bluuebunny/crossref_metadata_2025 huggingface dataset:
Tendonitis and Tendon Rupture After Treatment With Rituximab: A Case Series
Authors: Alqahtani Ali , Sabha Marwa , Abdelfattah Thaer , Srour Khaled , Dhayihi Turki , Kahaleh Bashar , Altorok Nezam
Published: April 2017

Clinical Data:

Rituximab is a mouse/human chimeric anti-CD20 IgG1 monoclonal antibody used to treat cancer and autoimmune conditions. Side effects of rituximab include fever, rash, cytopenia and hypotension, back pain, arthralgia, and myalgia. Here, we report on 3 patients who developed moderate to severe tendonitis after the second infusion of rituximab.

Therapeutic Challenge:

We report 3 patients who developed tendonitis after the second infusion of rituximab. These patients were undergoing treatment for connective tissue diseases. All 3 patients received 2 rituximab infusions, 2 weeks apart. The 3 cases developed clinical tendonitis that was confirmed by magnetic resonance imaging in 2 cases.

Interpretation:

This is the first case series reporting new onset tendonitis in patients with connective tissue diseases after rituximab therapy. All 3 cases developed tendonitis 1 week after receiving the second dose of rituximab. Clinical features of tendonitis resolved 3–4 months in all cases. The underlying pathogenic mechanism by which rituximab causes tendonitis is not clear, but tendonitis and tendon rupture have been reported after using other medications such as quinolones. The tendon damage was progressive leading to tendon rupture in 1 patient, highlighting the importance of early recognition. It is plausible that there is a cause–effect relation between tendonitis and administration of rituximab in our 3 cases, since none of these cases had previous history of tendonitis; however, more data are needed to confirm this observation.
Methylphenidate attenuates the response to cold pain but not to aversive auditory stimuli in healthy human: a double-blind randomized controlled study
Authors: Pud Dorit , Broitman Eelena , Hameed Omar , Suzan Erica , Aviram Joshua , Haddad May , Hadad Salim , Shemesh Rafi , Eisenberg Elon
Published: April 2017

Introduction:

We recently showed that the psycho-stimulant norepinephrine–dopamine reuptake inhibitor methylphenidate (MP) prolonged cold pain threshold and tolerance in adults with attention-deficit hyperactivity disorder (ADHD).

Objectives:

The objectives of the present study were to: (1) examine whether MP has antinociceptive properties in healthy men; (2) test MP's effects on responses to aversive auditory stimuli. The underlying aim was to determine whether MP exerts antinociceptive properties or more generalized, nonspecific attenuating effects on different aversive sensory modalities.

Methods:

This double-blind, crossover, randomized placebo-controlled study consisted of 2 sessions one week apart from each other. In each session, pain threshold (seconds) and tolerance (seconds) in response to painful cold stimulation were measured. Additionally, threshold (dB) and tolerance (seconds) to loud aversive auditory stimuli (500 Hz, 2000 Hz and white noise) were also tested prior to and 2 hours following the administration of a single dose of either 20 mg MP or an identical looking placebo.

Results:

Forty men, 26.1 ± 4.0 (mean ± SD) years were enrolled in the study. Wilcoxon signed-rank test analyses showed that MP, but not the placebo, produced a significant increase in cold pain threshold (from 4.1 ± 2.6 to 5.4 ± 3.1 seconds, P = 0.001 and from 4.5 ± 2.6 to 4.3 ± 2.7 seconds, P = 0.2, respectively) and tolerance (from 57.8 ± 54.0 to 73.8 ± 61.8 seconds, P = 0.001 and from 52.5 ± 53.7 sec to 57.0 ± 52.9 seconds, P = 0.1, respectively). No significant changes were found in any of the auditory parameters.

Conclusion:

These results suggest that MP has an effect on nociceptive pathways rather than a nonspecific, generalized attenuating effect on aversive sensory stimuli.
Efficacy of Single-dose and 2-dose Intravenous Administration of Ramosetron in Preventing Postoperative Nausea and Vomiting After Laparoscopic Gynecologic Operation: A Randomized, Double-blind, Placebo-controlled, Phase 2 Trial
Authors: Lee Banghyun , Kim Kidong , Suh Dong Hoon , Shin Hyun-Jung , No Jae Hong , Lee Jung Ryeol , Jee Byung Chul , Hwang Jung Won , Do Sang Hwan , Kim Yong Beom
Published: April 2017

This randomized trial investigated whether a 2-dose administration of intravenous ramosetron (5-hydroxytryptamine type 3 receptor antagonist) is more effective than a single-dose administration in preventing postoperative nausea and vomiting (PONV) in 89 patients who were scheduled to undergo laparoscopic operation for benign gynecologic diseases and to receive intravenous patient-controlled analgesia for relief of postoperative pain. After assignment at a ratio of 1:1, intravenous ramosetron (0.3 mg) was initially administered at the end of skin closure in all patients. Thereafter, ramosetron (0.3 mg) and placebo were administered to the study and control groups, respectively, at 4 hours after the operation. The baseline and operative characteristics were similar between the groups. The incidence of PONV during the 24-hour period after operation which was assessed as the primary endpoint did not differ between the groups. No serious adverse events occurred in either group. A 2-dose administration of intravenous ramosetron may not be superior to a single-dose administration in preventing PONV in patients undergoing laparoscopic operation for benign gynecologic diseases.
Etiology of Leaks Following Sleeve Gastrectomy: Current Evidence
Authors: Hussain Abdulzahra , Vasas Peter , Kirk Katie , Finney John , Balchandra Srinivasan
Published: April 2017

Purpose:

The purpose of this paper is to study the causes of leaks following sleeve gastrectomy (SG).

Materials and Methods:

Pubmed was searched during January 2016 for publications reporting leak after SG. A total of 205 publications were identified, of which 17 papers were selected.

Results:

In about 3018 patients, reinforcement was used compared with 4595 patients, in whom no reinforcement was applied; both groups were representing matched bariatric populations. The use of reinforcement/buttressing has resulted in different rates of leaks ranging from 0% to 3.9%; whereas with no reinforcement/buttressing, the leak rate was 0.16% to 3.5%. The use of reinforcement/buttressing did not result in reduction of leak to a statistical significance although the trend was suggesting so (P=0.06), whereas no reinforcement/buttressing did not statistically increase the leak rate (P=0.10).

Conclusions:

No statistical significant difference of leak with or without reinforcement. This mean case complexity and surgical technique and experience are the sole factors for leaks following SG.
Complications of Minimally Invasive Surgery in Children: A Prospective Morbidity and Mortality Analysis Using the Clavien-Dindo Classification
Authors: Pio Luca , Rosati Ubaldo , Avanzini Stefano , Pini Prato Alessio , Torre Michele , Disma Nicola M. , Montobbio Giovanni , Mattioli Girolamo
Published: April 2017

There is a lack of information about evaluation of pediatric minimal access surgery complications; the Clavien-Dindo classification was never used for a large series of laparoscopic and thoracoscopic pediatric procedures. With a prospective Morbidity and Mortality database, all the minimal access surgical procedures carried out between 2012 and 2016 were included in this study. Statistical analyses were used to valuate modification of surgical techniques in to 2 periods (period 1: January 2012 to February 2014; period 2: February 2014 to February 2016). A total of 1374 minimal access procedures were performed on 1371 patients. The overall complication rate was 2.9%. No differences, in terms of complications, were observed between elective and emergency procedures (P=0.3). There was a significant difference between the complication rate of thoracoscopic surgery (P=0.027). These results provide the relevance of adequate recording system and standardized classification for analyses and reduction of complications for pediatric minimal access procedures.
Minimally Invasive Treatment for Appendiceal Mass Formed After Acute Perforated Appendicitis
Authors: Zerem Enver , Kunosić Suad , Handanagić Almin , Jahić Dženan , Zerem Dina , Zerem Omar
Published: April 2017

The optimal treatment for appendiceal mass formed after appendiceal rupture due to acute appendicitis is surrounded with controversy. The treatment strategy ranges from open surgery (emergency or interval appendectomy), laparoscopic appendectomy, and image-guided drainage, to conservative treatment with or without antibiotics. Nonsurgical treatment (including conservative and drainage treatment), followed by interval appendectomy to prevent recurrence, is the traditional management of these patients. The need for interval appendectomy after a successful conservative or/and image-guided drainage treatment, has recently been questioned as the risk of recurrence is relatively small. Several authors consider that even in cases involving only ambulatory follow-up observation, without interval surgery after conservative management, the recurrence rate and risks of missing underlying pathologies were not high. This article evaluates the minimally invasive treatment modalities in the management of appendiceal mass, risk of undetected serious disease, and the need for interval appendectomy to prevent recurrence.
Feasibility of Transvesical Robotic VVF Repair in Porcine Model
Authors: Han Jang Hee , Kim Hong-Wook , Rha Koon Ho , Kim Jang Hwan
Published: April 2017

Extraperitoneal transvesicoscopic vesicovaginal fistula (VVF) repair has received limited use because of its narrow working space, longer operation time, and technical difficulty. The present study describes the feasibility of robotic-assisted transvesicoscopic VVF repair in an animal model. Two Yorkshire swine underwent robotic-assisted laparoscopic (RAL) VVF repair. With the 4 trocars, an artificial VVF was made in the supratrigonal area and VVF repair was performed in 3 layers as in open VVF repair methods. The mean operation time was 108 minutes. The operation time was prolonged in 1 case due to weak fixation of bladder to anterior abdominal wall. Equipment interference did not occur. Tissue manipulation and suturing were easy. The results of this study suggest that extraperitoneal RAL procedures for VVF repair may be an effective minimally invasive modality with reduced morbidity. A shorter operation time and easy suturing technique were the distinct merits of the extraperitoneal RAL technique.
The Feasibility of Thoracoscopic Resection in Bronchiectasis
Authors: Baysungur Volkan , Dogruyol Talha , Ocakcioglu Ilhan , Misirlioglu Aysun , Evman Serdar , Kanbur Serda , Alpay Levent , Tezel Cagatay
Published: April 2017

Introduction:

Minimally invasive surgery is the treatment of choice in early-stage lung cancer. However, experience in infectious lung disease, primarily bronchiectasis, is limited probably because of the presence of dense pleural adhesions, multiple lymph nodes, and spiral bronchial arteries. The present study shows our experience of video-assisted thoracoscopic surgery (VATS) lobectomy and segmentectomy in the treatment of bronchiectasis.

Materials and Methods:

Patients who underwent VATS lobectomy or segmentectomy in our clinic between April 2008 and 2015 were retrospectively evaluated. Surgery was indicated in patients with radiologic localized bronchiectasis who also had a history of recurrent lower respiratory tract infection or expectorating mucopurulent secretion. The patients were analyzed in terms of age, sex, thoracotomy conversion rate, postoperative drainage amount, chest tube removal time, length of hospital stay, morbidity, and mortality.

Results:

A total of 44 patients initially underwent VATS pulmonary anatomic resection and 41 procedures were completed on 40 patients. One patient had bilateral resection. Fifteen patients were male individuals and 26 were female individuals. The average age was 31.4 (15 to 57) years. Forty lobectomies and 1 segmentectomy were performed. The conversion rate was 6.8%. VATS was performed on 28 patients by 3 ports, 8 patients by 2 ports, and 5 patients by a single port. In terms of anatomic resections, 18 patients underwent left lower lobectomy, 8 right lower lobectomy, 8 middle lobectomy, 6 right upper lobectomy, and 1 patient underwent lingular segmentectomy. No major postoperative complication or mortality was observed. Prolonged air leak was observed in 2 patients and subcutaneous emphysema occurred in 2 patients. The average postoperative drainage amount, chest tube removal time, and length of hospital stay were 320 mL, 3.1 (1 to 11) days, and 4.6 (2 to 11) days, respectively.

Conclusions:

VATS pulmonary resection is a safe, feasible, and effective treatment in the surgery of bronchiectasis with low morbidity and mortality rates. Moreover, because of cosmetic results, patients with benign diseases such as bronchiectasis could be initiated by minimally invasive surgery options just like patients with malignancies.
Optical Coherence Tomography in Neuroretinitis: Epipapillary Infiltrates and Retinal Folds
Authors: Zatreanu Luca , Sibony Patrick A. , Kupersmith Mark J.
Published: April 2017

Neuroretinitis is a form of papillitis associated with the delayed onset of an exudative macular star among other inflammatory ocular findings. We describe 4 patients with neuroretinitis who displayed several distinctive and novel findings on spectral-domain optical coherence tomography (OCT) that include “epipapillary infiltrates” and an atypical pattern of inner retinal folds. The recognition of these findings on OCT may help in the early diagnosis of neuroretinitis.
Sleep-Induced Apraxia of Eyelid Opening
Authors: Reggie Sara N. , Chen John J. , Lee Michael S. , Chung Sophia M.
Published: April 2017

Background:

Apraxia of eyelid opening (AEO) primarily has been described as bilateral loss of volitional ability to open the eyes at certain times and often associated with neurodegenerative disease. Rarely, it can occur in isolation and as an idiopathic phenomenon. There are a few reports of unilateral AEO only on awakening from sleep. We report an additional 11 patients with this unusual variation of AEO.

Methods:

Retrospective, observational case series of patients collected from 3 separate neuro-ophthalmology practices.

Results:

All 11 patients were Caucasian women with a mean age of 59 years (range 35–80 years). All experienced AEO on awakening from sleep. Eight patients had unilateral AEO, and 3 had bilateral symptoms. The duration of episodes ranged from 3 weeks to several years. Ten of the patients reported manually elevating the eyelid to open it, while 1 patient waited for the eyelid to open spontaneously. After initial manual elevation, all patients reported normal function and position of the eyelids for the remainder of the day. Seven patients had a history of autoimmune disease. Slit-lamp and fundus examinations were negative for ocular pathology to explain the patients' symptoms, and 9 patients had unremarkable brain imaging.

Conclusions:

AEO occurring only on awakening from sleep is a rare entity. Neuroimaging and extensive laboratory testing are not indicated without associated neurologic or ocular findings. There may be a Caucasian female preponderance and autoimmune link in patients with AEO, but further studies are required.
Flexible parental care: Uniparental incubation in biparentally incubating shorebirds
Authors: Bulla Martin , Prüter Hanna , Vitnerová Hana , Tijsen Wim , Sládeček Martin , Alves José A. , Gilg Olivier , Kempenaers Bart
Published: April 2017

Recent findings suggest that relative investment of females and males into parental care depends on the population’s adult sex-ratio. For example, all else being equal, males should be the more caring sex if the sex ratio is male biased. Whether such outcomes are evolutionary fixed (i.e. related to the species’ typical sex-ratio) or whether they arise through flexible responses of individuals to the current population sex-ratio remains unclear. Nevertheless, a flexible response might be limited by evolutionary history when one sex loses the ability to care or when a single parent cannot successfully care. Here, we demonstrate that after the disappearance of one parent, individuals from 8 out of 15 biparentally incubating shorebird species were able to incubate uniparentally for 1-19 days (median = 3,N= 69). Such uniparental phases often resembled the incubation rhythm of species with obligatory uniparental incubation. Although it has been suggested that females of some shorebirds desert their brood after hatching, our findings indicate that either sex may desert prior to hatching. Strikingly, in 27% of uniparentally incubated clutches - from 5 species - we document successful hatching. Our data thus reveal the potential for a flexible switch from biparental to uniparental care.
CCFold: rapid and accurate prediction of coiled-coil structures and application to modelling intermediate filaments
Authors: Guzenko Dmytro , Strelkov Sergei V.
Published: April 2017

Accurate molecular structure of the protein dimer representing the elementary building block of intermediate filaments (IFs) is essential towards the understanding of the filament assembly, rationalizing their mechanical properties and explaining the effect of disease-related IF mutations. The dimer contains a ∼300-residue longα-helical coiled coil which is not assessable to either direct experimental structure determination or modelling using standard approaches. At the same time, coiled coils are well-represented in structural databases. Here we present CCFold, a generally applicable threading-based algorithm which produces coiled-coil models from protein sequence only. The algorithm is based on a statistical analysis of experimentally determined structures and can handle any hydrophobic repeat patterns in addition to the most common heptads. We demonstrate that CCFold outperforms general-purpose computational folding in terms of accuracy, while being faster by orders of magnitude. By combining the CCFold algorithm and Rosetta folding we generate representative dimer models for all IF protein classes. The source code is freely available athttps://github.com/biocryst/IF
PB-kPRED: knowledge-based prediction of protein backbone conformation using a structural alphabet
Authors: Vetrivel Iyanar , Mahajan Swapnil , Tyagi Manoj , Hoffmann Lionel , Sanejouand Yves-Henri , Srinivasan Narayanaswamy , de Brevern Alexandre G. , Cadet Frédéric , Offmann Bernard
Published: April 2017

Libraries of structural prototypes that abstract protein local structures are known as structural alphabets and have proven to be very useful in various aspects of protein structure analyses and predictions. One such library, Protein Blocks (PBs), is composed of 16 standard 5-residues long structural prototypes. This form of analyzing proteins involves drafting its structure as a string of PBs. Thus, predicting the local structure of a protein in terms of protein blocks is a step towards the objective of predicting its 3-D structure. Here a new approach, kPred, is proposed towards this aim that is independent of the evolutionary information available. It involves (i) organizing the structural knowledge in the form of a database of pentapeptide fragments extracted from all protein structures in the PDB and (ii) apply a purely knowledge-based algorithm, not relying on secondary structure predictions or sequence alignment profiles, to scan this database and predict most probable backbone conformations for the protein local structures.

Based on the strategy used for scanning the database, the method was able to achieve efficient mean Q16accuracies between 40.8% and 66.3% for a non-redundant subset of the PDB filtered at 30% sequence identity cut-off. The impact of these scanning strategies on the prediction was evaluated and is discussed. A scoring function that gives a good estimate of the accuracy of prediction was further developed. This score estimates very well the accuracy of the algorithm (R2of 0.82). An online version of the tool is provided freely for non-commercial usage athttp://www.bo-protscience.fr/kpred/.
High accuracy label-free classification of kinetic cell states from holographic cytometry
Authors: Hejna Miroslav , Jorapur Aparna , Song Jun S. , Judson Robert L.
Published: April 2017

Digital holographic microscopy permits live and label-free visualization of adherent cells. Here we report the application of this approach for high accuracy kinetic quantitative cytometry. We identify twenty-six label-free optical and morphological features that are biologically independent. When used as a basis for machine learning, these features allow blind single cell classification with up to 95% accuracy. We present methods to control for inherent holographic noise, thereby establishing a set of reliable quantitative features. Together, these contributions permit continuous digital holographic cytometry for three or more days. Applying our approach to human melanoma cells treated with a panel of cancer therapeutics, we can track the response of each cell, simultaneously classifying multiple behaviors such as cell cycle length, motility, apoptosis, senescence, and heterogeneity of response to each therapeutic. Importantly, we demonstrate relationships between these phenotypes over time. This work thus provides an experimental and computational roadmap for low cost live-cell imaging and kinetic classification of heterogeneous adherent cell populations.
ChIPWig: A Random Access-Enabling Lossless and Lossy Compression Method for ChIP-seq Data
Authors: Ravanmehr Vida , Kim Minji , Wang Zhiying , Milenković Olgica
Published: April 2017

Motivation

The past decade has witnessed a rapid development of data acquisition technologies that enable integrative genomic and proteomic analysis. One such technology is chromatin immunoprecipitation sequencing (ChIP-seq), developed for analyzing interactions between proteins and DNA via next-generation sequencing technologies. As ChIP-seq experiments are inexpensive and time-efficient, massive datasets from this domain have been acquired, introducing significant storage and maintenance challenges. To address the resulting Big Data problems, we propose a state-of-the-art lossless and lossy compression framework specifically designed for ChIP-seq Wig data, termed ChIPWig. Wig is a standard file format, which in this setting contains relevant read density information crucial for visualization and downstream processing. ChIPWig may be executed in two different modes: lossless and lossy. Lossless ChIPWig compression allows for random access and fast queries in the file through careful variable-length block-wise encoding. ChIPWig also stores the summary statistics of each block needed for guided access. Lossy ChIPWig, in contrast, performs quantization of the read density values before feeding them into the lossless ChIPWig compressor. Nonuniform lossy quantization leads to further reductions in the file size, while maintaining the same accuracy of the ChIP-seq peak calling and motif discovery pipeline based on the NarrowPeaks method tailor-made for Wig files. The compressors are designed using new statistical modeling approaches coupled with delta and arithmetic encoding.

Results

We tested the ChIPWig compressor on a number of ChIP-seq datasets generated by the ENCODE project. Lossless ChIPWig reduces the file sizes to merely 6% of the original, and offers an average 6-fold compression rate improvement compared to bigWig. The running times for compression and decompression are comparable to those of bigWig. The compression and decompression speed rates are of the order of 0.2 MB/sec using general purpose computers. ChIPWig with random access only slightly degrades the performance and running time when compared to the standard mode. In the lossy mode, the average file sizes reduce by 2-fold compared to the lossless mode. Most importantly, near-optimal nonuniform quantization with respect to mean-square distortion does not affect peak calling and motif discovery results on the data tested.

Availability and Implementation

Source code and binaries freely available for download athttps://github.com/vidarmehr/ChIPWig

Contact

milenkov@illinois.edu

Supplementary information

Is available on bioRxiv.
Predation of stocked salmon by riparian wildlife in semi-natural stream
Authors: Miyamoto Kouta , Squires Theodore E. , Araki Hitoshi
Published: April 2017

Predation after release is one of the major concerns of hatchery fish conservation and propagation. However, the relationship among the size of hatchery fish, the predator species, and their behaviors in natural environments is largely unknown. To understand the relationship, we conducted predation experiments in outdoor tanks and a semi-natural stream with exposure to local predators. Two different ranges of fork lengths of masu salmon (Oncorhynchus masou) were examined as prey sizes. Camera trap data showed that grey herons (Ardea cinerea) were the primary predator animal in the system, and that most herons utilized shallow areas in the morning or evening. Increasing the density of stocked salmon brought in more grey herons. More importantly, predation by grey herons resulted in the survival rate of larger salmon being significantly lower than that of the smaller salmon. Our results suggest that it is important to understand local predators, adjust the optimum body size of hatchery fish at release, and choose the appropriate stocking site and time of day for maximizing the effectiveness of fish stocking.
Direct conversion of human fibroblasts into osteoblasts and osteocytes with small molecules and a single factor, Runx2
Authors: Li Yanjiao , Wang YaoLong , Yu Juehua , Ma Zhaoxia , Bai Qiong , Wu Xingfei , Bao Pengfei , Li Lirong , Ma Daiping , Liu Jinxue , Liu Change , Chen Fangyun , Hu Min
Published: April 2017

Human osteoblasts can be induced from somatic cells by introducing defined factors, however, the strategy limits cells therapeutic applications for its multi-factor and complicated genetic manipulations that may bring uncertainty into the genome. Another important cell type in bone metabolism, osteocytes, which play a central role in regulating the dynamic nature of bone in all its diverse functions, have not been obtained from transdifferetiation so far. Herein, we have established procedures to convert human fibroblast directly into osteocyte-like and osteoblast-like cells using a single transcription factor, Runx2 and chemical cocktails by activating Wnt and cAMP/PKA pathways. These induced osteoblast-like cells express osteogenic markers and generate mineralized nodule deposition. A good performance of bone formation from these cells was observed in subcutaneous site of mouse at 4 weeks post-transplantation. Moreover, further studies convert human fibroblasts into osteocyte-like cells by orchestrating timing of the aforementioned chemical cocktails exposure. These osteocyte-like cells express osteocyte-specific markers and display characteristic morphology features of osteocytes. In summary, this study provides a promising strategy for cell-based therapy in bone regenerative medicine by direct reprogramming of fibroblasts into osteocytes and osteoblasts.
The diversity, structure and function of heritable adaptive immunity sequences in the Aedes aegypti genome
Authors: Whitfield Zachary J. , Dolan Patrick T. , Kunitomi Mark , Tassetto Michel , Seetin Matthew G. , Oh Steve , Heiner Cheryl , Paxinos Ellen , Andino Raul
Published: April 2017

The Aedes aegypti mosquito is a major vector for arboviruses including dengue, chikungunya and Zika virus. Combating the spread of these viruses requires a more complete understanding of the mosquito immune system. Recent studies have implicated genomic endogenous viral elements (EVEs) derived from non-retroviral RNA viruses in insect immunity. Because these elements are inserted into repetitive regions of the mosquito genome, their large-scale structure and organization with respect to other genomic elements has been difficult to resolve with short-read sequencing. To better define the origin, diversity and biological role of EVEs, we employed single-molecule, real-time sequencing technology to generate a high quality, long-read assembly of the Ae. aegypti-derived Aag2 cell line genome. We leverage the quality and contiguity of this assembly to characterize the diversity and genomic context of EVEs in the genome of this important model system. We find that EVEs in the Aag2 genome are acquired through recombination by LTR retrotransposons, and organize into larger loci (>50kbp) characterized by high LTR density. These EVE containing loci are associated with increased transcription factor binding sight density and increased production of anti-genomic piRNAs. We also detected piRNA processing corresponding to on-going viral infection. This global view of EVEs and piRNA responses demonstrates the ubiquity and diversity of these heritable elements that define small-RNA mediated antiviral immunity in mosquitoes.
Characterization of the stoichiometry of the complex formed by Staphylococcal LukSF and human C5aR receptor in living cells
Authors: Haapasalo Karita , Wollman Adam J.M , de Haas Carla , van Kessel Kok , van Strijp Jos , Leake Mark C.
Published: April 2017

Staphylococcus aureusPanton Valentine Leukocidin (PVL) is a pore-forming toxin comprising protein subunits LukS and LukF. Binding of LukS to human C5a receptor (hC5aR) on leukocytes induces secondary binding of LukF and assembly of lytic complexes. Previous analysis suggests that PVL consists of 4-plus-4 LukS/LukF subunits but the exact stoichiometry between LukS, LukF and hC5aR is not yet known. In this study we determine the stoichiometry and spatiotemporal dynamics of functional LukS/LukF-hC5aR complexes in living eukaryotic cells. By using rapid total internal reflection fluorescence (TIRF) and single-molecule photobleaching analysis we found that tetrameric LukS-hC5aR complexes are formed within a cluster of receptors. Upon binding to hC5aR each LukS subunit binds LukF leading to lytic pore formation and simultaneous dissociation of receptors from the complex. Our findings corroborate a hetero-octamer model but provide a new view on the kinetics of crucial virulence factor assembly on integrated host cell membrane receptors.
Topological demarcation by HMGB2 is disrupted early upon senescence entry across cell types and induces CTCF clustering
Authors: Zirkel Anne , Nikolic Milos , Sofiadis Konstantinos , Mallm Jan-Philipp , Brant Lilija , Becker Christian , Altmüller Janine , Franzen Julia , Koker Mirjam , Gusmao Eduardo G , Costa Ivan G , Ullrich Roland T , Wagner Wolfgang , Nürnberg Peter , Rippe Karsten , Papantonis Argyris
Published: April 2017

Ageing-relevant processes, like cellular senescence, are characterized by complex, often stochastic, events giving rise to heterogeneous cell populations. We hypothesized that entry into senescence of different primary human cells can be triggered by one early molecular event affecting the spatial organization of chromosomes. To test this, we combined whole-genome chromosome conformation capture, population and single-cell transcriptomics, super-resolution imaging, and functional analyses applied on proliferating and replicatively-senescent populations from three distinct human cell types. We found a number of genes involved in DNA conformation maintenance being suppressed upon senescence across cell types. Of these, the abundant high mobility group (HMG) B1 and B2 nuclear factors are quantitatively removed from cell nuclei before typical senescence markers appear, and mark a subset of topologically-associating domain (TAD) boundaries. Their loss coincides with obvious reorganization of chromatin interactions via the dramatic spatial clustering of CTCF foci. HMGB2 knock-down recapitulates this senescence-induced CTCF clustering, while also affecting insulation at TAD boundaries. We accordingly propose that HMGB-mediated deregulation of chromosome conformation constitutes a primer for the ensuing senescent program across cell types.
Model based safety ranking of opioid drugs using Adversity index
Authors: Asvalayana Krishna , Ghubade Samadhan , Paranjpe Sharayu , Gore Anil
Published: April 2017

Annual ADR report counts of opioid drugs are examined to develop a candidate index of overall safety of a drug. Actual counts for various drugs have been sourced fromwww.vigiaccess.org. A feature found to be common to all drugs considered is that an exponential function adequately describes the pattern of cumulative counts. In the exponential model, the parameter in the exponent (rate constant) is robust and remains the same whether counts are corrected for exposure or not. We propose use of this rate constant as ‘adversity index’ of a drug. Drugs in use can be ranked by value of adversity index, lower value suggesting safer drug.

Key points

Cumulative total of annual ADR report counts of opioid drugs follows an exponential pattern. Rate constant in the model is independent of volume of use of the drug. Hence it is a suitable index of overall safety.
MaxTiC: Fast ranking of a phylogenetic tree by Maximum Time Consistency with lateral gene transfers
Authors: Chauve Cédric , Rafiey Akbar , Davín Adrián A. , Scornavacca Celine , Veber Philippe , Boussau Bastien , Szöllősi Gergely J. , Daubin Vincent , Tannier Eric
Published: April 2017

Lateral gene transfers between ancient species contain information about the relative timing of species diversification. Specifically, the ancestors of a donor species must have existed before the descendants of the recipient species. Hence, the detection of a transfer event can be translated into a time constraint between nodes of a phylogeny if the donor and recipient can be identified. When a set of transfers is detected by interpreting the phylogenetic discordance between gene trees and a species tree, the set of all deduced time constraints can be used to rank the species tree,i.e.order totally its internal nodes. Unfortunately lateral gene transfer detection is challenging and current methods produce a significant proportion of false positives. As a result, often, no ranking of the species tree is compatible with the full set of time constraints deduced from predicted transfers. Here we propose a method, implemented in a software called MaxTiC (Maximum Time Consistency), which takes as input a species tree and a series of (possibly inconsistent) time constraints between its internal nodes, weighted by confidence scores. MaxTiC outputs a ranked species tree compatible with a subset of constraints with maximum cumulated confidence score. We extensively test the method on simulated datasets, under a wide range of conditions that we compare to measures on biological datasets. In most conditions the obtained ranked tree is very close to the real one, confirming the potential of dating the history of life with transfers by maximizing time consistency. MaxTiC is freely available, distributed along with a documentation and several examples:https://github.com/ssolo/ALE/tree/master/maxtic.
Predicting the Evolutionary Consequences of Trophy Hunting on a Quantitative Trait
Authors: Coulson Tim , Schindler Susanne , Traill Lochran , Kendall Bruce E.
Published: April 2017

Some ecologists suggest that trophy hunting (e.g. harvesting males with a desirable trait above a certain size) can lead to rapid phenotypic change, which has led to an ongoing discussion about evolutionary consequences of trophy hunting. Claims of rapid evolution come from the statistical analyses of data, with no examination of whether these results are theoretically plausible. We constructed simple quantitative genetic models to explore how a range of hunting scenarios affects the evolution of a trophy such as horn length. We show that trophy hunting does lead to trophy evolution defined as change in the mean breeding value of the trait. However, the fastest rates of phenotypic change attributable to trophy hunting via evolution that are theoretically possible under standard assumptions of quantitative genetics are 1 to 2 orders of magnitude slower than the fastest rates reported from statistical analyses. Our work suggests a re-evaluation of the likely evolutionary consequences of trophy hunting would be appropriate when setting policy. Our work does not consider the ethical or ecological consequences of trophy hunting.
Did position-effect guide the evolutionary dynamics of developmental gene expression?
Authors: Bagadia Meenakshi , Chandradoss Keerthivasan Raanin , Jain Yachna , Singh Harpreet , Lal Mohan , Sandhu Kuljeet Singh
Published: April 2017

Conserved noncoding elements (CNEs) have significant regulatory influence on their neighbouring genes. Loss of synteny to CNEs through genomic rearrangements can, therefore, impact the transcriptional states of the cognate genes. Yet, the evolutionary implications of such chromosomal position effects have not been studied. Through genome-wide analysis of CNEs and the cognate genes of representative species from 5 different mammalian orders, we observed significant loss of synteny to CNEs in rat lineage. The CNEs and genes losing synteny had significant association with the fetal, but not the post-natal, brain development as assessed through ontology terms, developmental gene expression, chromatin marks and genetic mutations. The loss of synteny correlated with the independent evolutionary loss of fetus-specific upregulation of genes in rat brain. DNA-breakpoints implicated in brain abnormalities of germ-line origin had significant representation between CNE and the gene that exhibited loss of synteny, signifying the underlying developmental tolerance of genomic rearrangements that had allowed the evolutionary splits of CNEs and the cognate genes in rodent lineage. These observations highlighted the non-trivial impact of chromosomal position-effect in shaping the evolutionary dynamics of mammalian brain development and might explain loss of brain traits, like cerebral folding of cortex, in rodent lineage.

Author Summary

Expression of genes is regulated by proximally located non-coding regulatory elements. Loss of linear proximity between gene and its regulatory element thus can alter the expression of gene. Such a phenomenon can be tested at whole genome scale using evolutionary methods. We compared the positions of genes and regulatory elements in 5 different mammals and identified the significant loss of proximities between gene and their regulatory elements in rat during evolution. Brain development related function was selectively enriched among the genes and regulatory elements that had lost the proximity in rat. The observed separation of genes and their regulatory elements was strongly associated with the evolutionary loss of developmental gene expression pattern in rat brain, which coincided with the loss of brain traits in rodents. The study highlighted the importance of relative chromosomal positioning of genes and their gene regulatory elements in the evolution of phenotypes.
A general method to fine-tune fluorophores for live-cell andin vivoimaging
Authors: Grimm Jonathan B. , Muthusamy Anand K. , Liang Yajie , Brown Timothy A. , Lemon William C. , Patel Ronak , Lu Rongwen , Macklin John J. , Keller Phillip J. , Ji Na , Lavis Luke D.
Published: April 2017

ABSTRACT

Pushing the frontier of fluorescence microscopy requires the design of enhanced fluorophores with finely tuned properties. We recently discovered that incorporation of four-membered azetidine rings into classic fluorophore structures elicits substantial increases in brightness and photostability, resulting in the ‘Janelia Fluor’ (JF) series of dyes. Here, we refine and extend this strategy, showing that incorporation of 3-substituted azetidine groups allows rational tuning of the spectral and chemical properties with unprecedented precision. This strategy yields a palette of new fluorescent and fluorogenic labels with excitation ranging from blue to the far-red with utility in live cells, tissue, and animals.
A causal role for right frontopolar cortex in directed, but not random, exploration
Authors: Zajkowski Wojciech , Kossut Malgorzata , Wilson Robert C.
Published: April 2017

The explore-exploit dilemma occurs anytime we must choose between exploring unknown options for information and exploiting known resources for reward. Previous work suggests that people use two different strategies to solve the explore-exploit dilemma: directed exploration, driven by information seeking, and random exploration, driven by decision noise. Here, we show that these two strategies rely on different neural systems. Using transcranial magnetic stimulation to inhibit the right frontopolar cortex, we were able to selectively inhibit directed exploration while leaving random exploration intact. This suggests a causal role for right frontopolar cortex in directed, but not random, exploration and that directed and random exploration rely on (at least partially) dissociable neural systems.
The G-box transcriptional regulatory code inArabidopsis
Authors: Ezer Daphne , Shepherd Samuel JK , Brestovitsky Anna , Dickinson Patrick , Cortijo Sandra , Charoensawan Varodom , Box Mathew S. , Biswas Surojit , Wigge Philip
Published: April 2017

Plants have significantly more transcription factor (TF) families than animals and fungi, and plant TF families tend to contain more genes—these expansions are linked to adaptation to environmental stressors (1, 2). Many TF family members bind to similar or identical sequence motifs, such as G-boxes (CACGTG), so it is difficult to predict regulatory relationships. We determine that the flanking sequences near G-boxes help determinein vitrospecificity, but that this is insufficient to predict the transcription pattern of genes near G-boxes. Therefore, we construct a gene regulatory network that identifies the set of bZIPs and bHLHs that are most predictive of the gene expression of genes downstream of perfect G-boxes. This network accurately predicts transcriptional patterns and reconstructs known regulatory subnetworks. Finally, we present Ara-BOX-cis (araboxcis.org), a website that provides interactive visualisations of the G-box regulatory network, a useful resource for generating predictions for gene regulatory relations.
Systematic characterization of A-to-I RNA editing hotspots in microRNAs across human cancers
Authors: Wang Yumeng , Xu Xiaoyan , Yu Shuangxing , Jeong Kang Jin , Zhou Zhicheng , Han Leng , Tsang Yiu Huen , Li Jun , Chen Hu , Mangala Lingegowda S. , Yuan Yuan , Eterovic A. Karina , Lu Yiling , Sood Anil K. , Scott Kenneth L. , Mills Gordon B. , Liang Han
Published: April 2017

RNA editing, a widespread post-transcriptional mechanism, has emerged as a new player in cancer biology. Recent studies have reported key roles for individual miRNA editing events, but a comprehensive picture of miRNA editing in human cancers remains largely unexplored. Here, we systematically characterized the miRNA editing profiles of 8595 samples across 20 cancer types from miRNA sequencing data of The Cancer Genome Atlas and identified 19 adenosine-to-inosine (A-to-I) RNA editing hotspots. We independently validated 15 of them by perturbation experiments in several cancer cell lines. These miRNA editing events show extensive correlations with key clinical variables (e.g., tumor subtype, disease stage, and patient survival time) and other molecular drivers. Focusing on the RNA editing hotspot in miR-200b, a key tumor metastasis suppressor, we found that the miR-200b editing level correlates with patient prognosis opposite to the pattern observed for the wild-type miR-200b expression. We further experimentally showed that, in contrast to wild-type miRNA, the edited miR-200b can promote cell invasion and migration through its impaired ability to inhibit ZEB1/ZEB2 and acquired concomitant ability to repress new targets, including LIFR, a well-characterized metastasis suppressor. Our study highlights the importance of miRNA editing in gene regulation and suggests its potential as a biomarker for cancer prognosis and therapy.
Two different, mutually exclusively distributed, TP53 mutations in ovarian and peritoneal tumor tissues of a serous ovarian cancer patient: indicative for tumor origin?
Authors: Sukhbaatar Nyamdelger , Bachmayr-Heyda Anna , Auer Katharina , Aust Stefanie , Deycmar Simon , Horvat Reinhard , Pils Dietmar
Published: April 2017

High-grade serous ovarian cancer (HGSOC) is characterized by a TP53 mutation rate of up to 96.7% and associated with a more aggressive tumor biology. The origin of HGSOC is thought to arise either from fallopian tube secretory cells or the ovarian surface epithelium/inclusion cysts, the former with more evidence. Peritoneal tumor spread is heterogeneous, either excessive in the peritoneum (with miliary appearance) or more confined to the ovaries with only few (bigger and exophytically growing) peritoneal implants. Using RNA sequencing and DNA digital droplet polymerase chain reaction (PCR), we identified two different functional TP53 mutations in one HGSOC patient: one exclusively in the ovarian tumor mass and the other exclusively in ascites tumor cells, peritoneal tumor masses, and a lymph node metastasis. In blood, both mutations could be detected, the one from the peritoneal tumors with much higher frequency, presumably because of the higher tumor load. We conclude that this mutually exclusive distribution of two different TP53 mutations in different tumor tissues indicates the development of two independent carcinomas in the peritoneal cavity, probably one originating from a precancerous lesion in the fallopian tube and the other from the ovaries. In addition, in the patient's ascites CD45 and EpCAM, double-positive cells were found—proliferating but testing negative for the above-mentioned TP53 mutations. This mutually exclusive distribution of two TP53 mutations is probably further evidence that HGSOC can originate either from the fallopian tube or (more seldom) the ovaries, the former more prone for excessive peritoneal tumor spread.
Functional validation reveals the novel missense V419L variant in TGFBR2 associated with Loeys–Dietz syndrome (LDS) impairs canonical TGF-β signaling
Authors: Cousin Margot A. , Zimmermann Michael T. , Mathison Angela J. , Blackburn Patrick R. , Boczek Nicole J. , Oliver Gavin R. , Lomberk Gwen A. , Urrutia Raul A. , Deyle David R. , Klee Eric W.
Published: April 2017

TGF-β-related heritable connective tissue disorders are characterized by a similar pattern of cardiovascular defects, including aortic root dilatation, mitral valve prolapse, vascular aneurysms, and vascular dissections and exhibit incomplete penetrance and variable expressivity. Because of the phenotypic overlap of these disorders, panel-based genetic testing is frequently used to confirm the clinical findings. Unfortunately in many cases, variants of uncertain significance (VUSs) obscure the genetic diagnosis until more information becomes available. Here, we describe and characterize the functional impact of a novel VUS in the TGFBR2 kinase domain (c.1255G>T; p.Val419Leu), in a patient with the clinical diagnosis of Marfan syndrome spectrum. We assessed the structural and functional consequence of this VUS using molecular modeling, molecular dynamic simulations, and in vitro cell-based assays. A high-quality homology-based model of TGFBR2 was generated and computational mutagenesis followed by refinement and molecular dynamics simulations were used to assess structural and dynamic changes. Relative to wild type, the V419L induced conformational and dynamic changes that may affect ATP binding, increasing the likelihood of adopting an inactive state, and, we hypothesize, alter canonical signaling. Experimentally, we tested this by measuring the canonical TGF-β signaling pathway activation at two points; V419L significantly delayed SMAD2 phosphorylation by western blot and significantly decreased TGF-β-induced gene transcription by reporter assays consistent with known pathogenic variants in this gene. Thus, our results establish that the V419L variant leads to aberrant TGF-β signaling and confirm the diagnosis of Loeys–Dietz syndrome in this patient.