later evolved into palpable purpura involving both lower extremities (Figure 1A). She reported no gastrointestinal (GI) or other symptoms. White blood cell (WBC) count and metabolic panel were normal. Antinuclear antibody (ANA) titer was 1:80. Perinuclear pattern antineutrophil cytoplasmic antibodies (p-ANCA) were positive. C-reactive protein (CRP) was elevated to 41.5 mg/liter (L). One lesion was biopsied, and pathology findings were consistent with LCV (Figure 1B). She was started on colchicine 0.6 mg daily with improvement in her rash and has received her second dose of UST without further complications.
Patient #2: A 29 year old woman with a 6 year history of Crohn’s ileocolitis. Her prior treatments include budesonide, mesalamine, and infliximab. While on infliximab, she developed jejunal and ileal ulcers on video capsule endoscopy. Infliximab was discontinued, and UST was started. Three months following initial IV induction therapy of UST, she developed pink purpuric papules and hemorrhagic vesicles involving her bilateral shins, dorsal feet, calves, and bilateral extensor forearms. The appearance of the rash was consistent with LCV (Figure 2). She was started on prednisone at 60 mg daily for 1 week with taper resulting in complete resolution of her rash. UST was continued with no recurrence. WBC count and metabolic panel were normal. ANCA was negative, and ANA titer was 1:80. CRP was elevated to 13.2 mg/L.
Literature review revealed only one prior published case report of a patient with inflammatory bowel disease developing LCV after administration of UST. In this case, UST was discontinued since re-administration caused the rash to return. Here we have two patients who developed LCV soon after initiating UST therapy, although after treatment with prednisone/colchicine, there was no recurrence with continuing UST. It is possible to develop LCV in association with CD alone; however, these patients had longstanding disease without occurrence of LCV until being started on UST. Moreover, patient #1, was in remission from a Crohn’s disease standpoint at the time of UST initiation and onset of the rash.
P100 REAL-WORLD COMPARISON OF ARTHRALGIAS WITH INFLIXIMAB VS. VEDOLIZUMAB IN THE TREATMENT OF BIO-NAIVE INFLAMMATORY BOWEL DISEASE
Authors: Ritter Timothy , Fourment Chris , Kuten Samantha , Van Anglen Lucinda 
Published: January 2020

Abstract

Background
Both infliximab (IFX) and vedolizumab (VDZ) are approved for the treatment of inflammatory bowel disease (IBD) in adults. VDZ is gut-specific and thought to be less effective in controlling extraintestinal manifestations than IFX. The purpose of this study was to compare the incidence and timing of arthralgias between IFX and VDZ.

Methods
We performed a retrospective cohort study of bio-naïve adult patients treated with IFX or VDZ for ulcerative colitis (UC) or Crohn’s disease (CD) at a large multicenter gastroenterology private practice. Patients were case-matched 1:1 based on age, gender, diagnosis, and baseline disease severity using the partial Mayo (pMayo) for UC and the modified Harvey-Bradshaw Index (mHBI) for CD. Arthralgias were captured out to 12 months of therapy and classified as pre-existing or new-onset based on time to occurrence. Those with pre-existing arthralgias were excluded from new-onset arthralgias analyses. Rates of arthralgias and time to new-onset arthralgias were compared between IFX and VDZ patients.

Results
A total of 77 IFX (58 UC, 19 CD) and 77 VDZ (58 UC, 19 CD) case-matched pairs were generated. Baseline demographics were similar between IFX and VDZ groups: mean age 45±16.9 vs 46±16.2, male gender 60% vs 61%. Rates of pre-existing arthralgias were 13/77 (17%) and 12/77 (16%) in IFX and VDZ cohorts (p=0.83), respectively. Resolution of pre-existing arthralgias was also similar between groups (6/13 vs 7/12, p=0.70). Of the remaining 64 IFX and 65 VDZ patients without arthralgias at baseline, 16 (25%) IFX patients and 17 (26%) VDZ patients experienced new-onset arthralgias (p=1.0). Median time to new-onset arthralgias was 5.0 (IQR 3.4–7.0) months in IFX patients, compared to 3.3 (IQR 1.4–5.3) months in VDZ patients (p=0.15). While VDZ patients appeared to develop new-onset arthralgias earlier, this was not significant (p=0.20) [Figure 1]. Of note, two IFX patients discontinued therapy due to suspected drug-induced lupus with arthralgias; there were no VDZ discontinuations due to arthralgias.

Conclusions
Our data suggests that resolution of pre-existing arthralgias and new-onset arthralgias are similar, despite the gut selectivity of VDZ compared to IFX. Additionally, there was no difference in overall time to new-onset arthralgias. These data need to be verified in a larger cohort.
P153 MET642, AN ORAL FXR AGONIST, IMPROVES COLITIS INDUCED BY ADOPTIVE T-CELL TRANSFER
Authors: Liu Xueqing , O’Connell Robert , Bendele Alison , Walker Melissa , Ohlsen Connor , Govek Steve , Nagasawa Johnny , Douglas Karensa , Milik Angelica , Lu Nhin , Qian Jing , Ortiz Alvaro , Chai Pauline , Zook Douglas , Lee Kyoung-Jin , Smith Nicholas , Wagner Brandee , Song Ken 
Published: January 2020

Abstract

Introduction
Farnesoid X receptor (FXR) is a ligand-activated nuclear hormone receptor expressed in the gastrointestinal tract, with high expression levels in the intestinal epithelium. Previously we have shown that FXR agonists with sustained activity decreased colitis in multiple chronic IBD models (i.e. Adoptive transfer colitis, Mdr1a-/- colitis, and SAMP1/YitFc ileitis). Because FXR agonists are dosed orally and do not have systemic immunosuppressive properties, they represent a novel and differentiated therapeutic approach for IBD. MET642 is an optimized, potent non-bile acid FXR agonist with sustained FXR activation. In this study, we examined the efficacy of MET642 in therapeutic treatment mode in adoptive T-cell transfer model.

Methods
Colitis was induced by transplanting CD4+CD45RBhi T-cells to recipient C.B-17 SCID mice. Body weights were monitored throughout study duration. Staring 21 days after T-cell transfer, mice were treated with vehicle (n=10), MET642 (0.1, 0.3 or 1 mg/kg p.o., daily, n=10), or anti-IL-12p40 (neutralizing both IL-12 and IL-23, 0.5mg/mouse, i.p., weekly, n=5) for 4 weeks. Terminal endpoints included colon weight to length ratio (W/L), colon histopathology and gene expression. Histopathology scores were determined for inflammation, erosion, gland loss and hyperplasia, each with a score of 0–5, and cumulative sum score of 0–20.

Results
CD4+CD45RBhi T-cell transfer led to a significant reduction in body weight and increase in colon W/L ratio; both were reversed by MET642 and anti-IL-12p40. All dose levels of MET642 significantly improved the histopathology sum score relative to vehicle treatment, with maximal efficacy reached at 0.3mg/kg. Similar to anti-IL-12p40, MET642 showed improvements across all individual histopathology endpoints. Gene expression analysis suggests FXR activation increases anti-microbial activity, improves gut barrier and transporter function, and suppresses inflammation.

Conclusion
MET642, an oral once daily FXR agonist, significantly improved colitis in the adoptive T-cell transfer model. Activation of FXR by MET642 potentially promotes pathways of gut anti-microbial function, barrier function, and suppression of inflammation. These findings support further development of MET642 as a novel oral therapeutic for treating IBD.
P094 A COMPARISON OF EXERCISE MEASURES AMONG ADULTS WITH INFLAMMATORY BOWEL DISEASE
Authors: Davis Suja , Melendez Carlos , Crane Patricia , Long Millie 
Published: January 2020

Abstract

Background
Individuals with IBD, comprised of Crohn’s disease (CD) and Ulcerative Colitis (UC), often have ongoing gastrointestinal symptoms that limit their ability to exercise. Importantly, exercise can help to maintain remission in individuals with IBD. Other positive health outcomes of exercise include improvement in quality of life, social and psychological well-being, weight maintenance, bone health, fatigue management and maintaining muscle mass and function. Unfortunately, many of the tools used to measure exercise are burdensome for clinical utility or are not applicable to the IBD population. The purpose of this secondary analysis was to determine if one question related to physical activity would capture exercise in adults with either UC or CD and those with active or inactive disease.

Methods
This study is a cross-sectional study using the data obtained from IBD Partners, an internet-based longitudinal cohort of adults ≥ 18 year of age living with IBD. This secondary analysis includes only those participants without a current ostomy or pouch, who completed demographic information, disease activity and exercise characteristics. Disease activity was measured via the simple clinical colitis activity index (SCCAI) for UC and the short Crohn’s disease activity index (sCDAI) for CD. Exercise was measured via the Godin Leisure -Time Activity Index (GLTA) questionnaire that assessed type of exercise and intensity for the past seven days. A separate measurement of physical activity included a single question: “How often did you participate in 1 or more physical activities of 20–30 minutes’ duration per session during your leisure time within the past 6 months?” measured via a 6-point ordered category item.

Results
A total of 8327 patients with IBD were included. Most (63%) of the participants had CD, and 54% were in remission. Majority of the participants were physically active based on GLTA scores (49.7%), and one question physical activity scores (62%; combined scores of 5 & 6). Polychoric correlation coefficient was computed, with a strong correlation between GLTA and the one question (r = 0.74, p &lt; 0.001). Ordinal regression analysis between the one physical activity question and IBD type (UC vs CD) yielded higher odds of physical activity with UC (Odds ratio (OR)=1.2, 95% CI [1.11 -1.31], p &lt; 0.0001). Similar results were noted with ordinal regression analysis between GLTA scores and UC;(OR=1.2, 95% CI [1.09 -1.3], p &lt; 0.0001).

Conclusions
Both GLTA and the single question of physical activity were highly correlated. The ordinal regression results were comparable for both measures. Adoption of the single physical activity question may adequately reflect exercise status in IBD patients and reduce burden for clinical use. Further longitudinal studies are need to support the use of one question in measuring exercise in those with IBD.