tbuckley/cabot-search huggingface dataset:
Fierce Selection and Interference in B-Cell Repertoire Response to Chronic HIV-1
Authors: Armita Nourmohammad, Jakub Otwinowski, Marta Łuksza, Thierry Mora, Aleksandra M Walczak
Journal: Molecular Biology and Evolution (2019)

During chronic infection, HIV-1 engages in a rapid coevolutionary arms race with the host's adaptive immune system. While it is clear that HIV exerts strong selection on the adaptive immune system, the characteristics of the somatic evolution that shape the immune response are still unknown. Traditional population genetics methods fail to distinguish chronic immune response from healthy repertoire evolution. Here, we infer the evolutionary modes of B-cell repertoires and identify complex dynamics with a constant production of better B-cell receptor (BCR) mutants that compete, maintaining large clonal diversity and potentially slowing down adaptation. A substantial fraction of mutations that rise to high frequencies in pathogen-engaging CDRs of BCRs are beneficial, in contrast to many such changes in structurally relevant frameworks that are deleterious and circulate by hitchhiking. We identify a pattern where BCRs in patients who experience larger viral expansions undergo stronger selection with a rapid turnover of beneficial mutations due to clonal interference in their CDR3 regions. Using population genetics modeling, we show that the extinction of these beneficial mutations can be attributed to the rise of competing beneficial alleles and clonal interference. The picture is of a dynamic repertoire, where better clones may be outcompeted by new mutants before they fix.
Challenges and Opportunities for Tobacco Control Policies in the 21st Century
Authors: Samir Soneji, Thomas A. Wills
Journal: JAMA Pediatrics (2019)

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Medical schools will need to expand further, says NHS England chief
Authors: Tom Moberly
Journal: BMJ (2019)

More medical school places will be needed as the NHS expands and more doctors seek opportunities to work flexibly, NHS England’s chief executive has told The BMJ .

In 2018 the number of medical school places available increased from 6000 a year to 7500. Speaking to The BMJ at the Health Foundation’s annual event last month, Simon Stevens said that a further expansion would be needed to meet future service demands.

“A 25% expansion in medical undergraduate intake is only the first stage,” he said. “It is unlikely to be enough. We are, I think, …
Ancient polymorphisms contribute to genome-wide variation by long-term balancing selection and divergent sorting in Boechera stricta
Authors: Baosheng Wang, Julius P. Mojica, Nadeesha Perera, Cheng-Ruei Lee, John T. Lovell, Aditi Sharma, Catherine Adam, Anna Lipzen, Kerrie Barry, Daniel S. Rokhsar, Jeremy Schmutz, Thomas Mitchell-Olds
Journal: Genome biology (2019)

Genomic variation is widespread, and both neutral and selective processes can generate similar patterns in the genome. These processes are not mutually exclusive, so it is difficult to infer the evolutionary mechanisms that govern population and species divergence. Boechera stricta is a perennial relative of Arabidopsis thaliana native to largely undisturbed habitats with two geographic and ecologically divergent subspecies. Here, we delineate the evolutionary processes driving the genetic diversity and population differentiation in this species.Using whole-genome re-sequencing data from 517 B. stricta accessions, we identify four genetic groups that diverged around 30-180 thousand years ago, with long-term small effective population sizes and recent population expansion after the Last Glacial Maximum. We find three genomic regions with elevated nucleotide diversity, totaling about 10% of the genome. These three regions of elevated nucleotide diversity show excess of intermediate-frequency alleles, higher absolute divergence (dXY), and lower relative divergence (FST) than genomic background, and significant enrichment in immune-related genes, reflecting long-term balancing selection. Scattered across the genome, we also find regions with both high FST and dXY among the groups, termed FST-islands. Population genetic signatures indicate that FST-islands with elevated divergence, which have experienced directional selection, are derived from divergent sorting of ancient polymorphisms.Our results suggest that long-term balancing selection on disease resistance genes may have maintained ancestral haplotypes across different geographical lineages, and unequal sorting of balanced polymorphisms may have generated genomic regions with elevated divergence. This study highlights the importance of ancestral balanced polymorphisms as crucial components of genome-wide variation.
Associations Between Linoleic Acid Intake and Incident Type 2 Diabetes Among U.S. Men and Women
Authors: Geng Zong, Gang Liu, Walter C. Willett, Anne J. Wanders, Marjan Alssema, Peter L. Zock, Frank B. Hu, Qi Sun
Journal: Diabetes Care (2019)

OBJECTIVE To investigate the association between intakes of n-6 polyunsaturated fatty acids (PUFAs) and type 2 diabetes risk in three prospective cohort studies of U.S. men and women. RESEARCH DESIGN AND METHODS We followed 83,648 women from the Nurses’ Health Study (NHS) (1980–2012), 88,610 women from NHSII (1991–2013), and 41,771 men from the Health Professionals Follow-Up Study (HPFS) (1986–2012). Dietary data were collected every 2–4 years by using validated food-frequency questionnaires. Self-reported incident diabetes, identified biennially, was confirmed by using a validated supplementary questionnaire. RESULTS During 4.93 million person-years of follow-up, 18,442 type 2 diabetes cases were documented. Dietary n-6 PUFAs accounted for 4.4–6.8% of total energy, on average, and consisted primarily of linoleic acid (LA) (≥98%). In multivariate-adjusted models, hazard ratios (95% CIs) of type 2 diabetes risk comparing extreme n-6 PUFA quintiles (highest vs. lowest) were 0.91 (0.85, 0.96) (Ptrend = 0.002) for total n-6 PUFAs and 0.92 (0.87, 0.98) (Ptrend = 0.01) for LA. In an isocaloric substitution model, diabetes risk was 14% (95% CI 5%, 21%) (P = 0.002) lower when LA isocalorically replaced saturated fats (5% of energy), 17% (95% CI 9%, 24%) (P &amp;lt; 0.001) lower for trans fats (2% of energy), or 9% (95% CI 17%, 0.1%) (P = 0.047) lower for carbohydrates (5% of energy). Replacing n-3 PUFAs or monounsaturated fats with LA was not significantly associated with type 2 diabetes risk. CONCLUSIONS Our study provides additional evidence that LA intake is inversely associated with risk of type 2 diabetes, especially when replacing saturated fatty acids, trans fats, or carbohydrates.
Gene-level differential analysis at transcript-level resolution
Authors: Lynn Yi, Harold Pimentel, Nicolas L. Bray, Lior Pachter
Journal: Genome biology (2018)

Compared to RNA-sequencing transcript differential analysis, gene-level differential expression analysis is more robust and experimentally actionable. However, the use of gene counts for statistical analysis can mask transcript-level dynamics. We demonstrate that 'analysis first, aggregation second,' where the p values derived from transcript analysis are aggregated to obtain gene-level results, increase sensitivity and accuracy. The method we propose can also be applied to transcript compatibility counts obtained from pseudoalignment of reads, which circumvents the need for quantification and is fast, accurate, and model-free. The method generalizes to various levels of biology and we showcase an application to gene ontologies.
Association of Estradiol and Visceral Fat With Structural Brain Networks and Memory Performance in Adults
Authors: Rachel G. Zsido, Matthias Heinrich, George M. Slavich, Frauke Beyer, Shahrzad Kharabian Masouleh, Juergen Kratzsch, Matthias Raschpichler, Karsten Mueller, Ulrike Scharrer, Markus Löffler, Matthias L. Schroeter, Michael Stumvoll, Arno Villringer, A. Veronica Witte, Julia Sacher
Journal: JAMA Network Open (2019)

Changes in estradiol during aging are associated with increased dementia risk. It remains unclear how estradiol supports cognitive health and whether risk factors, such as midlife obesity, are exacerbated by estrogen loss.To assess whether visceral adipose tissue (VAT) moderates the association between age and brain network structure and to investigate whether estradiol moderates the association between VAT and brain network structure.Cross-sectional study of data from 974 cognitively healthy adults in Germany who participated in the Health Study of the Leipzig Research Centre for Civilization Diseases, a previously described population-based cohort study. Two moderation analyses were performed, including VAT as the moderator variable between age and brain network structure and estradiol as the moderator variable between VAT and brain network structure. The study was conducted from August 1, 2011, to November 23, 2014. Analyses were conducted from August 2017 to September 2018.Serum estradiol levels from fasting blood and visceral adipose tissue volume from T1-weighted magnetic resonance imaging (MRI).Brain network covariance (individual loading on structural network derived from T1-weighted MRI) and memory performance (composite score from the Consortium to Establish a Registry for Alzheimer Disease [CERAD] verbal episodic memory test on learning [score range, 0-30], recall [score range, 0-10], and recognition [score range, 0-20]).Final analyses included data from 473 women (mean [SD] age, 50.10 [15.63] years) and 501 men (mean [SD] age, 51.24 [15.67] years). Visceral adipose tissue was associated with an exacerbation of the negative association of aging with network covariance for women (interaction term β = -0.02; 95% bias-corrected bootstrap CI, -0.03 to -0.01; P = .001) and men (interaction term β = -0.02; 95% bias-corrected bootstrap CI, -0.03 to -0.01; P < .001). Estradiol level was associated with a reduction in the negative association of VAT with network covariance in women (interaction term β = 0.63; 95% bias-corrected bootstrap CI, 0.14-1.12; P = .01), with no significant association in men. In the female midlife subgroup (age range, 35-55 years, when menopause transition occurs), low estradiol levels were associated with lower memory network covariance (Cohen d = 0.61; t80 = 2.76; P = .007) and worse memory performance (Cohen d = 0.63; t76 = 2.76; P = .007).This study reports a novel association between VAT, estradiol, and structural brain networks as a potential mechanism underlying cognitive decline in women. These findings appear to highlight the need for sex-specific strategies, including VAT and hormonal screening during midlife, to support healthy cognitive aging.
S136 REPROGRAMMING HEMATOPOIETIC STEM CELL FUNCTION VIA MODULATION OF MITOCHONDRIAL ACTIVITY
Authors: M. Girotra, M. Rincon‐Restrepo, A. Oggier, G. Coukos, O. Naveiras, S. Rezzi, N. Vannini
Journal: HemaSphere (2019)

Background: Hematopoietic stem cells (HSCs) are a small group of cells that ensure a steady production of all mature blood cells throughout an organism's lifetime. HSCs mediate this process by giving rise to progenitors that in turn produce terminally differentiated mature blood cell lineages via several rounds of cell division and well‐orchestrated differentiation steps. Cellular metabolism has emerged as a crucial regulator guiding this complex process. Especially, HSCs differ from their committed progeny by relying primarily on anaerobic glycolysis rather than mitochondrial oxidative phosphorylation for energy production. This distinct metabolic state protects the HSCs from cellular damage inflicted by reactive oxygen species (ROS) in active mitochondria. However, whether this change in the metabolic program is the cause or a consequence of the unique function of HSCs remains unknown. Aims: Having previously shown that mitochondrial activity can be used as a reliable readout for HSC fate, here we asked if modulation of mitochondrial activity results in enhancement of HSC function. Methods: We used in vitro mitochondrial activity and in vivo long‐term blood reconstitution assays as readouts of murine and human HSC functionality. Results: We previously demonstrated that modulation of mitochondrial metabolism in murine and human HSCs, by chemical uncouplers of the electron transport chain or via NAD+ boosting agent Nicotinamide Riboside (NR), results in better long‐term blood production in serially transplanted mice (Vannini N∗, Girotra M∗. et al., Nature Communication 2016 and, Vannini et al., Cell Stem Cell, in press). Here we proceeded to carry out a screen, using mitochondrial activity as readout, to identify metabolic modulators that enhance HSC function. We found two novel candidates, a natural compound and a vitamin precursor, that modulate mitochondrial activity in both mouse and human HSCs, and resulted in enhanced HSC function post bone‐marrow transplantation. Interestingly, we found that these candidates mediate their effects partially by inducing mitophagy, supporting recent studies highlighting the role of mitophagy as a key driver of HSC function. Moreover, our preliminary analysis reveals that they mediate similar effects in aged human HSCs, making them ideal candidates to revert age‐associated myeloid bias in human patients. Summary/Conclusion: Our data establishes a causal relationship between mitochondrial metabolism and HSC function via mitophagy. It also provides a valuable tool to identify optimal ex vivo conditions for HSC expansion, to improve the outcome for patients suffering from bone marrow insufficiency and to restore the functionality of the immune system in aged individuals.
SP0076 CASE PRESENTER: TRANSITION OF NEUROLUPUS PHASE INTO ADULTHOOD
Authors: Lovro Lamot
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Childhood-onset SLE (cSLE) accounts for approximately 20% of all SLE cases and is often regarded as one of the most complex rheumatic diseases. With the increase of five-year survival rate of cSLE patients to over 95%, there is a growing number of adolescents and young adults (AYA) transferring from pediatric to adult care. Even in the best-case scenario, there is often considerable challenges regarding this transition. Hence, it is not surprising that morbidity, mortality and disease activity in cSLE, as well as in many other chronic illnesses and conditions, worsen during or just after the transition. The reasons for these deteriorations are numerous, with most prominent arising from the nature of the disease and changes during the tumultuous period of adolescence, but also the differences between pediatric and adult clinical and healthcare settings. Besides, the AYA patients with chronic conditions often feel they are not well prepared for the transition to adult care, while the adult rheumatologists commonly report concerns about assuming the responsibility of patients with the pediatric-onset disease. Some of these concerns are probably motivated by increased vulnerability of AYA patients with cSLE, who are more likely than their adult counterparts to develop lupus nephritis and neuropsychiatric manifestations, as well as other organs involvement and atherosclerosis. Moreover, due to the severity of the disease, patients with cSLE are treated more aggressively, accumulating more drug-related toxicity than patients with adult-onset SLE, which results in significant SLE-related damage and complications such as osteoporosis during the childhood. On the other hand, there is decreased medication adherence in AYA, further complicated by the neurocognitive and memory impact of the disease, as well as high rates of comorbid depression and anxiety. Some additional problems in cSLE patients at transition age are sexuality, fertility, and pregnancy. All this makes patients with cSLE require specialized and multidisciplinary care at the transition, that is capable of addressing medical, psychosocial, educational and vocational needs. This presentation will be part of the comprehensive session discussing distinct features of the SLE during the different phases of life. It will emphasize specific challenges of the transition from pediatric to adult care, with the use of a compelling clinical case as an example. <h3>References:</h3> [1] Sadun RE,Schanberg LE. Transition and transfer of the patient with paediatric-onset lupus: a practical approach for paediatric and adult rheumatology practices. Lupus Science &amp; Medicine 2018;5:e000282. [2] Foster HE, Minden K, Clemente D, et al. EULAR/PReS standards and recommendations for the transitional care of young people with juvenile-onset rheumatic diseases. Ann Rheum Dis 2017;76:639–46. [3] Falcini F, Nacci F. Systemic lupus erythematosus in the young: the importance of a transition clinic. Lupus 2007;16:613–7. <h3>Disclosure of Interests:</h3> None declared
SP0094 DISEASES ON SALE – HOW I DEAL WITH ALL MY CONDITIONS
Authors: Tanita-Christina Wilhelmer
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> In her speech Tanita will explain how she experiences life with multiple conditions. There are a lot more than just symptoms of the main condition and emotions to deal with. Although being diagnosed with Adult Onset Stills Disease (AOSD), she suffers from additional morbidities. Like many other young people with RMD"s she has to manage all conditions at once. The list of comorbidities to "choose from" is very long, but there are some that made it to the top three: fatigue, depression and anxiety. The obstacles that come with this situation can be personal, interpersonal, concerning work, school or university. More illnesses lead to more doctors appointments, this results in missing work or private events. Helping others to understand the condition and communicating the needs is a big topic, as well as planning ahead and staying positive. Tanita will adress these issues and give best practice examples. <h3>Disclosure of Interests:</h3> None declared
THU0140 INSULIN RESISTANCE AND LIPID PROFILE IN RHEUMATOID ARTHRITIS PATIENTS WITHOUT DIABETES MELLITUS OR FASTING HYPERGLYCEMIA
Authors: Liubov Kondrateva, Tatiana Popkova, Evgeny Nasonov
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Diabetes mellitus (DM) is known to be associated with proatherogenic lipid profile and cardiovascular complications. Insulin resistance (IR) is the major pathophysiological mechanism contributing to type II DM development. Established in general population correlation between IR and dyslipidemia sometimes even without DM, should nevertheless be confirmed in patients (pts) with rheumatoid arthritis (RA). <h3>Objectives</h3> To analyze IR rates and identify IR predictive lipid profile in RA patients without DM or hyperglycemia. <h3>Methods</h3> Totally 47 RA pts (41 women, 6 men, 56 [39; 62] years old) without established DM and with normal fasting glucose levels (&lt;6,1 mmol/l) were enrolled in the study. Median disease duration was 6 [5;14] years. The majority of pts were IgM RF (83%) and anti-CCP (83%) seropositive, had low (40,4%) or moderate (42,6%) RA activity based on DAS28-ESR scores. RA pts were treated with glucocorticoids (51,1%), methotrexate (57,4%) or other disease-modifying antirheumatic drugs (23,4%), biological agents (17,0%) and statins (10,6%). IR was defined as Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index ≥2,77. Lipid profile included evaluation of the following parameters: serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides (TG). Additionally, non-HDL-C = TC - HDL-C and TG/HDL-C ratio were also evaluated. <h3>Results</h3> Median HOMA-IR levels were 1,7 [1,1;3,2]. HOMA-IR index correlates with age (r=0,3, p=0,04), body mass index (r=0,6, p&lt;0,001), waist circumference (r=0,6, p&lt;0,001), TC (r=0,3, p=0,02), non-HDL (r=0,3, p=0,03), TG concentrations (r=0,5, p&lt;0,001) and TG/HDL-C ratio (r=0,4, p=0,006). IR was detected in 15 (31,9%) RA pts. RA pts with (group 1, n=15) or without IR (group 2, n=32) were comparable in terms of age, sex, disease duration and activity, therapy, and comorbidities including arterial hypertension, myocardial infarction + coronary revascularization. Hypertriglyceridemia (≥1,7mmol/l) was more often present in pts with IR compared to pts without IR (33,3% vs 6,3%, p=0,03). <h3>Conclusion</h3> More than 30% of RA pts without DM and with normal serum fasting glucose concentration had IR. The IR was associated with increased TG levels and elevated TG/HDL-C ratio in RA pts. This proatherogenic lipid profile could be responsible for earlier development of cardiovascular complications. <h3>Disclosure of Interests</h3> None declared
Incidence of Type 2 Diabetes in People With a History of Hospitalization for Major Mental Illness in Scotland, 2001–2015: A Retrospective Cohort Study
Authors: Caroline A. Jackson, Kelly Fleetwood, Jan Kerssens, Daniel J. Smith, Stewart Mercer, Sarah H. Wild
Journal: Diabetes Care (2019)

To determine the incidence of type 2 diabetes in people with a history of hospitalization for major mental illness versus no mental illness in Scotland by time period and sociodemographics.We used national Scottish population-based records to create cohorts with a hospital record of schizophrenia, bipolar disorder, or depression or no mental illness and to ascertain diabetes incidence. We used quasi-Poisson regression models including age, sex, time period, and area-based deprivation to estimate incidence and relative risks (RRs) of diabetes by mental illness status. Estimates are illustrated for people aged 60 years and in the middle deprivation quintile in 2015.We identified 254,136 diabetes cases during 2001-2015. Diabetes incidence in 2015 was 1.5- to 2.5-fold higher in people with versus without a major mental disorder, with the gap having slightly increased over time. RRs of diabetes incidence were greater among women than men for schizophrenia (RR 2.40 [95% CI 2.01, 2.85] and 1.63 [1.38, 1.94]), respectively) and depression (RR 2.10 [1.86, 2.36] and 1.62 [1.43, 1.82]) but similar for bipolar disorder (RR 1.65 [1.35, 2.02] and 1.50 [1.22, 1.84]). Absolute and relative differences in diabetes incidence associated with mental illness increased with increasing deprivation.Disparities in diabetes incidence between people with and without major mental illness appear to be widening. Major mental illness has a greater effect on diabetes risk in women and people living in more deprived areas, which has implications for intervention strategies to reduce diabetes risk in this vulnerable population.