bluuebunny/crossref_metadata_2025 huggingface dataset:
Long noncoding RNAs in lipid metabolism
Authors: van Solingen Coen , Scacalossi Kaitlyn R. , Moore Kathryn J.
Published: March 2018

Purpose of review

Noncoding RNAs have emerged as important regulators of cellular and systemic lipid metabolism. In particular, the enigmatic class of long noncoding RNAs have been shown to play multifaceted roles in controlling transcriptional and posttranscriptional gene regulation. In this review, we discuss recent advances, current challenges and future opportunities in understanding the roles of lncRNAs in the regulation of lipid metabolism during health and disease.

Recent findings

Despite comprising the majority of the transcriptionally active regions of the human genome, lncRNA functions remain poorly understood, with fewer than 1% of human lncRNAs functionally characterized. Broadly defined as nonprotein coding transcripts greater than 200 nucleotides in length, lncRNAs execute their functions by forming RNA–DNA, RNA–protein, and RNA–RNA interactions that regulate gene expression through diverse mechanisms, including epigenetic remodeling of chromatin, transcriptional activation or repression, posttranscriptional regulation of mRNA, and modulation of protein activity. It is now recognized that in lipid metabolism, just as in other areas of biology, lncRNAs operate to regulate the expression of individual genes and gene networks at multiple different levels.

The complexity revealed by recent studies showing how lncRNAs can alter systemic and cell-type-specific cholesterol and triglyceride metabolism make it clear that we have entered a new frontier for discovery that is both daunting and exciting.
Poststatin era in atherosclerosis management: lessons from epidemiologic and genetic studies
Authors: Yvan-Charvet Laurent , Cariou Bertrand
Published: March 2018

Purpose of review

Cardiovascular diseases (CVD) are the leading cause of death worldwide with over 17 million deaths every year and represent a major public health challenge. The last decade has seen the emergence of novel antiatherogenic therapies.

Recent findings

Despite intensive lipid and blood pressure interventions, the burden of CVD is expected to markedly progress because of the global aging of the population and increasing exposure to detrimental lifestyle-related risk. Epidemiologic and genetic studies helped to better apprehend the biology of atherosclerosis and allowed pharmaceutical innovation and recent translational successes. This includes the development of novel lipid and glucose-lowering therapies and the leverage of anti-inflammatory therapies.

Here, we discuss promises and expectations of emerging scientific and pharmaceutical innovations and translational successes to meet the global therapeutic demand.
Management of pilonidal disease
Authors: Kallis Michelle P. , Maloney Caroline , Lipskar Aaron M.
Published: March 2018

Purpose of review

Pilonidal disease, and the treatment associated with it, can cause significant morbidity and substantial burden to patients’ quality of life. Despite the plethora of surgical techniques that have been developed to treat pilonidal disease, discrepancies in technique, recurrence rates, complications, time to return to work/school and patients’ aesthetic satisfaction between treatment options have led to controversy over the best approach to this common acquired disease of young adults.

Recent findings

The management of pilonidal disease must strike a balance between recurrence and surgical morbidity. The commonly performed wide excision without closure has prolonged recovery, while flap closures speed recovery time and improve aesthetics at the expense of increased wound complications. Less invasive surgical techniques have recently evolved and are straightforward, with minimal morbidity and satisfactory results.

As with any surgical intervention, the ideal treatment for pilonidal disease would be simple and cost-effective, cause minimal pain, have a limited hospital stay, low recurrence rate and require minimal time off from school or work. Less invasive procedures for pilonidal disease may be favourable as an initial approach for these patients reserving complex surgical treatment for refractory disease.
Clinical Implications of Real-time Integrative Sequencing in Management of Patients With Suspected Germline BAP1 Mutations
Authors: Sengupta Shayan , Weyand Angela C. , Upadhyaya Santhosh A. , Wu Yi-Mi , Robinson Dan R. , Mody Rajen J.
Published: March 2018

Germline mutation of BRCA-associated protein-1 has been implicated in the development of tumor predisposition syndrome and high risk for malignant mesothelioma, lung adenocarcinoma, uveal melanoma, and cutaneous melanoma. Here, we present the case of a patient with recurrent metastatic melanoma who was found to have germline BAP1 and somatic BRAF mutation by clinical genomic sequencing. Detection of a germline mutation prompted screening for other cancers and surveillance in family members. Prospective integrative sequencing for pediatric cancer patients may identify pathogenic germline mutations and may improve outcomes and treatment-related morbidity by early diagnosis of malignancy.
Symptomatic Cerebral Sinovenous Thrombosis Associated With l-Asparaginase In Children With Acute Lymphoblastic Leukemia: A Single Institution Experience Over 17 Years
Authors: Malhotra Payal , Jain Sandeep , Kapoor Gauri
Published: March 2018

Background:

Cerebral sinovenous thrombosis (CSVT) is a rare, yet important complication of acute lymphoblastic leukemia (ALL) therapy, associated with significant morbidity and mortality. Paucity of data from India prompted us to report our experience with CSVT over a period of 17 years.

Materials and Methods:

This is a retrospective analysis of 500 consecutive ALL patients, below 18 year of age, treated between January 1998 and December 2014, who developed symptomatic CVST.

Results:

Seven of the 467 eligible patients developed symptomatic CVST with an incidence of 1.5% (7/467). Six of the CVST events, occurred during induction and 1 during reinduction. Median time to symptoms was 21 days (range, 2 to 27 d) from first exposure to l-asparaginase therapy. Management included low–molecular-weight heparin (enoxaparin sodium) at a dose of 1 mg/kg twice a day for at least 3 months along with supportive care. There were 2 thrombosis-attributable deaths. The remaining patients tolerated rechallenge with l-asparaginase uneventfully during reinduction, under cover of heparin prophylaxis. Complete neurological recovery was observed in all surviving patients.

Conclusions:

Incidence of symptomatic l-asparaginase associated CSVT during ALL treatment was 1.5% with high case fatality rate (28%). It is noteworthy that full neurological recovery is likely in surviving patients, and rechallenge with l-asparaginase is safe with heparin prophylaxis. Currently available screening methods are not practically implementable in resource-limited settings.
Effect of inpatient rehabilitation on activities of daily living in pediatric cancer patients in Japan
Authors: Taguchi Kazue , Ueno Tomoyuki , Shimizu Yukiyo , Ishimoto Ryu , Hada Yasushi
Published: March 2018

Most pediatric cancer patients decline physical performance therapy, resulting in limitations in the activities of daily living. The objective of this study was to investigate the effects of rehabilitation in pediatric patients with cancer using the functional independence measure (FIM) score. This retrospective study included 25 inpatient children diagnosed with cancer at a single university hospital from January 2016 to December 2016. All patients underwent rehabilitative intervention during their hospital stay. We investigated the contents of the rehabilitation program and the FIM scores before and after the rehabilitative intervention. The average FIM scores improved in all patients; however, only the total-FIM scores (+4.96 points, P=0.009) and motor-FIM scores (+4.04 points, P=0.005) improved significantly. Conversely, cognitive-FIM score did not significantly improve (+0.92 points, P=0.159). In addition, motor-FIM subgroup scores for locomotion (walk/wheelchair and stairs) were significantly higher (+0.36 points, P=0.039 and +0.64 points, P=0.046, respectively) after rehabilitative intervention, regardless of the length of hospital stay. This study showed that FIM score, particularly motor-FIM score and locomotion subgroup scores, significantly improved owing to participation in inpatient rehabilitation. In conclusion, we found that rehabilitative intervention improved physical activity, especially locomotion.
White Paper: Movement System Diagnoses in Neurologic Physical Therapy
Authors: Hedman Lois D. , Quinn Lori , Gill-Body Kathleen , Brown David A. , Quiben Myla , Riley Nora , Scheets Patricia L.
Published: March 2018

Background and Purpose:

The APTA recently established a vision for physical therapists to transform society by optimizing movement to promote health and wellness, mitigate impairments, and prevent disability. An important element of this vision entails the integration of the movement system into the profession, and necessitates the development of movement system diagnoses by physical therapists. At this point in time, the profession as a whole has not agreed upon diagnostic classifications or guidelines to assist in developing movement system diagnoses that will consistently capture an individual's movement problems. We propose that, going forward, diagnostic classifications of movement system problems need to be developed, tested, and validated. The Academy of Neurologic Physical Therapy's Movement System Task Force was convened to address these issues with respect to management of movement system problems in patients with neurologic conditions. The purpose of this article is to report on the work and recommendations of the Task Force.

Summary of Key Findings:

The Task Force identified 4 essential elements necessary to develop and implement movement system diagnoses for patients with primarily neurologic involvement from existing movement system classifications. The Task Force considered the potential impact of using movement system diagnoses on clinical practice, education and, research. Recommendations were developed and provided recommendations for potential next steps to broaden this discussion and foster the development of movement system diagnostic classifications.

Recommendations for Clinical Practice:

The Task Force proposes that diagnostic classifications of movement system problems need to be developed, tested, and validated with the long-range goal to reach consensus on and adoption of a movement system diagnostic framework for clients with neurologic injury or disease states.

Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A198).
Use of an Errorless Learning Approach in a Person With Concomitant Traumatic Spinal Cord Injury and Brain Injury: A Case Report
Authors: Hartmann Annie , Kegelmeyer Deb , Kloos Anne
Published: March 2018

Individuals with concomitant spinal cord injury and traumatic brain injury have cognitive deficits that may limit the ability to learn novel motor tasks necessary for functional independence. Errorless learning has been shown to improve cognitive task performance in persons with brain injury but little is known about its usefulness for improving novel motor task learning.

Case Description:

A 44-year-old man with traumatic spinal cord and brain injuries from a motor vehicle accident was admitted to an inpatient rehabilitation hospital. His spinal cord injury was classified as T4 American Spinal Injury Association Impairment Scale (AIS) A, and his cognitive status was level IV on the Ranchos Los Amigos Scale. Initially, the patient required maximal assistance from 2 clinicians to complete a slide board transfer, propelled his wheelchair 25 ft with minimal assistance, and scored 9/56 on the Function in Sitting Test.

Intervention:

The therapist applied traditional motor-learning approaches during the first 37 days of the patient's inpatient rehabilitation facility stay without meaningful gains in functional mobility. A subsequent change to errorless learning was made for the following 32 days until discharge.

Outcomes:

After use of errorless learning, the patient performed novel mobility-related tasks of slide board transfers with minimal assistance and wheelchair propulsion without physical assistance up to 150 ft; the Function in Sitting Test score improved to 18/56. His sensorimotor system progressed to an AIS classification of AIS B, while his cognition emerged to a level V on the Ranchos Los Amigos Scale.

Discussion:

Errorless learning may have facilitated acquisition of novel transfer and mobility skills in this individual with dual diagnoses. This approach may have value for patients with neurologic conditions who have both motor and cognitive impairment.

Video Abstract available for more insights from the authors (see Video, Supplemental Digital Content 1, http://links.lww.com/JNPT/A201).
Long-Term Retention of Musculoskeletal Ultrasound Training During Residency
Authors: Irwin Robert W. , Smith Jeffrey , Issenberg S. Barry
Published: March 2018

The Accreditation Council for Graduate Medical Education and the American Board of Physical Medicine and Rehabilitation developed milestones for evaluation of resident physicians that include proper musculoskeletal ultrasound examination of major joints. To date, there have been no published data demonstrating acquisition and retention of these skills and correlation with the milestone evaluation. The investigators developed and implemented a curriculum in musculoskeletal ultrasound examination for Physical Medicine and Rehabilitation residents at a large academic medical center. The investigators chose the following six joints for training and evaluation: ankle, elbow, hip, knee, shoulder, and wrist/hand. The program included: (1) didactic lectures on anatomy and ultrasound technique; (2) peer-led demonstrations of the procedure on a standardized patient (SP); (3) individual practice on standardized patients; (4) faculty observation and feedback; (5) review sessions and additional practice; and (6) assessment of skills in an objective structured clinical examination. From 2013 to 2017, 30 physical medicine and rehabilitation residents were trained and evaluated. The results, based on objective structured clinical examination scores, showed that most residents achieved the appropriate level of competency for their year. A blended, standardized curriculum in musculoskeletal ultrasound instruction with assessment by an objective structured clinical examination can be used to evaluate musculoskeletal ultrasound skills and can help align this education with residency milestones.
Trajectories of Quality of Life and Associated Risk Factors in Patients With Knee Osteoarthritis
Authors: Han Alex , Gellhorn Alfred C.
Published: March 2018

Objective

Knee osteoarthritis (OA) has a significant impact on quality of life (QOL). Although QOL is generally thought to diminish over time, it is unknown whether different patient groups demonstrate unique patterns of change in QOL. We sought to identify and characterize QOL trajectories in knee OA.

Design

This prospective cohort study included 1013 individuals with symptomatic knee OA from the osteoarthritis initiative. We used group-based trajectory modeling to identify distinct temporal patterns of change in the Knee Injury and Osteoarthritis Outcome Score QOL subscale for 8 yrs. Baseline covariates included age, sex, ethnicity, education, co-morbidities, body mass index, substance use, depression, knee pain, and functional tests.

Results

Group-based trajectory modeling revealed the following three distinct QOL trajectories: a high QOL trajectory (32% of the cohort) experiencing improvement for 8 yrs as well as moderate (49%) and low QOL (20%) trajectories maintaining similar levels over time. Low QOL trajectory membership was significantly associated with younger age (P < 0.001), nonwhite race (P < 0.001), less education (P < 0.001), more co-morbidities (P < 0.001), higher body mass index (P < 0.001), and more depressive symptoms (P < 0.001). Higher QOL trajectory members were less likely to undergo knee replacement surgery (P < 0.001).

Conclusions

Distinct QOL trajectories exist in knee OA and are associated with modifiable factors, with a subset of patients showing potential to improve their QOL over time.
10 Years of Nephrogenic Systemic Fibrosis
Authors: Endrikat Jan , Dohanish Susan , Schleyer Nicolas , Schwenke Susanne , Agarwal Sheela , Balzer Thomas
Published: March 2018

Objectives

The aim of this study was to critically assess the evaluation and categorization process for nephrogenic systemic fibrosis (NSF) based on reports received by Bayer from 2006 to 2016.

Materials and Methods

A total of 779 NSF reports received by Bayer globally from 2006 to 2016 were included in the analysis. Arlington Medical Resources provided gadolinium-based contrast agent (GBCA) market share. Reports were conservatively categorized based on the Cowper/Girardi criteria. A statistical model simulated the impact of market share and market introduction on the number of unconfounded reports.

Results

For all reports, reported onset of disease ranged from 1996 and 2012. Of 779 reports, 325 involved a Bayer product only, 208 involved only products from other companies (or unknown GBCA), and 246 involved both Bayer and non-Bayer products. Most of all reports (86%) originated from the United States.

Through 2006, Magnevist and Omniscan dominated the US market (>80% combined market share). All other GBCAs with fewer NSF reports comprised the remaining combined market share of less than 20% or were introduced after May 2007, after safety recommendations came into effect.

A total of 563 reports (220 single-agent and 343 multiagent reports) involved Magnevist. In at least 150 of the 343 reports, a different GBCA (Omniscan, 118; OptiMARK, 15; MultiHance, 6; and macrocyclic agent, 11) showed the closest temporal relationship to onset of NSF-like symptoms.

The simulation model demonstrated that patients receiving a GBCA with lower market share and late market introduction are less likely to be observed in an unconfounded setting.

Conclusions

Year of market introduction, as well as US market share in 2000 to 2007, greatly influenced the absolute number of NSF reports for each GBCA, their a priori probability to cause NSF, as well as their a priori probability to be associated with unconfounded cases of NSF. Variability in case interpretation and pharmacovigilance approaches also influence the absolute number of unconfounded cases and should therefore not be used for comparative risk assessments. This should be primarily based on objective product parameters such as structure, stability, pharmacokinetics, and dose.
The diversity of ice algal communities on the Greenland Ice Sheet as revealed by oligotyping
Authors: Lutz Stefanie , McCutcheon Jenine , McQuaid James B. , Benning Liane G.
Published: March 2018

The Arctic is being disproportionally affected by climate change compared with other geographic locations, and is currently experiencing unprecedented melt rates. The Greenland Ice Sheet (GrIS) can be regarded as the largest supraglacial ecosystem on Earth, and ice algae are the dominant primary producers on bare ice surfaces throughout the course of a melt season. Ice-algal-derived pigments cause a darkening of the ice surface, which in turn decreases albedo and increases melt rates. The important role of ice algae in changing melt rates has only recently been recognized, and we currently know little about their community compositions and functions. Here, we present the first analysis of ice algal communities across a 100 km transect on the GrIS by high-throughput sequencing and subsequent oligotyping of the most abundant taxa. Our data reveal an extremely low algal diversity with Ancylonema nordenskiöldii and a Mesotaenium species being by far the dominant taxa at all sites. We employed an oligotyping approach and revealed a hidden diversity not detectable by conventional clustering of operational taxonomic units and taxonomic classification. Oligotypes of the dominant taxa exhibit a site-specific distribution, which may be linked to differences in temperatures and subsequently the extent of the melting. Our results help to better understand the distribution patterns of ice algal communities that play a crucial role in the GrIS ecosystem.
Evolution of carbapenem resistance in Acinetobacter baumannii during a prolonged infection
Authors: Hawkey Jane , Ascher David B. , Judd Louise M. , Wick Ryan R. , Kostoulias Xenia , Cleland Heather , Spelman Denis W. , Padiglione Alex , Peleg Anton Y. , Holt Kathryn E.
Published: March 2018

Acinetobacter baumannii is a common causative agent of hospital-acquired infections and a leading cause of infection in burns patients. Carbapenem-resistant A. baumannii is considered a major public-health threat and has been identified by the World Health Organization as the top priority organism requiring new antimicrobials. The most common mechanism for carbapenem resistance in A. baumannii is via horizontal acquisition of carbapenemase genes. In this study, we sampled 20 A. baumannii isolates from a patient with extensive burns, and characterized the evolution of carbapenem resistance over a 45 day period via Illumina and Oxford Nanopore sequencing. All isolates were multidrug resistant, carrying two genomic islands that harboured several antibiotic-resistance genes. Most isolates were genetically identical and represented a single founder genotype. We identified three novel non-synonymous substitutions associated with meropenem resistance: F136L and G288S in AdeB (part of the AdeABC efflux pump) associated with an increase in meropenem MIC to ≥8 µg ml−1; and A515V in FtsI (PBP3, a penicillin-binding protein) associated with a further increase in MIC to 32 µg ml−1. Structural modelling of AdeB and FtsI showed that these mutations affected their drug-binding sites and revealed mechanisms for meropenem resistance. Notably, one of the adeB mutations arose prior to meropenem therapy but following ciprofloxacin therapy, suggesting exposure to one drug whose resistance is mediated by the efflux pump can induce collateral resistance to other drugs to which the bacterium has not yet been exposed.
Transmission and lineage displacement drive rapid population genomic flux in cystic fibrosis airway infections of a Pseudomonas aeruginosa epidemic strain
Authors: Williams David , Fothergill Joanne L. , Evans Benjamin , Caples Jessica , Haldenby Sam , Walshaw Martin J. , Brockhurst Michael A. , Winstanley Craig , Paterson Steve
Published: March 2018

Pseudomonas aeruginosa chronic infections of cystic fibrosis (CF) airways are a paradigm for within-host evolution with abundant evidence for rapid evolutionary adaptation and diversification. Recently emerged transmissible strains have spread globally, with the Liverpool Epidemic Strain (LES) the most common strain infecting the UK CF population. Previously we have shown that highly divergent lineages of LES can be found within a single infection, consistent with super-infection among a cross-sectional cohort of patients. However, despite its clinical importance, little is known about the impact of transmission on the genetic structure of these infections over time. To characterize this, we longitudinally sampled a meta-population of 15 genetic lineages within the LES over 13 months among seven chronically infected CF patients by genome sequencing. Comparative genome analyses of P. aeruginosa populations revealed that the presence of coexisting lineages contributed more to genetic diversity within an infection than diversification in situ. We observed rapid and substantial shifts in the relative abundance of lineages and replacement of dominant lineages, likely to represent super-infection by repeated transmissions. Lineage dynamics within patients led to rapid changes in the frequencies of mutations across suites of linked loci carried by each lineage. Many loci were associated with important infection phenotypes such as antibiotic resistance, mucoidy and quorum sensing, and were repeatedly mutated in different lineages. These findings suggest that transmission leads to rapid shifts in the genetic structure of CF infections, including in clinically important phenotypes such as antimicrobial resistance, and is likely to impede accurate diagnosis and treatment.
YES1amplification: a mechanism of acquired resistance to EGFR inhibitors identified by transposon mutagenesis and clinical genomics
Authors: Fan Pang-Dian , Narzisi Giuseppe , Jayaprakash Anitha D. , Venturini Elisa , Robine Nicolas , Smibert Peter , Germer Soren , Yu Helena A. , Jordan Emmet J. , Paik Paul K. , Janjigian Yelena Y. , Chaft Jamie E. , Wang Lu , Jungbluth Achim A. , Middha Sumit , Spraggon Lee , Qiao Huan , Lovly Christine M. , Kris Mark G. , Riely Gregory J. , Politi Katerina , Varmus Harold , Ladanyi Marc
Published: March 2018

In approximately 30% of patients withEGFR-mutant lung adenocarcinomas whose disease progresses on EGFR inhibitors, the basis for acquired resistance remains unclear. We have integrated transposon mutagenesis screening in anEGFR-mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify novel mechanisms of resistance to EGFR inhibitors. The most prominent candidate genes identified by insertions in or near the genes during the screen wereMET, a gene whose amplification is known to mediate resistance to EGFR inhibitors, and the gene encoding the Src family kinase YES1. Cell clones with transposon insertions that activated expression ofYES1exhibited resistance to all three generations of EGFR inhibitors and sensitivity to pharmacologic and siRNA-mediated inhibition ofYES1. Analysis of clinical genomic sequencing data from cases of acquired resistance to EGFR inhibitors revealed amplification ofYES1in 5 cases, 4 of which lacked any other known mechanisms of resistance. Pre-inhibitor samples, available for 2 of the 5 patients, lackedYES1amplification. None of 136 post-inhibitor samples had detectable amplification of other Src family kinases (SRC, FYN).YES1amplification was also found in 2 of 17 samples fromALKfusion-positive lung cancer patients who had progressed on ALK TKIs. Taken together, our findings identify acquired amplification ofYES1as a novel, recurrent, and targetable mechanism of resistance to EGFR inhibition inEGFR-mutant lung cancers, and demonstrate the utility of transposon mutagenesis in discovering clinically relevant mechanisms of drug resistance.

SIGNIFICANCE

Despite high response rates to treatment with small molecule inhibitors of EGFR tyrosine kinase activity, patients withEGFR-mutant lung adenocarcinomas eventually develop resistance to these drugs. In many cases, the basis of acquired resistance remains unclear. We have used a transposon mutagenesis screen in anEGFR-mutant cell line and clinical genomic sequencing in cases of acquired resistance to identify amplification ofYES1as a novel and targetable mechanism of resistance to EGFR inhibitors inEGFR-mutant lung cancers.
Mean-Variance QTL Mapping on a Background of Variance Heterogeneity
Authors: Corty Robert W. , Valdar William
Published: March 2018

Most QTL mapping approaches seek to identify “mean QTL”, genetic loci that influence the phenotype mean, after assuming that all individuals in the mapping population have equal residual variance. Recent work has broadened the scope of QTL mapping to identify genetic loci that influence phenotype variance, termed “variance QTL”, or some combination of mean and variance, which we term “mean-variance QTL”. Even these approaches, however, fail to address situations where some other factor, be it an environmental factor or a distant genetic locus, influences phenotype variance. We term this situation “background variance heterogeneity” (BVH) and used simulation to explore its effects on the power and false positive rate of tests for mean QTL, variance QTL, and mean-variance QTL. Specifically, we compared traditional tests, linear regression for mean QTL and Levene’s test for variance QTL, with tests more recently developed, namely Cao’s tests for all three types of QTL, and tests based on the double generalized linear model (DGLM), which, unlike the other approaches, explicitly models BVH. Simulations showed that, when used in conjunction with a permutation procedure, the DGLM-based tests accurately control false positive rate and are more powerful than the other tests. We also discovered that the rank-based inverse normal transform, often used to corral unruly phenotypes, can be used to mitigate the adverse effects of BVH in some circumstances. We applied the DGLM approach, which we term “mean-variance QTL mapping”, to publicly available data on a mouse backcross of CAST/Ei into M16i and, after accommodating BVH driven by father, identified a new mean QTL for bodyweight at three weeks of age.
Polycomb repressive complex 1 defines the nucleosome landscape but not accessibility at target genes
Authors: King Hamish W , Klose Robert J
Published: March 2018

Polycomb group (PcG) proteins are transcriptional repressors that play important roles regulating gene expression during animal development. In vitro experiments have shown that PcG protein complexes can compact chromatin limiting the activity of chromatin remodelling enzymes and access of the transcriptional machinery to DNA. In fitting with these ideas, gene promoters associated with PcG proteins have been reported to be less accessible than other gene promotors. However, it remains largely untested in vivo whether PcG proteins define chromatin accessibility or other chromatin features. To address this important question, we measured chromatin accessibility and examined the nucleosome landscape at PcG protein-bound promoters in mouse embryonic stem cells using the assay for transposase accessible chromatin (ATAC)-seq. Combined with genetic ablation strategies, we unexpectedly discover that although PcG protein-occupied gene promoters exhibit reduced accessibility, this does not rely on PcG proteins. Instead, the Polycomb repressive complex 1 (PRC1) appears to play a unique role in driving elevated nucleosome occupancy and decreased nucleosomal spacing in Polycomb chromatin domains. Our new genome-scale observations argue, in contrast to the prevailing view, that PcG proteins and Polycomb chromatin domains do not significantly affect chromatin accessibility and highlight an underappreciated complexity in the relationship between chromatin accessibility, the nucleosome landscape and PcG-mediated transcriptional repression.
Genotyping Polyploids from Messy Sequencing Data
Authors: Gerard David , Ferrão Luis Felipe Ventorim , Garcia Antonio Augusto Franco , Stephens Matthew
Published: March 2018

Detecting and quantifying the differences in individual genomes (i.e. genotyping), plays a fundamental role in most modern bioinformatics pipelines. Many scientists now use reduced representation next-generation sequencing (NGS) approaches for genotyping. Genotyping diploid individuals using NGS is a well-studied field and similar methods for polyploid individuals are just emerging. However, there are many aspects of NGS data, particularly in polyploids, that remain unexplored by most methods. Our contributions in this paper are four-fold: (i) We draw attention to, and then model, common aspects of NGS data: sequencing error, allelic bias, overdispersion, and outlying observations. (ii) Many datasets feature related individuals, and so we use the structure of Mendelian segregation to build an empirical Bayes approach for genotyping polyploid individuals. (iii) We develop novel models to account for preferential pairing of chromosomes and harness these for genotyping. (iv) We derive oracle genotyping error rates that may be used for read depth suggestions. We assess the accuracy of our method in simulations and apply it to a dataset of hexaploid sweet potatoes (Ipomoea batatas). An R package implementing our method is available at https://cran.r-project.org/package=updog.
The identification of an anti-thrombin molecule via the screening of semi-random DNA libraries
Authors: Feng Fan , Li Zijin , Chen Zhenlang , Wang Le , Huang Jie , Wan Yulin , Shi Yunfan , Liu Qiuyun
Published: March 2018

Thrombosis remains one of the leading causes of mortality and morbidity in the world. Thrombin is a key enzyme involved in the blood clotting processes, which can be intervened by low concentrations of Hirudin. The C-terminal dodecapeptide of Hirudin was capable of inhibiting thrombosis. This peptide has been partially randomized in this report, and the coding sequences have been expressed in yeast as chimerical peptides for secretion into the culture media. Two other semi-random modules have been processed likewise. The supernatant was subsequently tested for anti-thrombin activities. DNA sequencing indicated that the putative positive clone encoded a single serine residue followed by a stop codon. The Ninhydrin assay of the culture supernatant of the positive clone indicated a high content of amino acid. Electrospray Mass Spectrometry showed a distinct peak at 430.5 when the expression products fromPichia pastoriswere examined, suggesting that the compound may be a dimannosylated serine, as yeast possesses glycosylation at serine residues. The observed effects of α-Mannosidase treatments on the function of yeast induction products are consistent with this assumption. Partial randomization of peptides and proteins may accelerate directed evolution, yielding unprecedented number of variants for functional interrogation and drug development.
Genome-wide profiling of an enhancer-associated histone modification reveals the influence of asthma on the epigenome of the airway epithelium
Authors: McErlean Peter , Kelly Audrey , Dhariwal Jaideep , Kirtland Max , Watson Julie , Ranz Ismael , Cousins David J. , Solari Roberto , Edwards Michael R. , Johnston Sebastian L. , Lavender Paul ,   MRC-GSK Strategic Alliance Consortium
Published: March 2018

Asthma is a chronic airway disease driven by complex genetic-environmental interactions. The role of epigenetic modifications in bronchial epithelial cells (BECs) in asthma is poorly understood. We undertook genome-wide profiling of the enhancer-associated histone modification H3K27ac in BECs from people with asthma and healthy controls. We identified 49,903 regions exhibiting differential H3K27ac enrichment in asthma, clustered at genes associated with type-2-high asthma (CLCA1) and epithelial processes (EMT). Asthma dramatically influenced the BEC enhancer landscape and we identified asthma-associated Super-Enhancers encompassing genes encoding transcription factors (TP63) and enzymes regulating lipid metabolism (NOX4). We integrated published protein, epigenomic and transcriptomic datasets and identified epithelium-specific transcription factors associated with H3K27ac in asthma (TP73) and dynamic relationships between asthma-associated changes in H3K27ac, DNA methylation, genetic susceptibility and transcriptional profiles. Finally, we used a CRISPR-based approach to recapitulate the H3K27ac-asthma landscape in vitro and provide proof of principal that asthma-associated gene expression (SERPINB2) is driven in part by aberrant histone acetylation, validating the combination of genome-wide and epigenome-editing approaches in deciphering the molecular mechanisms underlying asthma pathogenesis.
A machine-learning-guided mutagenesis platform for accelerated discovery of novel functional proteins
Authors: Saito Yutaka , Oikawa Misaki , Nakazawa Hikaru , Niide Teppei , Kameda Tomoshi , Tsuda Koji , Umetsu Mitsuo
Published: March 2018

Molecular evolution based on mutagenesis is widely used in protein engineering. However, optimal proteins are often difficult to obtain due to a large sequence space that requires high costs for screening experiments. Here, we propose a novel approach that combines molecular evolution with machine learning. In this approach, we conduct two rounds of mutagenesis where an initial library of protein variants is used to train a machine-learning model to guide mutagenesis for the second-round library. This enables to prepare a small library suited for screening experiments with high enrichment of functional proteins. We demonstrated a proof-of-concept of our approach by altering the reference green fluorescent protein (GFP) so that its fluorescence is changed to yellow while improving its fluorescence intensity. Using 155 and 78 variants for the initial and the second-round libraries, respectively, we successfully obtained a number of proteins showing yellow fluorescence, 12 of which had better fluorescence performance than the reference yellow fluorescent protein (YFP). These results show the potential of our approach as a powerful platform for accelerated discovery of functional proteins.
Identifying small molecule binding sites for epigenetic proteins at domain-domain interfaces
Authors: Bowkett David , Talon Romain , Tallant Cynthia , Schofield Chris , von Delft Frank , Knapp Stefan , Bruton Gordon , Brennan Paul E.
Published: March 2018

Epigenetics is of rapidly growing field in drug discovery. Of particular interest is the role of post-translational modifications to histone and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains, is that with the notable exception of bromodomains, they tend not to possess a well enclosed binding site amenable to small molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains there are opportunities for designing inhibitors that bind at a domain-domain interface which provide a more suitable interaction pocket. Examination of X-ray structures of multiple domains involved in recognizing and modifying post-translational histone marks using the SiteMap algorithm identified potential binding sites at domain-domain interfaces. For the tandem plant homeodomain-bromodomain of SP100C, a potential inter-domain site identified computationally was validated experimentally by the discovery of ligands by X-ray crystallographic fragment screening.
Differences in tropical vs. temperate diversity in arthropod predators provide insights into causes of latitudinal gradients of species diversity
Authors: Privet Kaïna , Petillon Julien
Published: March 2018

High diversity in tropical compared to temperate regions has long intrigued ecologists. Terrestrial arthropods are among the most speciose orders in tropical rainforests. Previous studies show that arthropod herbivores account for much tropical diversity, yet differences in diversity of arthropod predators between tropical and temperate systems have not been quantified. Here, we present the first standardized tropical-temperate forest comparison of species richness and evenness for understory spiders, a dominant and mega-diverse taxa of generalist predators. Species richness was 13-82 times higher in tropical vs. temperate forests. Evenness was also higher with tropical assemblages having 12-55 times more common and 10-40 times more dominant species. By contrast, proportion of rare species were only up to two times greater than that of temperate measurements. These differences in diversity far surpass previous estimates, and exceed tropical-temperate difference for herbivorous taxa. Thus, the extreme diversity of arthropod predators is associated not only with the higher diversity of prey in tropical vs. temperate ecosystems, but probably also with increased diet breadth of understory spiders in the tropics. This work contradicts the widely accepted hypothesis that tropical diversity is associated with more specialization of predators.
Selection for synchronized cell division in simple multicellular organisms
Authors: Olejarz Jason , Kaveh Kamran , Veller Carl , Nowak Martin A.
Published: March 2018

The evolution of multicellularity was a major transition in the history of life on earth. Conditions under which multicellularity is favored have been studied theoretically and experimentally. But since the construction of a multicellular organism requires multiple rounds of cell division, a natural question is whether these cell divisions should be synchronous or not. We study a simple population model in which there compete simple multicellular organisms that grow either by synchronous or asynchronous cell divisions. We demonstrate that natural selection can act differently on synchronous and asynchronous cell division, and we offer intuition for why these phenotypes are generally not neutral variants of each other.
Repeat-driven generation of antigenic diversity in a major human pathogen Trypanosoma cruzi
Authors: Talavera-López Carlos , Messenger Louisa A. , Lewis Michael D. , Yeo Matthew , Reis-Cunha João Luís , Bartholomeu Daniella C. , Calzada José E. , Saldaña Azael , Ramírez Juan David , Guhl Felipe , Ocaña-Mayorga Sofía , Costales Jaime A. , Gorchakov Rodion , Jones Kathryn , Garcia Melissa Nolan , Grisard Edmundo C. , Teixeira Santuza M. R. , Carrasco Hernán , Bottazzi Maria Elena , Hotez Peter J. , Murray Kristy O. , Grijalva Mario J. , Burleigh Barbara , Miles Michael A. , Andersson Björn
Published: March 2018

Trypanosoma cruzi, a zoonotic kinetoplastid protozoan with a complex genome, is the causative agent of American trypanosomiasis (Chagas disease). The parasite uses a highly diverse repertoire of surface molecules, with roles in cell invasion, immune evasion and pathogenesis. Thus far, the genomic regions containing these genes have been impossible to resolve and it has been impossible to study the structure and function of the several thousand repetitive genes encoding the surface molecules of the parasite. We here present an improved genome assembly of a T. cruzi clade I (TcI) strain using high coverage PacBio single molecule sequencing, together with Illumina sequencing of 34 T. cruzi TcI isolates and clones from different geographic locations, sample sources and clinical outcomes. Resolution of the surface molecule gene structure reveals an unusual duality in the organisation of the parasite genome, a core genomic region syntenous with related protozoa flanked by unique and highly plastic subtelomeric regions encoding surface antigens. The presence of abundant interspersed retrotransposons in the subtelomeres suggests that these elements are involved in a recombination mechanism for the generation of antigenic variation and evasion of the host immune response. The comparative genomic analysis of the cohort of TcI strains revealed multiple cases of such recombination events involving surface molecule genes and has provided new insights into T. cruzi population structure.
Evidence that the cell cycle is a series of uncoupled, memoryless phases
Authors: Chao Hui Xiao , Fakhreddin Randy I. , Shimerov Hristo K. , Kumar Rashmi J. , Gupta Gaorav P. , Purvis Jeremy E.
Published: March 2018

The cell cycle is canonically described as a series of 4 phases: G1 (gap phase 1), S (DNA synthesis), G2 (gap phase 2), and M (mitosis). Various models have been proposed to describe the durations of each phase, including a two-state model with fixed S-G2-M duration and random G1 duration1,2; a “stretched” model in which phase durations are proportional3; and an inheritance model in which sister cells show correlated phase durations2,4. A fundamental challenge is to understand the quantitative laws that govern cell-cycle progression and to reconcile the evidence supporting these different models. Here, we used time-lapse fluorescence microscopy to quantify the durations of G1, S, G2, and M phases for thousands of individual cells from three human cell lines. We found no evidence of correlation between any pair of phase durations. Instead, each phase followed an Erlang distribution with a characteristic rate and number of steps. These observations suggest that each cell cycle phase is memoryless with respect to previous phase durations. We challenged this model by perturbing the durations of specific phases through oncogene activation, inhibition of DNA synthesis, reduced temperature, and DNA damage. Phase durations remained uncoupled in individual cells despite large changes in durations in cell populations. To explain this behavior, we propose a mathematical model in which the independence of cell-cycle phase durations arises from a large number of molecular factors that each exerts a minor influence on the rate of cell-cycle progression. The model predicts that it is possible to force correlations between phases by making large perturbations to a single factor that contributes to more than one phase duration, which we confirmed experimentally by inhibiting cyclin-dependent kinase 2 (CDK2). We further report that phases can show coupling under certain dysfunctional states such as in a transformed cell line with defective cell cycle checkpoints. This quantitative model of cell cycle progression explains the paradoxical observation that phase durations are both inherited and independent and suggests how cell cycle progression may be altered in disease states.
A co-evolutionary perspective on business processes
Authors: Uli Vincenzo
Published: March 2018

Purpose

What new empirical implications can emerge in the organizational adaptation domain by adopting a multi-level co-evolutionary theoretical perspective? How does the performance appraisal process affect the evolution of the organization? The purpose of this paper, positioned within the organizational evolution research field, is to untangle the complexity behind emergence, development, and extinction of business processes over time, highlighting the inner mechanisms behind the adaptation process.

Design/methodology/approach

The work is presented as a longitudinal, single case study of a service firm. Scholars concur in considering this approach particularly reliable when investigating the evolution of a practice (Feldman, 2000; Howard-Grenville, 2005; Lazaric and Denis, 2005). Data have been collected during 2014 through three main methods: unstructured interviews, meeting observations, and direct observation of participants.

Findings

From the analysis, it emerges that the impact of the performance appraisal routine on individual and group dynamics is the main determinant behind organizational inertia and resistance to change. In particular, the degree of managerial control exerted, the feedback scheme applied, and the group interaction mechanisms are predictors of the degree of business process exploitation or exploration within a practice.

Research limitations/implications

In order to address the exploratory nature of the work, further developments may deepen the analysis investigating and comparing the findings obtained in different business contexts, highlighting important similarities or differences in various sectors. Different empirical settings might also be beneficial in further investigating the complexity of additional dimensions of routines’ evolution, especially at the group and organization level of analysis.

Practical implications

The insights from the case may serve as useful inputs to improve the efficiency of the service firm examined, and to identify possible mechanisms to foster knowledge production and replication within the practice.

Originality/value

The paper, by adopting a co-evolutionary perspective, has been conceived as a deliberate search for new empirical implications in the organizational evolution research domain at multiple levels of analysis.