tbuckley/cabot-search huggingface dataset:
Signals of Variation in Human Mutation Rate at Multiple Levels of Sequence Context
Authors: Rachael C Aikens, Kelsey E Johnson, Benjamin F Voight
Journal: Molecular Biology and Evolution (2019)

Our understanding of the human mutation rate helps us build evolutionary models and interpret patterns of genetic variation observed in human populations. Recent work indicates that the frequencies of specific polymorphism types have been elevated in Europe, and that many more, subtler signatures of global polymorphism variation may yet remain unidentified. Here, we present an analysis of the 1000 Genomes Project supported by analysis in the Simons Genome Diversity Panel, suggesting additional putative signatures of mutation rate variation across populations and the extent to which they are shaped by local sequence context. First, we compiled a list of the most significantly variable polymorphism types in a cross-continental statistical test. Clustering polymorphisms together, we observe three sets that showed distinct shared patterns of relative enrichment among ancestral populations, and we characterize each one of these putative "signatures" of polymorphism variation. For three of these signatures, we found that a single flanking base pair of sequence context was sufficient to determine the majority of enrichment or depletion of a polymorphism type. However, local genetic context up to 2-3 bp away contributes additional variability and may help to interpret a previously noted enrichment of certain polymorphism types in some East Asian groups. Moreover, considering broader local genetic context highlights patterns of polymorphism variation, which were not captured by previous approaches. Building our understanding of mutation rate in this way can help us to construct more accurate evolutionary models and better understand the mechanisms that underlie genetic change.
Host Range and Genetic Plasticity Explain the Coexistence of Integrative and Extrachromosomal Mobile Genetic Elements
Authors: Jean Cury, Pedro H Oliveira, Fernando de la Cruz, Eduardo P C Rocha
Journal: Molecular Biology and Evolution (2018)

Self-transmissible mobile genetic elements drive horizontal gene transfer between prokaryotes. Some of these elements integrate in the chromosome, whereas others replicate autonomously as plasmids. Recent works showed the existence of few differences, and occasional interconversion, between the two types of elements. Here, we enquired on why evolutionary processes have maintained the two types of mobile genetic elements by comparing integrative and conjugative elements (ICE) with extrachromosomal ones (conjugative plasmids) of the highly abundant MPFT conjugative type. We observed that plasmids encode more replicases, partition systems, and antibiotic resistance genes, whereas ICEs encode more integrases and metabolism-associated genes. ICEs and plasmids have similar average sizes, but plasmids are much more variable, have more DNA repeats, and exchange genes more frequently. On the other hand, we found that ICEs are more frequently transferred between distant taxa. We propose a model where the different genetic plasticity and amplitude of host range between elements explain the co-occurrence of integrative and extrachromosomal elements in microbial populations. In particular, the conversion from ICE to plasmid allows ICE to be more plastic, while the conversion from plasmid to ICE allows the expansion of the element's host range.
THU0499 RISK FACTORS FOR SHOULDER PAIN PERSISTENCE IN ROTATOR CUFF DISORDERS
Authors: Sandica Albina, Ana-Maria Ramazan
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> A large proportion of patients with atraumatic painful shoulder have an unfavorable outcome with long-term disability (1). Predictors of no recovery in patients with shoulder disorders were identified previously: repetitive overhead activity in sport and work (2) duration of complaints, somatization, low social support, older age, unemployment, musculoskeletal comorbidity, recurrent complaint (3,4). <h3>Objectives</h3> To identify the risk factors for over 6 mounth pain persistence in patients with rotator cuff disorders <h3>Methods</h3> Our prospective study included 51 hospitalized patients with atraumatic shoulder pain. The assessment was clinical and shoulder MRI for confirmation of rotator cuff disorders. We have studied the influence of the patient's characteristics and the influence of the condition's characteristics for pain persistence. Statistical analysis was performed in SPSS-18, p&lt;0.05 was significant. <h3>Results</h3> No significant correlations were found between pain persistence and age, gender, smoking status, occupational overuse, physical demands before the onset of pain, marital status, continuous pain, lesions on shoulder MRI. The association with the following elements is statistically significant for pain persistence: opposite shoulder previously affected (p=0.01), diabetes mellitus(p=0.04), insidious onset(p=0.004), the high educational level(p=0.02), physical therapy(p=0.03), local injection (p=0.08). Using multinominal regression we observed only acute onset of the pain shoulder (RR=7.1) and physiotherapy treatment (RR=0.1) with p=0.026. <h3>Conclusion</h3> The factors that determine the shoulder pain persistence are non-specific and can be sometimes psyhosocial, local, physical or other comorbidities like diabetes. <h3>References</h3> [1] Herin F et al. Predictors of chronic shoulder pain after 5 years in a working population. Pain. Volume 153, Issue 11, Pages 2253-2259, November 2012 [2] Coggon D., Ntani G., Vargas-Prada S., et al. International variation in absence from work attributed to musculoskeletal illness: findings from the CUPID study. Occup Environ Med. 2013 Aug;70(8):575-84. [3] Keijsers E et al. Psychosocial factors predicted nonrecovery in both specific and nonspecific diagnoses at arm, neck, and shoulder. J Clin Epidemiol. 2010 Dec;63(12):1370-9; [4] Feleus A et al. Prognostic indicators for non-recovery of non-traumatic complaints at arm, neck and shoulder in general practice—6 months follow-up. Rheumatology 2007;46:169–176 <h3>Disclosure of Interests</h3> None declared
Assessment of Vitreous Structure and Visual Function after Neodymium:Yttrium–Aluminum–Garnet Laser Vitreolysis
Authors: Justin H. Nguyen, Jeannie Nguyen-Cuu, Fei Yu, Kenneth M. Yee, Jonathan Mamou, Ronald H. Silverman, Jeffrey Ketterling, J. Sebag
Journal: Ophthalmology (2019)
Evolution of Portulacineae Marked by Gene Tree Conflict and Gene Family Expansion Associated with Adaptation to Harsh Environments
Authors: Ning Wang, Ya Yang, Michael J Moore, Samuel F Brockington, Joseph F Walker, Joseph W Brown, Bin Liang, Tao Feng, Caroline Edwards, Jessica Mikenas, Julia Olivieri, Vera Hutchison, Alfonso Timoneda, Tommy Stoughton, Raúl Puente, Lucas C Majure, Urs Eggli, Stephen A Smith
Journal: Molecular Biology and Evolution (2018)

Several plant lineages have evolved adaptations that allow survival in extreme and harsh environments including many families within the plant clade Portulacineae (Caryophyllales) such as the Cactaceae, Didiereaceae, and Montiaceae. Here, using newly generated transcriptomic data, we reconstructed the phylogeny of Portulacineae and examined potential correlates between molecular evolution and adaptation to harsh environments. Our phylogenetic results were largely congruent with previous analyses, but we identified several early diverging nodes characterized by extensive gene tree conflict. For particularly contentious nodes, we present detailed information about the phylogenetic signal for alternative relationships. We also analyzed the frequency of gene duplications, confirmed previously identified whole genome duplications (WGD), and proposed a previously unidentified WGD event within the Didiereaceae. We found that the WGD events were typically associated with shifts in climatic niche but did not find a direct association with WGDs and diversification rate shifts. Diversification shifts occurred within the Portulacaceae, Cactaceae, and Anacampserotaceae, and whereas these did not experience WGDs, the Cactaceae experienced extensive gene duplications. We examined gene family expansion and molecular evolutionary patterns with a focus on genes associated with environmental stress responses and found evidence for significant gene family expansion in genes with stress adaptation and clades found in extreme environments. These results provide important directions for further and deeper examination of the potential links between molecular evolutionary patterns and adaptation to harsh environments.
PF619 LENALIDOMIDE IN COMBINATION WITH DEXAMETHASONE AS FIRST‐LINE THERAPY IN TRANSPLANT‐INELIGIBLE PATIENTS WITH MULTIPLE MYELOMA: INTERIM RESULTS OF THE OBSERVATIONAL STUDY FIRST‐NIS
Authors: H. Nückel, H.‐J. Hurtz, H. Schulz, M. Schulze, M. Koenigsmann, T. Dechow, M. Merling, L. Houet, C. Vannier, K. Potthoff
Journal: HemaSphere (2019)

Background: The lenalidomide‐dexamethasone (Rd) combination is a non‐alkylator‐based oral first‐line treatment option in transplant‐ineligible patients (pts) with multiple myeloma (MM). Approval of this regimen was based on the results of the pivotal phase III FIRST trial comparing Rd to the melphalan‐prednisone‐thalidomide (MPT) combination. Median OS was 10 months longer with Rd continuous versus MPT (Facon T et al., Blood 2018). Real‐world effectiveness and safety data of this commonly used first‐line treatment approach in the elderly population are still scarce. Aims: The focus of the first interim analysis is to evaluate baseline characteristics and early evidence for safety and effectiveness of first‐line Rd therapy documented in a real‐world patient population. Methods: The prospective, multicenter, non‐interventional, observational FIRST‐NIS study was designed to collect data on 167 pts with multiple myeloma receiving Rd as first‐line therapy from about 50 sites across Germany. Primary objective was to evaluate effectiveness of Rd assessed by 24‐month progression‐free survival (PFS) rate. Secondary endpoints included overall survival (OS), PFS, objective response rate (ORR), duration of response (DOR), quality of life (QoL) and safety. Descriptive statistics were used to analyze the data. The prespecified interim analysis was performed 24 months after the enrollment of the 50 th patient. Results: At the cut‐off date of the interim analysis (July 3rd, 2018), 167 pts had been enrolled. Thereof, 155 pts qualified for effectiveness analysis and 159 pts for safety analysis. Baseline characteristics of all pts and of pts stratified by age (≤ 75 years, &gt; 75 years) are presented (Table 1). The ORR was 53.5% in all pts, 60.9% in pts ≤ 75 years and 50.5% in pts &gt; 75 years. 52.8% of pts developed grade 3/4 adverse events (AEs). Grade 3/4 AEs that occurred in at least 5% of pts were anemia (n = 9, 5.7%) and pneumonia (n = 8, 5.0%). Summary/Conclusion: The preliminary data of this interim analysis demonstrate a favorable risk‐benefit profile of Rd in the real‐world setting. Rd seems to be a reasonable first‐line treatment option that can also be provided to elderly pts &gt; 75 years. The ORR results at this early analysis, however, are inferior compared to the outcomes of the pivotal phase III FIRST trial. One reason might be the high proportion of pts aged &gt; 75 years in the FIRST‐NIS, i.e. 70% versus 35% in the FIRST trial. Results need to be confirmed in the final analysis. image
Is TAFRO syndrome a subtype of idiopathic multicentric Castleman disease?
Authors: Shino Fujimoto, Tomoyuki Sakai, Hiroshi Kawabata, Nozomu Kurose, Sohsuke Yamada, Kazue Takai, Sadao Aoki, Junya Kuroda, Makoto Ide, Keigo Setoguchi, Norifumi Tsukamoto, Haruka Iwao‐Kawanami, Takafumi Kawanami, Shuichi Mizuta, Toshihiro Fukushima, Yasufumi Masaki
Journal: American Journal of Hematology (2019)

Abstract Castleman disease (CD) is a rare lymphoproliferative disorder that can be unicentric or multicentric. Multicentric CD (MCD) is further subdivided into human herpesvirus type‐8‐associated, POEMS syndrome‐associated, and idiopathic (iMCD). TAFRO syndrome is a newly identified disorder of unknown etiology characterized by t hrombocytopenia, a nasarca, f ever, r eticulin myelofibrosis, renal dysfunction, and o rganomegaly. The TAFRO syndrome is sometimes regarded as a subtype of iMCD (TAFRO‐iMCD), whereas iMCD without TAFRO syndrome is considered “not otherwise specified” (iMCD‐NOS). However, a proportion of patients with TAFRO syndrome have been diagnosed without lymph node biopsies (TAFRO syndrome without proven iMCD; TAFRO‐w/op‐iMCD). To clarify the clinical features of iMCD‐NOS, TAFRO‐iMCD, and TAFRO‐w/op‐iMCD, we retrospectively analyzed 220 patients extracted from the database of the Multicenter Collaborative Retrospective Study for Establishing the Concept of TAFRO Syndrome. The patients included 87 with iMCD‐NOS, 63 with TAFRO‐iMCD, and 19 with TAFRO‐w/op‐iMCD. Patients in all three groups exhibited anemia, hypoalbuminemia, and elevated serum C‐reactive protein and interleukin‐6 levels. No significant differences in clinical, laboratory, and prognostic features were noted between the TAFRO‐iMCD, and TAFRO‐w/op‐iMCD groups. However, the iMCD‐NOS group exhibited polyclonal hyper‐γ‐globulinemia. The five‐year survival rates of patients in the iMCD‐NOS and TAFRO‐involved groups were 100% and 66.5%, respectively (dropping markedly during the first few months in the latter). The iMCD‐NOS and the TAFRO‐iMCD samples typically showed plasma cell and mixed‐type histologies, respectively. Thus, iMCD can be classified into two distinct subtypes, iMCD‐NOS and TAFRO‐iMCD. As such, TAFRO‐iMCD and TAFRO‐w/op‐iMCD may be considered the same entity, requiring prompt diagnosis and intensive care.
Transcytosis route mediates rapid delivery of intact antibodies to draining lymph nodes
Authors: Laura Kähäri, Ruth Fair-Mäkelä, Kaisa Auvinen, Pia Rantakari, Sirpa Jalkanen, Johanna Ivaska, Marko Salmi
Journal: Journal of Clinical Investigation (2019)

Lymph nodes (LNs) filter lymph to mount effective immune responses. Small soluble lymph-borne molecules from the periphery enter the draining LNs via a reticular conduit system. Intact antibodies and other larger molecules, in contrast, are physically unable to enter the conduits, and they are thought to be transported to the LNs only within migratory DCs after proteolytic degradation. Here, we discovered that lymph-borne antibodies and other large biomolecules enter within seconds into the parenchyma of the draining LN in an intact form. Mechanistically, we found that the uptake of large molecules is a receptor-independent, fluid-phase process that takes place by dynamin-dependent vesicular transcytosis through the lymphatic endothelial cells in the subcapsular sinus of the LN. Physiologically, this pathway mediates a very fast transfer of large protein antigens from the periphery to LN-resident DCs and macrophages. We show that exploitation of the transcytosis system allows enhanced whole-organ imaging and spatially controlled lymphocyte activation by s.c. administered antibodies in vivo. Transcytosis through the floor of the subcapsular sinus thus represents what we believe to be a new physiological and targetable mode of lymph filtering.
Abstract 16951: Myocyte-derived Exosomes Acutely Protect DMD-human Cardiomyocytes Against Stress-induced Injury Through a Surface Protein and ERK1/2-p38/MAPK Signaling
Authors: Melanie Gartz, Ashley Quinn, Jennifer L Strande
Journal: Circulation (2017)

Introduction: Exosomes deliver protective signaling in the heart. However, the blockade of endogenous exosome secretion improved skeletal muscle degeneration in the Duchenne muscular dystrophy (DMD...
THU0536 LONG TERM IMMUNITY IN A PAEDIATRIC COHORT OF PATIENTS WITH RHEUMATIC DISEASES FROM A TERTIARY HOSPITAL IN SPAIN
Authors: Laura Fernández Silveira, M.J Gimenez, E Andreu-Alapont, Patricia Falomir-Salcedo, E Serrano-Poveda, M.I. Gonzalez-Fernández, B Lopez-Montesinos, Inmaculada Calvo
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Pediatric patients with rheumatic diseases (RD) are at increased risk of infections. Vaccines have been proved to be very effective to prevent them. Nevertheless the long-term immunity after vaccination remains quite unknown in this group. <h3>Objectives:</h3> To comapre the long term seroprotecction in pediatric patients with rheumatic diseases who recieved measles, rubella, mumps, tetanus, diphteria, hepatitis B, hib and meningoccocus C vaccination acording to the routine immunization schedule in Spain, and healthy children. <h3>Methods:</h3> We designed a cross-sectional study including consecutive pediatric patients with RD who attended the rheumatology clinic and healthy children older than 10 y.o. The administered vaccines, treatment and pathology of each patient will be recorded. Their antibodies titters against each antigen were quantified and compared to healthy children. <h3>Results:</h3> 60 patients (median age 13 y.o IQR 10.2-12-7) and 15 healthy children (mean age 11.3 y.o. IQR 11.3-12.7) were included. In the patients group 62% were female, and 35% in healthy. Diagnosis: 85% Idiopathic juvenile arthritis, 18% Lupus or juvenile dermatomiositis. 46% had received biologic treatment sometime. Seroprotection rate was (patient vs control): measles 85%% vs 81%%, rubeola 78.8% vs 73.3%, parotiditis 84.7% vs 66.7%; VHB 27.% vs 10.5%, diphteria 89.5% vs 81%, tetanos 64.9% vs 61.1%. Hib 42% vs 53%, pneumococo 92.4% vs 100%, meningococcus C 12% vs 11%. p&gt;0.05 <h3>Conclusion:</h3> No statistical differences were detected, althought the scarce number of control subjects might have infuenced this result. There is a tendence towards a lower antibody persistence anti-Hib in patients compared to healthy children. The response to life virus vaccine and tetanus seem to be as good as in healthy chidren. <h3><b>Disclosure of Interests:</b>&nbsp;:</h3> Laura Fernández Silveira: None declared, M.J Gimenez: None declared, E Andreu-Alapont: None declared, Patricia Falomir-Salcedo: None declared, E Serrano-Poveda: None declared, M.I. Gonzalez-Fernández: None declared, B Lopez-Montesinos: None declared, Inmaculada Calvo Grant/research support from: received research grants from Pfizer, Roche, Novartis, Clementia, Sanofi, MSD, BMS and GSK, Consultant for: Advisory boards: Novartis, AbbVie, Speakers bureau: AbbVie, Roche, Novartis, SOBI&nbsp;
Single-Cell Transcriptomics Reveals Chemotaxis-Mediated Intraorgan Crosstalk During Cardiogenesis
Authors: Haiqing Xiong, Yingjie Luo, Yanzhu Yue, Jiejie Zhang, Shanshan Ai, Xin Li, Xuelian Wang, Yun-Long Zhang, Yusheng Wei, Hui-Hua Li, Xinli Hu, Cheng Li, Aibin He
Journal: Circulation Research (2019)

Rationale: We hypothesized that the differentiation processes of cardiac progenitor cell (CP) from first and second heart fields (FHF and SHF) may undergo the unique instructive gene regulatory networks or signaling pathways, and the precise SHF progression is contingent on the FHF signaling developmental cues. Objective: We investigated how the intraorgan communications control sequential building of discrete anatomic regions of the heart at single-cell resolution. Methods and Results: By single-cell transcriptomic analysis of Nkx2-5 (NK2 homeobox 5) and Isl1 (ISL LIM homeobox 1) lineages at embryonic day 7.75, embryonic day 8.25, embryonic day 8.75, and embryonic day 9.25, we present a panoramic view of distinct CP differentiation hierarchies. Computational identifications of FHF- and SHF-CP descendants revealed that SHF differentiation toward cardiomyocytes underwent numerous step-like transitions, whereas earlier FHF progressed toward cardiomyocytes in a wave-like manner. Importantly, single-cell pairing analysis demonstrated that SHF-CPs were attracted to and expanded FHF-populated heart tube region through interlineage communications mediated by the chemotactic guidance (MIF [macrophage migration inhibitory factor]-CXCR2 [C-X-C motif chemokine receptor 2]). This finding was verified by pharmacological blockade of this chemotaxis in embryos manifesting limited SHF cell migration and contribution to the growth of the outflow tract and right ventricle but undetectable effects on the left ventricle or heart tube initiation. Genetic loss-of-function assay of Cxcr2 showed that the expression domain of CXCR4 was expanded predominantly at SHF. Furthermore, double knockout of Cxcr2/Cxcr4 exhibited defective SHF development, corroborating the redundant function. Mechanistically, NKX2-5 directly bound the Cxcr2 and Cxcr4 genomic loci and activated their transcription in SHF. Conclusions: Collectively, we propose a model in which the chemotaxis-mediated intraorgan crosstalk spatiotemporally guides the successive process of positioning SHF-CP and promoting primary heart expansion and patterning upon FHF-derived heart tube initiation.
AB1098 COMPARISON OF THE PERFORMANCE OF CLASSIFICATION/DIAGNOSTIC CRITERIA FOR POLYMYALGIA RHEUMATICA. SINGLE CENTERSTUDY OF 100 PATIENTS
Authors: D. Prieto-Peña, Monica Calderón-Goercke, Miguel A. González-Gay, Ricardo Blanco
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Polymyalgia rheumatica (PMR) diagnosis is based on the combination of shoulder and pelvic girdle pain associated with elevated acute phase reactants. Traditionally, Bird et al. <sup>1</sup> and Chuang et al.<sup>2</sup> criteria have been used for establishing PMR diagnosis. In 2012 an international working group developed new European League Against Rheumatism (EULAR)/American Collegue of Rheumatology (ACR) classification criteria for PMR.<sup>3</sup> Objectives: a) To compare the performance of Bird et al., Chuang et al. and 2012 EULAR/ACR classification criteria for PMR in a single-center study. b) To describe the characteristics of the patients excluded by these criteria. <h3>Methods</h3> We included 100 patients with new-onset PMR who were consecutively diagnosed over a 7-year period by experienced rheumatologists from a single center. PMR diagnosis was confirmed during a prospective 24-months follow-up after excluding other mimicking conditions. Rheumatoid factor (RF) and anticitrullinated protein antibodies (ACPA) were determined in all patients. Subjects were classified by each of the three different criteria. <h3>Results</h3> We studied 100 patients (61 women/39 men); mean age 67.1 ± 10.2 years. 96% of the patients fulfilled Bird et. al criteria, 94% fulfilled Chuang et al. criteria and 84% of the patients fulfilled 2012 EULAR/ACR criteria (TABLE 1, 2 and 3). We assessed the characteristics of the 16 patients who did not fulfilled 2012 EULAR/ACR criteria: 6 of them were under 50 years of age (range age 43-48 years). Another 10 patients did not complain of pain/stiffness in the shoulder girdle at any time. However, they had typical inflammatory pain involving the pelvic girdle and elevated acute phase reactants. <h3>Conclusion</h3> In our single-center experience we found that 2012 EULAR/ACR criteria classified most of our patients. However, patients who presented predominant pelvic girdle affection and those who were under 50 years old despite showing all the rest of clinical and analytical required criteria were excluded. Some of these patients did fulfill Bird and/or Chuang criteria. <h3>References</h3> [1] Bird HA, et al. Ann Rheum Dis.1979;38:434-9 [2] Chuang T, et al. Ann Intern Med. 1982; 97:672-80 [3] Dasgupta B, et al. Ann Rheum Dis. 2012; 71:484-92 <h3>Disclosure of Interests</h3> D. Prieto-Peña: None declared, Monica Calderón-Goercke: None declared, Miguel A González-Gay Grant/research support from: Prof. MA Gonzalez-Gay received grants/research supports from Abbvie, MSD, Jansen and Roche., Speakers bureau: Consultation fees/participation in company sponsored speaker's bureau from Pfizer, Lilly, Sobi, Celgene, Novartis, Roche and Sanofi., Ricardo Blanco Grant/research support from: Abbvie, MSD, and Roche, Consultant for: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen, Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen