bluuebunny/crossref_metadata_2025 huggingface dataset:
Error field optimization in DIII-D using extremum seeking control
Authors: Lanctot M.J. , Olofsson K.E.J. , Capella M. , Humphreys D.A. , Eidietis N. , Hanson J.M. , Paz-Soldan C. , Strait E.J. , Walker M.L.
Published: June 2016

DIII-D experiments have demonstrated a new real-time approach to tokamak error field control based on maximizing the toroidal angular momentum. This approach uses extremum seeking control theory to optimize the error field in real time without inducing instabilities. Slowly-rotating n  =  1 fields (the dither), generated by external coils, are used to perturb the angular momentum, monitored in real-time using a charge-exchange spectroscopy diagnostic. Simple signal processing of the rotation measurements extracts information about the rotation gradient with respect to the control coil currents. This information is used to converge the control coil currents to a point that maximizes the toroidal angular momentum. The technique is well-suited for multi-coil, multi-harmonic error field optimizations in disruption sensitive devices as it does not require triggering locked tearing modes or plasma current disruptions. Control simulations highlight the importance of the initial search direction on the rate of the convergence, and identify future algorithm upgrades that may allow more rapid convergence that projects to convergence times in ITER on the order of tens of seconds.
Benchmarking the next generation of homology inference tools
Authors: Saripella Ganapathi Varma , Sonnhammer Erik L. L. , Forslund Kristoffer
Published: June 2016

Motivation: Over the last decades, vast numbers of sequences were deposited in public databases. Bioinformatics tools allow homology and consequently functional inference for these sequences. New profile-based homology search tools have been introduced, allowing reliable detection of remote homologs, but have not been systematically benchmarked. To provide such a comparison, which can guide bioinformatics workflows, we extend and apply our previously developed benchmark approach to evaluate the ‘next generation’ of profile-based approaches, including CS-BLAST, HHSEARCH and PHMMER, in comparison with the non-profile based search tools NCBI-BLAST, USEARCH, UBLAST and FASTA.

Method: We generated challenging benchmark datasets based on protein domain architectures within either the PFAM + Clan, SCOP/Superfamily or CATH/Gene3D domain definition schemes. From each dataset, homologous and non-homologous protein pairs were aligned using each tool, and standard performance metrics calculated. We further measured congruence of domain architecture assignments in the three domain databases.

Results: CSBLAST and PHMMER had overall highest accuracy. FASTA, UBLAST and USEARCH showed large trade-offs of accuracy for speed optimization.

Conclusion: Profile methods are superior at inferring remote homologs but the difference in accuracy between methods is relatively small. PHMMER and CSBLAST stand out with the highest accuracy, yet still at a reasonable computational cost. Additionally, we show that less than 0.1% of Swiss-Prot protein pairs considered homologous by one database are considered non-homologous by another, implying that these classifications represent equivalent underlying biological phenomena, differing mostly in coverage and granularity.

Availability and Implementation: Benchmark datasets and all scripts are placed at ( http://sonnhammer.org/download/Homology_benchmark ).

Contact:  forslund@embl.de

Supplementary information : Supplementary data are available at Bioinformatics online.
A novel role for poly(C) binding proteins in programmed ribosomal frameshifting
Authors: Napthine Sawsan , Treffers Emmely E. , Bell Susanne , Goodfellow Ian , Fang Ying , Firth Andrew E. , Snijder Eric J. , Brierley Ian
Published: June 2016

Translational control through programmed ribosomal frameshifting (PRF) is exploited widely by viruses and increasingly documented in cellular genes. Frameshifting is induced by mRNA secondary structures that compromise ribosome fidelity during decoding of a heptanucleotide ‘slippery’ sequence. The nsp2 PRF signal of porcine reproductive and respiratory syndrome virus is distinctive in directing both −2 and −1 PRF and in its requirement for a trans-acting protein factor, the viral replicase subunit nsp1β. Here we show that the the trans-activation of frameshifting is carried out by a protein complex composed of nsp1β and a cellular poly(C) binding protein (PCBP). From the results of in vitro translation and electrophoretic mobility shift assays, we demonstrate that a PCBP/nsp1β complex binds to a C-rich sequence downstream of the slippery sequence and here mimics the activity of a structured mRNA stimulator of PRF. This is the first description of a role for a trans-acting cellular protein in PRF. The discovery broadens the repertoire of activities associated with poly(C) binding proteins and prototypes a new class of virus–host interactions.
Differences in Sensitivity to a Triazole Fungicide Among Stagonosporopsis Species Causing Gummy Stem Blight of Cucurbits
Authors: Li Hao-Xi , Stevenson Katherine L. , Brewer Marin T.
Published: June 2016

Gummy stem blight (GSB) is a destructive disease of cucurbits caused by three closely related Stagonosporopsis species. In the southeastern United States, GSB management relies heavily on triazole fungicides. Our objectives were to determine if resistance to triazoles has developed in populations of GSB fungi in the southeastern United States, and if so, to investigate the molecular basis of resistance. A tebuconazole sensitivity assay was conducted on 303 Stagonosporopsis citrulli and 19 S. caricae isolates collected from the southeastern United States in 2013 and 2014, as well as three S. citrulli, three S. cucurbitacearum, and six S. caricae isolates from other regions or years. Tebuconazole resistance was detected for all 19 S. caricae isolates from the southeastern United States and one S. caricae isolate from Brazil. All S. citrulli and S. cucurbitacearum isolates were sensitive to tebuconazole. For resistant and sensitive isolates of S. caricae, coding and promoter regions of the target gene Cyp51 were sequenced and expression levels of Cyp51 and ScAtrG (an ATP-binding cassette transporter) were measured. Tebuconazole resistance was not associated with mutations within Cyp51, multiple copies of Cyp51, changes in the promoter region, or increased expression of Cyp51 or ScAtrG. Tebuconazole resistance may explain the increase in frequency of S. caricae isolates recovered from GSB-infected cucurbits in Georgia.
Simultaneous bilateral tibial tubercle avulsion fracture in a male teenager: case report and literature review
Authors: Nicolini Alexandre P. , Carvalho Rogerio T. , Ferretti Mario , Cohen Moises
Published: June 2016

Tibial tuberosity avulsion fractures are injuries accounting for less than 3% of all epiphyseal and 1% of all physeal injuries in adolescents. Bilateral injuries are very rare, with only 19 cases described in the literature. These types of fractures occur commonly in male teenagers during sport activities and are often associated with other orthopaedic disorders. We report the case of a male teenager with simultaneous bilateral tibial tubercle fractures, describe the evolution and treatment of this injury and review the literature on this subject. Level of evidence: Case report.
Atelosteogenesis type III: orthopedic management
Authors: Sarikaya Ilker A. , Gorgun Baris , Erdal Ozan A.
Published: June 2016

Atelosteogenesis type III is a rare autosomal dominant skeletal dysplasia caused by mutations in the synthesis of the protein filamin B (FLNB). The mutation in the gene coding for FLNB causes the osteochondrodysplastic features of this disorder. Clinically, osteochondrodysplasia causes unbalanced skeletal maturation and absent or mostly hypoplastic bones, such as the pelvis, vertebrae, ribs, or long bones. In the literature, an orthopedic management for this disorder has not been well described. We report the case and orthopedic management of a 6-year-old female patient with atelosteogenesis type III after 3 years of follow-up.
Percutaneous aspiration and irrigation technique for the treatment of pediatric septic hip: effectiveness and predictive parameters
Authors: Weigl Daniel M. , Becker Tali , Mercado Eyal , Bar-On Elhanan
Published: June 2016

Septic arthritis of the hip has been treated traditionally by surgical drainage. Recent reports have described repeated aspirations as an adequate and safe treatment. The aim of the present study was to assess the success of treatment of septic arthritis of the hip by repeated aspirations and to identify predictive factors for failure. Medical records were retrospectively reviewed for all patients treated by ultrasound-guided aspiration and intravenous antibiotics between 2002 and 2010. The demographic, clinical, laboratory, and outcome data were recorded. Findings were compared between patients who responded to this treatment and those who subsequently required surgery. A total of 42 patients fulfilled the inclusion criteria. Of the total 33 responded to repeated aspirations and nine required surgical drainage. The mean age of patients requiring surgery was 8.3 years compared with 2.6 years for those responding to aspirations. Age older than 10 years was associated with a 57% rate of failed conservative treatment compared with 14% for age younger than 10 years. There was no significant difference between the groups in any of the other parameters measured. Follow-up of the operated group after an average of 7.44 years showed no unfavorable results. In children with septic arthritis of the hip, hip decompression may be achieved with repeated aspirations and lavage combined with antibiotics, sparing patients the risks of anesthesia and surgery. Age older than 10 years at admission may serve as the cutoff for initial conservative treatment. The postponement of surgery did not cause any long-term morbidity. Level of evidence: Level III; patients compared on the basis of outcome of conservative treatment of septic hip arthritis.
Normal Percentile Reference Curves and Correlation of Acetabular Index and Acetabular Depth Ratio in Children
Authors: Novais Eduardo N. , Pan Zhaoxing , Autruong Patrick T. , Meyers Mariana L. , Chang Frank M.
Published: June 2016

Background:

Radiographic surveillance of the hip is vital in the diagnosis and treatment of developmental dysplasia of the hip (DDH) in children. The acetabular index (AI) and the acetabular depth ratio (ADR) are radiographic parameters for evaluation of acetabular morphology. Normal reference curves for these parameters that allow for serial evaluation of acetabular development in a manner that is independent of age are necessary and clinically useful. The purpose of this study was (1) to establish normal values of AI and ADR in the normally developing pediatric hip up to age 14, (2) to generate percentile reference curves of both parameters, (3) to determine the extent of correlation between AI and ADR, and (4) to assess intrarater and interrater reliability of AI measurement.

Methods:

We identified 1734 patients who underwent anterior-posterior pelvic radiography between 2004 and 2014. A total of 1152 patients (age range, 0.15 to 13.97 y; 2304 hips) were identified as radiographically normal in the radiology report, signed by the attending pediatric radiologist on the basis of the absence of structural deformity of the hip and previously established reference values for DDH assessment. A review of the medical records confirmed that patients had no diagnosis of DDH or any other orthopaedic hip pathology. The AI and ADR were measured in all radiographs. Normal values and fully parametric percentile curves were generated from birth to skeletal maturity. Correlation between AI and ADR was assessed using linear regression analysis.

Results:

Normal AI decreased, and ADR increased, with age. Percentile curves were generated for AI and ADR. Using the provided equations, measured values can be converted to age-appropriate percentile and Z-score. The 2 parameters exhibited strong correlation (Pearson correlation=−0.789, P<0.001). For every unit increase in ADR, AI decreased by 0.94 degrees.

Conclusions:

We present updated normative values of AI that expand up to age 14, and novel reference values for ADR. The reference curves allow for the easy conversion of measured values to percentile and Z-score. Using the presented method during surveillance of the pathologic hip, change in acetabular development can now be assessed in a manner that is independent of age and the natural development of the acetabulum.

Level of Evidence:

Level IV—case series.
Performing a Definitive Fusion in Juvenile CP Patients is a Good Surgical Option
Authors: Yaszay Burt , Sponseller Paul D. , Shah Suken A. , Asghar Jahangir , Miyanji Firoz , Samdani Amer F. , Bartley Carrie , Newton Peter O.
Published: June 2016

Background:

In juveniles with progressive curves, there is debate regarding the use of growth friendly implants versus definitive fusion. This study presents outcomes of juvenile cerebral palsy (CP) scoliosis patients who underwent definitive fusion before age 11.

Methods:

A review of a prospective, multicenter registry identified patients 10 years and younger who had a definitive posterior fusion for their CP scoliosis. Preoperative and postoperative demographic and radiographic changes were evaluated with descriptive statistics. Repeated measures analysis of variance were utilized to compare outcome scores.

Results:

Fourteen children with a mean age of 9.7 years (8.3 to 10.8 y) and a minimum of 2 years follow-up (range 2 to 3 y) were identified. The mean preoperative curve magnitude and pelvic obliquity was 84±25 degrees (range 63 to 144 degrees) and 25±14 degrees, respectively. All patients were skeletally immature with open triradiate cartilage. Three patients had unit rods with wires while the rest incorporated pedicle screws. Immediately postoperation, the average major curve was 25±17 degrees (P≤0.001, 71% correction rate). At most recent follow-up, the average major curve increased to 30±18 degrees (P≤0.001) for a 65% correction rate. Pelvic obliquity improved to 4±4 degrees (84% correction, P≤0.001) immediately postoperation and to 6±5 degrees (P=0.002) at latest follow-up for a 76% correction rate. None of the patients required revision surgery for progression. From pre to most recent follow-up, the CPchild Health outcome scores improved from 47 to 58 (P=0.019). One patient had a deep infection, and 1 patient had a broken rod that did not require any further treatment.

Conclusions:

Progressive scoliosis in juvenile CP patients requires the surgeon to balance the need for further growth with the risks of progression or repeated surgical procedures. Our study demonstrates that definitive fusion once the curves approach 90 degrees results in significant radiographic and quality of life improvements, but further follow-up is needed to determine whether those results remain after skeletal maturity.

Level of Evidence:

Level IV—therapeutic.
Value of General Medical Knowledge Examinations in Performance Assessment of Practicing Physicians With Potential Competence and Performance Deficiencies
Authors: Wenghofer Elizabeth F. , Henzel Thomas R. , Miller Stephen H. , Norcross William , Boal Peter
Published: June 2016

Introduction:

Problems with a physician's performance may arise at any point during their career. As such, there is a need for effective, valid tools and processes to accurately assess and identify deficiencies in competence or performance. Although scores on multiple-choice questions have been shown to be predictive of some aspects of physician performance in practicing physicians, their relationship to overall clinical competence is somewhat uncertain particularly after the first 10 years of practice. As such, the purpose of this study was to examine how a general medical knowledge multiple-choice question examination is associated with a comprehensive assessment of competence and performance in experienced practicing physicians with potential competence and performance deficiencies.

Methods:

The study included 233 physicians, of varying specialties, assessed by the University of California, San Diego Physician Assessment and Clinical Education Program (PACE), between 2008 and 2012, who completed the Post-Licensure Assessment System Mechanisms of Disease (MoD) examination. Logistic regression determined if the examination score significantly predicted passing assessment outcome after correcting for gender, international medical graduate status, certification status, and age.

Results:

Most physicians (89.7%) received an overall passing assessment outcome on the PACE assessment. The mean MoD score was 66.9% correct, with a median of 68.0%. Logistic regression (P = .038) was significant in indicating that physicians with higher MoD examination scores had an increased likelihood of achieving a passing assessment outcome (odds ratio = 1.057).

Discussion:

Physician MoD scores are significant predictors of overall physician competence and performance as evaluated by PACE assessment.
Locally Advanced Cervical Cancer
Authors: Manders Dustin B. , Morón Abel , McIntire Donald , Miller David S. , Richardson Debra L. , Kehoe Siobhan M. , Albuquerque Kevin V. , Lea Jayanthi S.
Published: June 2016

Objective:

Adherence to treatment regimen and schedule is recommended to improve control of disease and overall survival (OS) in locally advanced cervical cancer. However, treatment-related toxicities and patient and physician factors all impact timely completion of treatment. We sought to correlate adherence to treatment plan with survival and toxicities of patients treated for locally advanced cervical cancer.

Materials and Methods:

A retrospective review of patients treated for advanced cervical cancer at our institution between 2003 and 2011 was performed. Demographics, clinicopathologic variables, treatment, and disease outcomes were collected. Endpoints of disease outcome were disease-free survival and OS. Statistical analyses were performed using the Kaplan-Meier method, log-rank test, and Cox regression analysis.

Results:

A total of 162 patients met the inclusion criteria and were included in study analysis. A total of 95% of patients were treated with both radiation and concurrent chemotherapy. Mean radiation dose to point A was 72 Gy. In total, 77% had complete response to primary therapy. Severe (grade 3/4) late radiation toxicities were seen in 10.5% of patients. Stage and total radiation dose to point A were significant predictors of survival for the entire cohort. Among patients receiving at least 72 Gy and brachytherapy, duration of treatment was significantly associated with both disease-free survival and OS.

Conclusions:

Adherence to both optimal treatment time and radiation dose is significantly associated with improved survival. Total radiation dose is an independent predictor of survival among patients with locally advanced cervical cancer.
Prevalence and Correlates of HIV Disclosure Among Children and Adolescents in Low- and Middle-Income Countries: A Systematic Review
Authors: Britto Carl , Mehta Kayur , Thomas Rwituja , Shet Anita
Published: June 2016

Objective:

Disclosure of HIV status among children and adolescents living with HIV has both beneficial and challenging aspects. To address existing knowledge gaps and update the literature on childhood disclosure, we conducted a systematic review on caregivers' perceptions and practices of HIV disclosure in low- and middle-income countries (LMICs).

Methods:

Standard databases were searched for studies conducted in LMICs, published in English between 2004 and 2015. Excluded articles were reviews or case reports, and those not reporting childhood disclosure. Data regarding prevalence, correlates and impact of disclosure, were presented as frequencies.

Results:

Two authors independently screened 982 articles. After applying eligibility criteria, 22 articles representing 12 countries and 2,843 children were reviewed. The proportion of fully disclosed children ranged from 1.7% to 41.0%. Up to 49.5% children were provided “deflected” information (use of a non-HIV-related reason for explaining illness and health care visits). Factors associated with full disclosure included antiretroviral treatment initiation and caregivers' felt need for maintaining optimal adherence. Barriers to disclosure included fear of negative psychological reactions and inadvertent disclosure to others. Caregivers perceived a strong need for active participation from health care providers to aid the process of disclosure.

Conclusions:

Full disclosure of HIV status was not common among children and adolescents in LMICs, while the practice of deflected disclosure was prominent. Caregivers perceived the need for support from health care providers during the disclosure process. Evidence-based guidelines incorporating the developmental status of the child, locally prevalent cultures, and caregiver perceptions are prerequisite to enhancing disclosure in these settings.
Advances in eyelid reconstruction
Authors: Dhar Shumon I. , Kopp Robert , Tatum Sherard A.
Published: June 2016

Purpose of review

To describe the principles of eyelid reconstruction that must balance aesthetic and functional concerns of one of the most important areas of physical beauty on the human body. Our review seeks to give an overview of how to utilize a variety of techniques along the reconstructive ladder from direct closure to complex grafts and local flaps.

Recent findings

We describe novel modifications of existing flaps that have been traditionally used in eyelid reconstruction along with analysis of many time honored techniques and current research in improving our understanding of the factors which allow a successful reconstruction.

A familiarity with the variety of options for reconstruction will give the surgeon the fluidity to analyze a defect and choose the best possible method.
Attention deficit hyperactivity disorder medications in children with heart disease
Authors: Berger Stuart
Published: June 2016

Purpose of review

Attention deficit hyperactivity disorder (ADHD) is quite common in the general pediatric population, Its incidence is thought to be even higher in the population of patients with congenital heart disease, especially in those patients with complex disease and who have had cardiac surgical interventions early in life. There has been controversy as to the safety of ADHD medications, especially in the latter population of patients. This compendium is meant to review the effects of the ADHD medications and the safety of these medications in patients with either known or undiagnosed congenital heart disease.

Recent findings

The concern with regard to the use of ADHD medications has been as a result of the reports of sudden unexpected deaths among patients taking stimulant drugs for ADHD. Therefore, the question of whether or not stimulant drugs increase the risk of adverse cardiovascular events has led to a discussion of the appropriate use of these drugs in patients with known cardiovascular disease, as well as a discussion as to the appropriate evaluation in order to identify undiagnosed ‘at-risk’ patients with congenital heart disease or arrhythmias. This article will review and amplify these discussions, as well as the conclusions that have come forth as a result of these discussions.

Currently available data suggest that there is no evidence for serious adverse cardiovascular complications in children with known cardiovascular diseases including patients of congenital heart disease who are treated with stimulant medications. Despite this, if the patient does have known cardiac disease, or if the history and physical examination is suggestive of cardiac disease, it is suggested that consultation/evaluation with a pediatric cardiologist occur. It is extremely unlikely that stimulant medications would be contraindicated in almost any condition that falls under this category. However, a few specific cardiac conditions might tailor the choice of the specific ADHD medication. Therefore the coordination of care between the primary care physician, the ADHD medication-prescribing physician, and the pediatric cardiologist may be very important in this circumstance.
Burkholderia cepacia pseudobacteremia traced to contaminated antiseptic used for skin antisepsis prior to blood collection
Authors: Tandel Kundan , Bhatt Puneet , Sen Sourav , Gupta Rajiv Mohan , Hazra Nandita , Praharaj A.K. , Kumar Satish , Sahni A.K.
Published: June 2016

Background:

Burkholderia (previously Pseudomonas) cepacia is a Gram-negative bacillus commonly found in soil and moist environments and capable of surviving and growing in nutrient-poor surroundings. It is a problematic pulmonary pathogen in patients with cystic fibrosis and is associated with a poor prognosis. Small hospital outbreaks are frequent, usually because of a single contaminated source such as disinfectant.

Aim:

To identify the source and route of infection of B. cepacia grown from 12 patients from a surgical ICU.

Methods:

We carried out an environmental and epidemiological investigation to identify the source and route of infection. Environmental samples previously reported to be potential reservoirs of B. cepacia were collected and processed.

Results:

Out of 67 blood samples received in a 2-month period from the ICU (surgical) of a tertiary care centre, B. cepacia was isolated from blood specimens of 12 patients, whereas 34 samples grew organisms other than B. Cepacia, 20 specimens were culture negative. There were no cases of B. Cepacia in the last 1 year before this outbreak. We isolated B. cepacia from the cetrimide + chlorhexidine solution used for skin antisepsis prior to blood collection.

Conclusion:

B. cepacia has the potential to cause fatal infections and its multidrug resistance makes its presence dangerous in hospital settings. The surveillance of B. cepacia infections should not be neglected, especially in the ICUs. Given the high transmissibility of the microorganism and previous epidemic reports, strict infection control measures should be applied in the case of diagnosis of B. cepacia infection.
Streptococcus constellatus Tubo-ovarian Abscess in a Non–Sexually Active Adolescent Female
Authors: Mills David , Sharon Bazak , Schneider Kari
Published: June 2016

Tubo-ovarian abscess (TOA) in non–sexually active female adolescents is a rare presentation to the pediatric emergency department. In the following case, bilateral TOA secondary to Streptococcus constellatus was diagnosed in a 13-year-old virginal female. The patient was seen 4 months before presentation for interventional radiology-guided drainage and antibiotic treatment for an intra-abdominal abscess due to suspected appendiceal rupture. Exploratory laparotomy on the most recent presentation demonstrated an appendix with inflammation and serositis on pathology report, a concern for chronic appendicitis with microperforation and subsequent bacterial translocation of the bilateral ovaries. This case report identifies a rare cause, pathogen, and the patient's demographics presenting with bilateral TOA. Most importantly, this case demonstrates the need for emergency medicine physicians to have a high index of suspicion for TOA in patients with a significant medical history of intra-abdominal pathology to promptly diagnose and treat high-morbidity pathology.
Pre–Trauma Center Management of Intracranial Pressure in Severe Pediatric Traumatic Brain Injury
Authors: Hansen Gregory , McDonald Patrick J. , Martin Doug , Vallance Jeff K.
Published: June 2016

Objectives

Pre–trauma center care is a critical component in severe pediatric traumatic brain injury (TBI). For geographically large trauma catchment areas, optimizing increased intracranial pressure (ICP) management may potentially improve outcomes. This retrospective study examined ICP management in nontrauma centers and during interfacility transport to the trauma center.

Methods

Charts from a pediatric level I trauma center were reviewed for admissions between 2008 and 2013. Patients with a Glasgow Coma Scale score of 8 or less, head Abbreviated Injury Scale score of 3 or higher, and requiring intubation at a nontrauma center were included. Exclusion criteria included head injury secondary to drowning, stroke, obstetrical complications, asphyxia, and afflicted head trauma (younger than 5 years). Trauma center charts contained coalesced data from first responders, nontrauma centers, and transport.

Results

Twenty-five patients (74%) had increased ICP upon admission at trauma center, 48% experienced ICPs greater than 20 cm H2O within 12 hours of admission, 12% required an urgent craniotomy, and 16% had herniation syndromes on neuroimaging. Pre–trauma center ICP management included osmotherapy and head-of-bed elevation. Sixty-four percent of patients with increased ICP at trauma center admission received pre–trauma center ICP management.

Conclusions

Early increased ICP is a common presentation of severe pediatric TBI during pre–trauma center management. However, what constitutes optimal care remains unknown. Given the difficulties of diagnosing early increased ICP in this setting, prophylactic raising ICP-lowering strategies may be considered.
Paul Emanuel Polani. 1 January 1914 — 18 February 2006
Authors: Giannelli F.
Published: June 2016

Paul Emanuel Polani: an indefatigable man of medium height and athletic constitution, with piercing brown eyes and warm, gentle manners; a sharp, deeply cultured intellect with an unquenchable desire to learn; a mind always seeking deeper understanding through study, observation and correlation; a person of deep controlled emotions, lasting affections, strong morals, and profound respect for his fellow human beings; a life affected by the troubled Italian politics of the 1920s and 1930s, and forced by war to delay dreams of genetic research and to show instead great medical and surgical prowess. In his late thirties Paul Polani began to fulfil his research dreams. He realized that, contrary to expectations, sex determination in humans did not follow the
Drosophila
-based model, because humans with an XO sex chromosome complement are female, while those with a Y chromosome are male even when they have two X chromosomes. He also discovered that Down syndrome is sometimes caused by chromosomal translocations that, if inherited from unaffected carriers, may cause familial clustering of the disease. This was the first stimulus to the development of prenatal chromosomal tests. Then in 1960 he established a multidisciplinary unit at Guy's Hospital, London, to investigate diseases of mainly genetic aetiology, and apply research findings to clinical care, while adhering to clear ethical principles. In doing so he demonstrated originality, breadth of vision, and inspiring leadership, and is rightly considered one of the most influential founders of modern medical genetics.
Antagonistic roles of Polycomb repression and Notch signaling in the maintenance of somatic cell fate inC. elegans.
Authors: Pueschel Ringo , Coraggio Francesca , Marti Alisha , Meister Peter
Published: June 2016

Reprogramming of somatic cells in intact nematodes allows characterization of cell plasticity determinants, which knowledge is crucial for regenerative cell therapies. By inducing muscle or endoderm transdifferentiation by the ectopic expression of selector transcription factors, we show that cell fate is remarkably robust in fully differentiated larvae. This stability depends on the presence of the Polycomb-associated histone H3K27 methylation, but not H3K9 methylation: in the absence of this epigenetic mark, many cells can be transdifferentiated which correlates with definitive developmental arrest. A candidate RNAi screen unexpectedly uncovered that knock-down of somatic NotchLIN-12signaling rescues this larval arrest. Similarly in a wild-type context, genetically increasing NotchLIN-12signaling renders a fraction of the animals sensitive to induced transdifferentiation. This reveals an antagonistic role of the Polycomb repressive complex 2 stabilizing cell fate and Notch signaling enhancing cell plasticity.
Repeated range expansion and niche shift in a volcanic hotspot archipelago: radiation of Hawaiian Euphorbia (Euphorbiaceae)
Authors: Yang Ya , Morden Clifford W. , Sporck-Koehler Margaret J. , Sack Lawren , Berry Paul E.
Published: June 2016

AimThe taxon cycle hypothesis describes the cyclic movement of taxa during range expansion and contraction, accompanied by an evolutionary shift from open and often coastal vegetation to closed, and often inland forest vegetation in island systems. The Hawaiian Archipelago is an ideal system to test this hypothesis given the linear fashion of island formation and a relatively well-understood geological history.

LocationHawaiian Islands.

MethodsWe sampled 153 individuals in 15 of the 16 native species of HawaiianEuphorbiasectionAnisophyllumon six major Hawaiian Islands, plus 11 New World close relatives, to elucidate the biogeographic movement of this lineage along the Hawaiian island chain. We used a concatenated chloroplast DNA data set of more than eight kilobases in aligned length and applied maximum likelihood and Bayesian inference for phylogenetic reconstruction. Connectivity among islands and habitat types was estimated using BayesTraits. Age and phylogeographic patterns were co-estimated using BEAST. In addition, we used nuclear ribosomal ITS and the low-copy genesLEAFYandG3pdhCto investigate the reticulate relationships within this radiation.

ResultsWe estimate that HawaiianEuphorbiafirst arrived on Kauai or Niihau ca. 5 million years ago and subsequently diverged into 16 species on all major Hawaiian Islands. During this processEuphorbiadispersed from older to younger islands in a stepping-stone fashion through open, dispersal-prone habitats. Taxa that occupy closed vegetation on Kauai and Oahu evolvedin situfrom open vegetation taxa of the same island. Consequently, widespread species tend to occupy habitats with open vegetation, whereas single island endemic species predominantly occur in habitats with closed canopy and are only found on the two oldest islands of Kauai and Oahu.

Main conclusionsThe spatial and temporal patterns of dispersal and range shifts in HawaiianEuphorbiasupport an intra-volcanic-archipelago version of the taxon cycle hypothesis.
Statistical inference of protein structural alignments using information and compression
Authors: Collier James H. , Allison Lloyd , Lesk Arthur M. , Stuckey Peter J. , Banda Maria Garcia de la , Konagurthu Arun S.
Published: June 2016

Structural molecular biology depends crucially on computational techniques that compare protein three-dimensional structures and generate structural alignments (the assignment of one-to-one correspondences between subsets of amino acids based on atomic coordinates.) Despite its importance, the structural alignment problem has not been formulated, much less solved, in a consistent and reliable way. To overcome these difficulties, we present here a framework for precise inference of structural alignments, built on the Bayesian and information-theoretic principle of Minimum Message Length (MML). The quality of any alignment is measured by its explanatory power - the amount of lossless compression achieved to explain the protein coordinates using that alignment. We have implemented this approach in the programMMLignerhttp://lcb.infotech.monash.edu.au/mmlignerto distinguish statistically significant alignments, not available elsewhere. We also demonstrate the reliability ofMMLigner’s alignment results compared with the state of the art. Importantly,MMLignercan also discover different structural alignments of comparable quality, a challenging problem for oligomers and protein complexes.
Stem Cell Plasticity and Niche Dynamics in Cancer Progression
Authors: Picco Noemi , Gatenby Robert A. , Anderson Alexander R. A.
Published: June 2016

Objective

Cancer stem cells (CSCs) have been hypothesized to initiate and drive tumor growth and recurrence due to their self-renewal ability. If correct, this hypothesis implies that successful therapy must focus primarily on eradication of this CSC fraction. However, recent evidence suggests stemness is niche dependent and may represent one of many phenotypic states that can be accessed by many cancer genotypes when presented with specific environmental cues. A better understanding of the relationship of stemness to niche-related phenotypic plasticity could lead to alternative treatment strategies.

Methods

Here we investigate the role of environmental context in the expression of stem-like cell properties through in-silico simulation of ductal carcinoma. We develop a two-dimensional hybrid discrete-continuum cellular automata model to describe the single cell scale dynamics of multi-cellular tissue formation. Through a suite of simulations we investigate interactions between a phenotypically heterogeneous cancer cell population and a dynamic environment.

Results

We generate homeostatic ductal structures that consist of a mixture of stem and differentiated cells governed by both intracellular and environmental dynamics. We demonstrate that a wide spectrum of tumor-like histologies can result from these structures by varying microenvironmental parameters.

Conclusion

Niche driven phenotypic plasticity offers a simple first-principle explanation for the diverse ductal structures observed in histological sections from breast cancer.

Significance

Conventional models of carcinogenesis largely focus on mutational events. We demonstrate that variations in the environmental niche can produce intraductal cancers independent of genetic changes in the resident cells. Therapies targeting the microenvironmental niche, may offer an alternative cancer prevention strategy.
High-Throughput Screening and CRISPR-Cas9 Modeling of Causal Lipid-Associated Expression Quantitative Trait Locus Variants
Authors: Raghavan Avanthi , Wang Xiao , Rogov Peter , Wang Li , Zhang Xiaolan , Mikkelsen Tarjei S. , Musunuru Kiran
Published: June 2016

Genome-wide association studies have identified a number of novel genetic loci linked to serum cholesterol and triglyceride levels. The causal DNA variants at these loci and the mechanisms by which they influence phenotype and disease risk remain largely unexplored. Expression quantitative trait locus analyses of patient liver and fat biopsies indicate that many lipid-associated variants influence gene expression in a cis-regulatory manner. However, linkage disequilibrium among neighboring SNPs at a genome-wide association study-implicated locus makes it challenging to pinpoint the actual variant underlying an association signal. We used a methodological framework for causal variant discovery that involves high-throughput identification of putative disease-causal loci through a functional reporter-based screen, the massively parallel reporter assay, followed by validation of prioritized variants in genome-edited human pluripotent stem cell models generated with CRISPR-Cas9. We complemented the stem cell models with CRISPR interference experimentsin vitroand in knock-in micein vivo. We provide validation for two high-priority SNPs, rs2277862 and rs10889356, being causal for lipid-associated expression quantitative trait loci. We also highlight the challenges inherent in modeling common genetic variation with these experimental approaches.

Author Summary

Genome-wide association studies have identified numerous loci linked to a variety of clinical phenotypes. It remains a challenge to identify and validate the causal DNA variants in these loci. We describe the use of a high-throughput technique called the massively parallel reporter assay to analyze thousands of candidate causal DNA variants for their potential effects on gene expression. We use a combination of genome editing in human pluripotent stem cells, “CRISPR interference” experiments in other cultured human cell lines, and genetically modified mice to analyze the two highest-priority candidate DNA variants to emerge from the massively parallel reporter assay, and we confirm the relevance of the variants to nearby gene expression. These findings highlight a methodological framework with which to identify and functionally validate causal DNA variants.
Jmjd2/Kdm4 demethylases are required for expression ofIl3raand survival of acute myeloid leukemia cells
Authors: Agger Karl , Miyagi Satoru , Pedersen Marianne Terndrup , Kooistra Susanne M. , Johansen Jens Vilstrup , Helin Kristian
Published: June 2016

Acute myeloid leukemias (AMLs) with a rearrangement of the mixed-linage leukemia (MLL) gene are aggressive hematopoietic malignancies. Here, we explored the feasibility of using the H3K9- and H3K36-specific demethylases Jmjd2/Kdm4 as putative drug targets in MLL-AF9 translocated leukemia. UsingJmjd2a,Jmjd2b, andJmjd2cconditional triple-knockout mice,we show that Jmjd2/Kdm4 activities are required for MLL-AF9 translocated AML in vivo and in vitro. We demonstrate that expression of the interleukin 3 receptor α (Il3ra also known as Cd123) subunit is dependent on Jmjd2/Kdm4 through a mechanism involving removal of H3K9me3 from the promoter of theIl3ragene. Importantly, ectopic expression of Il3ra in Jmjd2/Kdm4 knockout cells alleviates the requirement of Jmjd2/Kdm4 for the survival of AML cells, showing thatIl3rais a critical downstream target of Jmjd2/Kdm4 in leukemia. These results suggest that the JMJD2/KDM4 proteins are promising drug targets for the treatment of AML.
Crystal structure of poly[N,N-diethyl-2-hydroxyethan-1-aminium [μ3-cyanido-κ3C:C:N-di-μ-cyanido-κ4C:N-dicuprate(I)]]
Authors: Corfield Peter W. R. , Cleary Emma , Michalski Joseph F.
Published: June 2016

In the title compound, {(C6H16NO)[Cu2(CN)3]}n, the cyanide groups link the CuIatoms into an open three-dimensional anionic network, with the molecular formula Cu2(CN)3−. One CuIatom is tetrahedrally bound to four CN groups, and the other CuIatom is bonded to three CN groups in an approximate trigonal-planar coordination. The tetrahedrally coordinated CuIatoms are linked into centrosymmetric dimers by the C atoms of two end-on bridging CN groups which bring the CuIatoms into close contact at 2.5171 (7) Å. Two of the cyanide groups bonded to the CuIatoms with trigonal-planar surrounding link the dimeric units into columns along theaaxis, and the third links the columns together to form the network. TheN,N-diethylethanolamine molecules used in the synthesis have become protonated at the N atoms and are situated in cavities in the network, providing charge neutrality, with no covalent interactions between the cations and the anionic network.
2-[(2-Fluorophenyl)(1H-indol-3-yl)methyl]-1H-indole
Authors: Anil Kumar R. , Naveen S. , Shrungesh Kumar T. O. , Mahadevan K. M. , Kumara M. N. , Lokanath N. K.
Published: June 2016

In the title compound, C23H17FN2, the indole ring systems are oriented orthogonally, as indicated by the dihedral angle between them of 88.49 (5)°. The fluorophenyl ring is nearly perpendicular to one of the indole ring systems [dihedral angle = 85.31 (16)°] and twisted by 63.6 (6)° from the other. In the crystal, N—H...π, C—H...π and C—H...F interactions occur, forming a three-dimensional network.
(N-{Amino[(diaminomethylidene)amino]methylidene}-N-methylmethanaminium)tribromidozinc(II)
Authors: Germán-Acacio Juan M. , Rivas Arzate Chrystian , Cardenas-Valencia Zeus , Flores-Alamo Marcos , Morales-Morales David
Published: June 2016

In the title compound, [ZnBr3(C4H12N5)], the ZnIIcation is tetrahedrally coordinated by three bromide ions and the (N-{amino[(diaminomethylene)amino]methylene}-N-methylmethanaminium) cation that binds through the central N atom. The complex is of interest as a potential antidiabetic drug of the biguanide family. The crystal structure is stabilized by an extensive series of N—H...Br and C—H...Br hydrogen bonds, which combine to form a three-dimensional structure.
Does country governance foster revenue efficiency of Islamic and conventional banks in GCC countries?
Authors: Kamarudin Fakarudin , Sufian Fadzlan , Md. Nassir Annuar
Published: June 2016

Purpose

– The purpose of this paper is to provide new empirical evidence on the impact of country governance on the revenue efficiency of Islamic and conventional banks. The empirical analysis is confined to Islamic and conventional banks operating in the Gulf Cooperation Council (GCC) countries banking sectors during the period of 2007-2011.

Design/methodology/approach

– The analysis comprises two main stages. In the first stage, the authors employ the data envelopment analysis (DEA) method to compute the revenue efficiency of Islamic and conventional banks. The authors then used the multivariate panel regression analysis with the ordinary least square and generalized method of moments as an estimation method to investigate the potential determinants and the effect of country governance on the revenue efficiency.

Findings

– The empirical findings indicate that greater voice and accountability, government effectiveness, and rule of law enhance the revenue efficiency of both Islamic and conventional banks. The authors find that regulatory quality exerts positive influence on Islamic banks, while the impact of political stability and control of corruption enhances the revenue efficiency of conventional banks.

Originality/value

– The study on the specific revenue efficiency concept of Islamic and conventional banking is still in its formative stage. In regards, majority of the studies that examined the effect of governance on bank efficiency have focused more on the corporate or bank governance that affects the governance within the institution. Thus, to the best of the knowledge, no study has been done to address the effect of country governance on the revenue efficiency of Islamic and conventional banks specifically on the GCC countries.