bluuebunny/crossref_metadata_2025 huggingface dataset:
How Has Virtual Hepatectomy Changed the Practice of Liver Surgery?
Authors: Mise Yoshihiro , Hasegawa Kiyoshi , Satou Shouichi , Shindoh Junichi , Miki Kenji , Akamatsu Nobuhisa , Arita Junichi , Kaneko Junichi , Sakamoto Yoshihiro , Kokudo Norihiro
Published: March 2017

Objective:

To assess how virtual hepatectomy (VH), conducted using surgical planning software, influences the outcomes of liver surgery.

Background:

Imaging technology visualizes the territories of the liver vessels, which were previously impossible. However, the clinical impact of VH has not been evaluated.

Methods:

From 2004 to 2013, we performed 1194 VHs preoperatively. Outcomes of living donor liver transplantation (LDLT) and hepatectomy for hepatocellular carcinoma (HCC)/colorectal liver metastases (CRLM) were compared between patients in whom VH was performed (VH) and those without VH evaluation (non-VH).

Results:

In LDLT, the rate of right liver graft use was higher in the VH (62.1%) than in the non-VH (46.5%) (P < 0.01), which did not increase morbidity of donor surgery. Duration of recipient surgery in the VH in which middle hepatic vein branch reconstruction was skipped was shorter than that in the VH with venous reconstruction. Among HCC patients with impaired liver function, portal territory-oriented resection was conducted more often in the VH than in the non-VH. The 5-year disease-free survival rate for localized HCC was higher in the VH than in the non-VH (37.2% vs 23.9%; P = 0.04). In CRLM, long-term outcomes were similar in the VH and non-VH despite the larger tumor load in the VH.

Conclusions:

VH in LDLT allows double equipoise for the recipient and donor by optimizing decision-making on graft selection and venous reconstruction. VH offers a chance for radical hepatectomy even in HCC patients with impaired liver function and CRLM patients with advanced tumors, without compromising survival.
Clearance of BK Virus Nephropathy by Combination Antiviral Therapy With Intravenous Immunoglobulin
Authors: Kable Kathy , Davies Carmen D. , O'connell Philip J. , Chapman Jeremy R. , Nankivell Brian John
Published: March 2017

Background

Reactivation of BK polyoma virus causes a destructive virus allograft nephropathy (BKVAN) with graft loss in 46%. Treatment options are limited to reduced immunosuppression and largely ineffective antiviral agents. Some studies suggest benefit from intravenous immunoglobulin (IVIG).

Methods

We evaluated effectiveness of adjuvant IVIG to eliminate virus from blood and tissue, in a retrospective, single-center cohort study, against standard-of-care controls. Both groups underwent reduced immunosuppression; conversion of tacrolimus to cyclosporine; and mycophenolate to leflunomide, oral ciprofloxacin, and intravenous cidofovir.

Results

Biopsy-proven BKVAN occurred in 50 kidneys at 7 (median interquartile range, 3-12) months after transplantation, predominantly as histological stage B (92%), diagnosed following by dysfunction in 46%, screening viremia in 20%, and protocol biopsy in 34%. After treatment, mean viral loads fell from 1581 ± 4220 × 103 copies at diagnosis to 1434 ± 70 639 midtreatment, and 0.138 ± 0.331 after 3 months (P < 0.001). IVIG at 1.01 ± 0.18 g/kg was given to 22 (44%) patients. The IVIG group more effectively cleared viremia (hazard ratio, 3.68; 95% confidence interval, 1.56-8.68; P = 0.003) and BK immunohistochemistry from repeated tissue sampling (hazard ratio, 2.24; 95% confidence interval, 1.09-4.58; P = 0.028), and resulted in faster (11.3 ± 10.4 months vs 29.1 ± 31.8 months, P = 0.015) and more complete resolution of viremia (33.3% vs 77.3%, P = 0.044). Numerically, fewer graft losses occurred with IVIG (27.3% vs 53.6% for control, P = 0.06), although graft and patient survivals were not statistically different. Acute renal dysfunction requiring pulse corticosteroid was common (59.1% vs 78.6%, P = 0.09), respectively, after immunosuppression reduction.

Conclusions

Combination treatment incorporating adjuvant IVIG was more effective eliminating virus from BKVAN, compared with conventional therapy. Validation by multicenter randomized trial is needed.
Absence of Intragraft B Cells in Rejection Biopsies After Rituximab Induction Therapy: Consequences for Clinical Outcome
Authors: van den Hoogen Martijn W.F. , Steenbergen Eric J. , Baas Marije C. , Florquin Sandrine , Hilbrands Luuk B.
Published: March 2017

Background

The pathophysiological role of intragraft B cells during renal allograft rejection is unclear.

Methods

We studied B-cell infiltration during acute rejection in 53 patients who participated in a clinical trial in which adult renal transplant patients were randomized between a single intraoperative dose of rituximab (375 mg/m2) or placebo as induction therapy. Two independent pathologists scored all biopsies in a blinded fashion according to the Banff classification and scored for the presence of B cells and plasma cells using CD79a and CD138 as markers.

Results

The majority of acute rejections were T cell–mediated. The proportion of acute rejections with an antibody-mediated component tended to be lower in rituximab-treated patients (4/23, 17.4%) than in placebo-treated patients (11/30, 36.7%; P = 0.14). Biopsies of rituximab-treated patients had significantly lower scores for B cells (0.00; range, 0.00-0.50 vs 1.70; range, 0.60-3.30; P < 0.0001) and plasma cells (0.10; range, 0.00-1.90 vs 0.40; range, 0.00-7.50; P = 0.006). During acute rejection, intragraft clusters of B cells were not observed after rituximab induction therapy. However, the depletion of intragraft B cells during acute rejection did not affect steroid resistance, proteinuria, graft function at 2 years follow-up, or patient and graft survival at a median follow-up of 4.1 years (range, 2.0-6.2 years).

Conclusions

These data do not support a harmful influence of intragraft B cells present during acute allograft rejection on the clinical course within the first few years after renal transplantation.
Decoys reveal the genetic and biochemical roles of redundant plant E3 ubiquitin ligases
Authors: Lee Chin-Mei , Feke Ann , Adamchek Christopher , Webb Kristofor , Pruneda-Paz José , Bennett Eric J. , Kay Steve A. , Gendron Joshua M.
Published: March 2017

The ubiquitin proteasome system (UPS) is the main cellular route for protein degradation in plants and is important for a wide range of biological processes including daily and seasonal timing. The UPS relies on the action of E3 ubiquitin ligases to specifically recognize substrate proteins and facilitate their ubiquitylation. In plants, there are three major challenges that inhibit studies of E3 ligase function: 1) rampant genetic redundancy, 2) labile interactions between an E3 ligase and its cognate substrates, and 3) a lack of tools for rapid validation of bona fide substrates. To overcome these 3 challenges, we have developed a decoy method that allows for rapid genetic analysis of E3 ligases,in vivoidentification of substrates using immunoprecipitation followed by mass spectrometry, and reconstitution of the ubiquitylation reaction in mammalian cells to rapidly validate potential substrates. We employ the strategy to study the plant F-box proteins, ZTL, LKP2, and FKF1 revealing differential genetic impacts on circadian clock period and seasonal flowering. We identify a group of circadian clock transcriptional regulators that interact with ZTL, LKP2, and FKF1in vivoproviding a host of potential substrates that have not been seen previously. We then validate one substrate of ZTL, the plant circadian clock transcription factor CHE, and show that ZTL mediates CHE ubiquitylation and that the levels of the CHE protein cycle in daily timecourses. This work further untangles the complicated genetic roles of this family of E3 ligases and suggests that ZTL is a master regulator of a diverse set of critical clock transcription factors. Furthermore, the method that is validated here can be tool employed widely to overcome traditional challenges in studying redundant plant E3 ubiquitin ligases.
Compensating for intersegmental dynamics across the shoulder, elbow and wrist joints during feedforward and feedback control
Authors: Maeda Rodrigo S. , Cluff Tyler , Gribble Paul L. , Pruszynski J. Andrew
Published: March 2017

Moving the arm is complicated by mechanical interactions that arise between limb segments. Such intersegmental dynamics cause torques applied at one joint to produce movement at multiple joints and, in turn, the only way to create single joint movement is by applying torques at multiple joints. Here, we investigated whether the nervous system accounts for intersegmental limb dynamics across the shoulder, elbow, and wrist joints during self-initiated reaching and when countering external mechanical perturbations. Our first experiment tested whether the timing and amplitude of shoulder muscle activity accounts for interaction torques produced during single-joint elbow movements from different elbow initial orientations and over a range of movement speeds. We found that shoulder muscle activity reliably preceded movement onset and elbow agonist activity, and was scaled to compensate for the magnitude of interaction torques arising because of forearm rotation. Our second experiment tested whether elbow muscles compensate for interaction torques introduced by single-joint wrist movements. We found that elbow muscle activity preceded movement onset and wrist agonist muscle activity, and thus the nervous system predicted interaction torques arising because of hand rotation. Our third and fourth experiments tested whether shoulder muscles compensate for interaction torques introduced by different hand orientations during self-initiated elbow movements and when countering mechanical perturbations that caused pure elbow motion. We found that the nervous system predicted the amplitude and direction of interaction torques, appropriately scaling the amplitude of shoulder muscle activity during self-initiated elbow movements and rapid feedback control. Taken together, our results demonstrate that the nervous system robustly accounts for intersegmental dynamics, and that the process is similar across the proximal to distal musculature of the arm as well as between feedforward (i.e., self-initiated) and feedback (i.e., reflexive) control.

NEW & NOTEWORTHY

Intersegmental dynamics complicate the mapping between applied joint torques and the resulting joint motions. Here, we provide evidence that the nervous system robustly predicts these intersegmental limb dynamics across the shoulder, elbow and wrist joints during reaching and when countering external perturbations.
High fidelity hypothermic preservation of primary tissues in organ transplant preservative for single cell transcriptome analysis
Authors: Wang Wanxin , Penland Lolita , Gokce Ozgun , Croote Derek , Quake Stephen
Published: March 2017

Background

High-fidelity preservation strategies for primary tissues are in great demand in the single cell RNAseq community. A reliable method will greatly expand the scope of feasible collaborations and maximize the utilization of technical expertise. When choosing a method, standardizability is as important a factor to consider as fidelity due to the susceptibility of single-cell RNAseq analysis to technical noises. Existing approaches such as cryopreservation and chemical fixation are less than ideal for failing to satisfy either or both of these standards.

Results

Here we propose a new strategy that leverages preservation schemes developed for organ transplantation. We evaluated the strategy by storing intact mouse kidneys in organ transplant preservative solution at hypothermic temperature for up to 4 days (6 hrs, 1, 2, 3, and 4 days), and comparing the quality of preserved and fresh samples using FACS and single cell RNAseq. We demonstrate that the strategy effectively maintained cell viability, transcriptome integrity, cell population heterogeneity, and transcriptome landscape stability for samples after up to 3 days of preservation. The strategy also facilitated the definition of the diverse spectrum of kidney resident immune cells, to our knowledge the first time at single cell resolution.

Conclusions

Hypothermic storage of intact primary tissues in organ transplant preservative maintains the quality and stability of the transcriptome of cells for single cell RNAseq analysis. The strategy is readily generalizable to primary specimens from other tissue types for single cell RNAseq analysis.
The Co-regulation Data Harvester forTetrahymena thermophila: automated high-throughput gene annotation and functional inference in a microbial eukaryote
Authors: Tsypin Lev M. , Turkewitz Aaron P.
Published: March 2017

Identifying co-regulated genes can provide a useful approach for defining pathway-specific machinery in an organism. To be efficient, this approach relies on thorough genome annotation, which is not available for most organisms with sequenced genomes. Studies inTetrahymena thermophila,the most experimentally accessible ciliate, have generated a rich transcriptomic database covering many well-defined physiological states. Genes that are involved in the same pathway show significant co-regulation, and screens based on gene co-regulation have identified novel factors in specific pathways, for example in membrane trafficking. However, a limitation has been the relatively sparse annotation of theTetrahymenagenome, making it impractical to approach genome-wide analyses. We have therefore developed an efficient approach to analyze both co-regulation and gene annotation, called the Co-regulation Data Harvester (CDH). The CDH automates identification of co-regulated genes by accessing theTetrahymenatranscriptome database, determines their orthologs in other organisms via reciprocal BLAST searches, and collates the annotations of those orthologs' functions. Inferences drawn from the CDH reproduce and expand upon experimental findings inTetrahymena.The CDH, which is freely available, represents a powerful new tool for analyzing cell biological pathways inTetrahymena.Moreover, to the extent that genes and pathways are conserved between organisms, the inferences obtained via the CDH should be relevant, and can be explored, in many other systems.
Temporal and Clonal Progression in a Pediatric Ependymoma Patient Through Multiple Treatments
Authors: Miller Christopher A. , Dahiya Sonika , Li Tiandao , Fulton Robert S. , Smyth Matthew D. , Dunn Gavin P. , Rubin Joshua B. , Mardis Elaine R.
Published: March 2017

Background

Multiple recurrences after complete resection and irradiation of supratentorial ependymoma are common and frequently result in patient death. However, the molecular basis for treatment resistance, the impact that radiation and other adjuvant therapies have in promoting recurrence, and the use of this information to rationally design effective approaches to treat recurrent ependymoma are unknown. Due to the rarity of these tumors and the even less likely banking of multiple recurrent samples from the same patient, we initiated a study to characterize the evolution of a single patient’s ependymoma in response to therapy.

Methods and Findings

A combination of high depth, whole genome and exome-based DNA sequencing of germline and tumor specimens, RNA sequencing of tumor specimens, and advanced computational analyses were employed to reconstruct the natural history of a supratentorial ependymoma case in which there were four local recurrences. The findings reveal the extent to which treatment with radiation and chemotherapies resulted in the diversification of the tumor subclonal architecture and shaped the neo-antigen landscape, and provide new insights into possible molecular mechanisms of oncogenesis, treatment response and recurrence.

Conclusions

Although the recurrent tumors we studied were clearly shaped by therapy, the founding clone was never eradicated by any treatment. We conclude that DNA and RNA sequencing may provide critical prognostic indicators to identify ependymoma patients that should be observed, rather than irradiated, post gross total resection.
Evolution of age-specific decline in stress phenotypes is driven by both antagonistic pleiotropy and mutation accumulation
Authors: Everman Elizabeth R. , Morgan Theodore J.
Published: March 2017

Efforts to more fully understand and test evolutionary theories of aging have produced distinct predictions for mutation accumulation (MA) and antagonistic pleiotropy (AP) mechanisms. We build on these predictions through the use of association mapping and investigation of the change in additive effects of polymorphisms across age and among traits for multiple stress response phenotypes. We found that cold stress survival with acclimation, cold stress survival without acclimation, and starvation resistance declined with age and that changes in the genetic architecture of each phenotype were consistent with MA predictions. We used a novel test for MA and AP by calculating the additive effect of polymorphisms across ages and found support for both MA and AP mechanisms in the age-related decline in stress tolerance. These patterns suggest both MA and AP contribute to age-related change in stress response and highlight the utility of association mapping to identify genetic shifts across age.
Combining theory, model and experiment to understand how theta rhythms are generated in the hippocampus
Authors: Ferguson Katie A. , Chatzikalymniou Alexandra P. , Skinner Frances K.
Published: March 2017

Scientists have observed theta rhythms (3–12 Hz) in the hippocampus for decades, but we do not have a clear understanding of how they are generated. This is largely due to the complex, multi-scale and nonlinear nature of the brain. To obtain insight into mechanisms underlying the generation of theta rhythms, we develop cellular-based network models of the hippocampus based on a whole hippocampusin vitropreparation that spontaneously generates theta rhythms. Building on theoretical and computational analyses, we find that spike frequency adaptation and post-inhibitory rebound constitute a basis for theta generation in large, minimally connected CA1 pyramidal (PYR) cell network models with fast-firing parvalbumin-positive (PV+) inhibitory cells. The particular theta frequency is more controlled by PYR to PV+ cell interactions rather than PV+ to PYR cell ones. We identify two scenarios by which theta rhythms can emerge and they can be differentiated by the ratio of excitatory to inhibitory currents to PV+ cells, but not to PYR cells. Only one of the scenarios is consistent with data from the whole hippocampus preparation, which leads to the prediction that the connection probability from PV+ to PYR cells needs to be larger than from PYR to PV+ cells. Our models can serve as a platform on which to build and develop an understanding ofin vivotheta generation, and of microcircuit dynamics in the hippocampus.

Significance

Brain rhythms have been linked to cognition and are disrupted in disease. This makes it essential to understand mechanisms underlying their generation. Theory and mathematical models help provide an understanding and generate hypotheses. Together with experiment they contribute a framework to dissect the cellular contributions to network activity. However, models are inherently biological approximations, and thus the specific experimental and theoretical context upon which they are built will shape their output. If the approximations and contexts are not taken into account, particularly when using previously constructed models, misinterpretations can arise. Here, we use both theory and microcircuit models derived from a specific experimental context to provide insight into cellular-based mechanisms involved in theta rhythm generation in the hippocampus.
Discovering the Interactions between Circular RNAs and RNA-binding Proteins from CLIP-seq Data using circScan
Authors: Li Bin , Zhang Xiao-Qin , Liu Shu-Rong , Liu Shun , Sun Wen-Ju , Lin Qiao , Luo Yu-Xia , Zhou Ke-Ren , Zhang Chen-Min , Tan Ye-Ya , Yang Jian-Hua , Qu Liang-Hu
Published: March 2017

Although tens of thousands of circular RNAs (circRNAs) have been identified in mammalian genomes, only few of them have been characterized with biological functions. Here, we report a new approach, circScan, to identify regulatory interactions between circRNAs and RNA-binding proteins (RBPs) by discovering back-splicing reads from Cross-Linking and Immunoprecipitation followed by high-throughput sequencing (CLIP-seq) data. By using our method, we have systematically scanned ~1500 CLIP-seq datasets, and identified ~12540 and ~1090 novel circRNA-RBP interactions in human and mouse genomes, respectively, which include all known interactions between circRNAs and Argonaute (AGO) proteins. More than twenty novel interactions were further experimentally confirmed by RNA Immunoprecipitation quantitative PCR (RIP-qPCR). Importantly, we uncovered that some natural circRNAs interacted with cap-independent translation factors eukaryotic initiation factor 3 (eIF3) and N6-Methyladenosine (m6A), indicating they can be translated into proteins. These findings demonstrate that circRNAs are regulated by various RBPs, suggesting they may play important roles in diverse biological processes.
Common Variant Associations with Fragile X Syndrome
Authors: Crowley James J , Szatkiewicz Jin , Kähler Anna K , Giusti-Rodriguez Paola , Ancalade NaEshia , Booker Jessica K , Carr Jennifer L , Crawford Greg E , Losh Molly , Stockmeier Craig A , Taylor Annette K , Piven Joseph , Sullivan Patrick F
Published: March 2017

Fragile X syndrome is a common cause of intellectual disability. It is usually caused by a de novo mutation which often occur on multiple haplotypes and should not be detectible using genome-wide association (GWA). We conducted GWA 89 male FXS cases and 266 male controls, and detected multiple genome-wide significant signals near FMR1 (odds ratio=8.10, P=2.5×10−10). These findings withstood robust attempts at falsification. Fine-mapping did not serve to narrow the interval (minimum P=1.13×l0−14), and functional genomic integration (including 5C data we generated for this region) did not provide a mechanistic hypothesis. Controls carrying a risk haplotype had significantly longer and more variable FMR1 CGG repeats than controls with the protective haplotype (P=4.75×10−5) which may predispose toward increases in CGG number to the pre-mutation range over many generations. This is a salutary reminder of the complexity of even “simple” monogenetic disorders.
Preponderance of Enterovirus Species C in RD-L20B cell culture negative stool samples from children diagnosed with Acute Flaccid Paralysis in Nigeria
Authors: Adeniji J.A. , Oragwa A.O. , George U.E. , Ibok U.I. , Faleye T.O.C. , Adewumi M.O.
Published: March 2017

Abstracts

Recently, a reverse transcriptase seminested polymerase chain reaction (RT-snPCR) assay was recommended by the WHO for direct detection of enteroviruses from clinical specimen. In this study, we use the assay and its modification to screen acute flaccid paralysis (AFP) samples previously confirmed negative for enteroviruses by the RD-L20B algorithm.

Thirty paired stool suspensions collected in 2015 as part of the national AFP surveillance program in different states of Nigeria were analyzed in this study. The samples were previously confirmed negative for enteroviruses by the polio laboratory in accordance with the WHO recommended RD-L20B cell culture based algorithm. Two samples previously confirmed to contain enteroviruses were included as positive controls. All samples were subjected to RNA extraction, and the RT-snPCR assay and its modifications. All amplicons were sequenced and enteroviruses identified using the enterovirus genotyping tool.

Overall, amplicons were recovered from the two controls and 50% (15/30) of samples screened. Fourteen were successfully typed of which, 7.1% (1/14), 21.4% (3/14), 64.3% (9/14) and 7.1% (1/14) were EV-A, EV-B, EV-C and a mixture of EV-B and C (EV-C99 and E25), respectively. The two controls were identified as EV-C99 and CV-A1, both EV-Cs. The PV-2 detected had VP1 ILE143. Hence, a vaccine strain.

The results of this study showed that about 50% of enterovirus infections (including some Sabin PV2s) are being missed by the RD-L20B cell culture based algorithm. This highlights the value of the RT-snPCR assay and its modifications. The circulation and preponderance of EV-Cs in Nigeria was also confirmed.
Gene expression polymorphism underpins evasion of host immunity in an asexual lineage of the Irish potato famine pathogen
Authors: Pais Marina , Yoshida Kentaro , Giannakopoulou Artemis , Pel Mathieu A. , Cano Liliana M. , Oliva Ricardo F. , Witek Kamil , Lindqvist-Kreuze Hannele , Vleeshouwers Vivianne G. A. A. , Kamoun Sophien
Published: March 2017

Outbreaks caused by asexual lineages of fungal and oomycete pathogens are an expanding threat to crops, wild animals and natural ecosystems (Fisher et al. 2012,Kupferschmidt 2012). However, the mechanisms underlying genome evolution and phenotypic plasticity in asexual eukaryotic microbes remain poorly understood (Seidl and Thomma 2014). Ever since the 19thcentury Irish famine, the oomycetePhytophthora infestanshas caused recurrent outbreaks on potato and tomato crops that have been primarily caused by the successive rise and migration of pandemic asexual lineages (Cooke et al. 2012, Yoshida et al. 2013,Yoshida et al. 2014). Here, we reveal patterns of genomic and gene expression variation within aP. infestansasexual lineage by compared sibling strains belonging to the South American EC-1 clone that has dominated Andean populations since the 1990s (Forbes et al. 1997, Oyarzun et al. 1998, Delgado et al. 2013, Yoshida et al. 2013, Yoshida et al. 2014). We detected numerous examples of structural variation, nucleotide polymorphisms and gene conversion within the EC-1 clone. Remarkably, 17 genes are not expressed in one of the two EC-1 isolates despite apparent absence of sequence polymorphisms. Among these, silencing of an effector gene was associated with evasion of disease resistance conferred by a potato immune receptor. These results highlight the exceptional genetic and phenotypic plasticity that underpins host adaptation in a pandemic clonal lineage of a eukaryotic plant pathogen.
Structural basis for EarP-mediated arginine glycosylation of translation elongation factor EF-P
Authors: Krafczyk Ralph , Macošek Jakub , Gast Daniel , Wunder Swetlana , Jagtap Pravin Kumar Ankush , Mitra Prithiba , Jha Amit Kumar , Rohr Jürgen , Hoffmann-Röeder Anja , Jung Kirsten , Hennig Janosch , Lassak Jürgen
Published: March 2017

Glycosylation is a universal strategy to post-translationally modify proteins. The recently discovered arginine rhamnosylation activates the polyproline specific bacterial translation elongation factor EF-P. EF-P is rhamnosylated on arginine 32 by the glycosyltransferase EarP. However, the enzymatic mechanism remains elusive. In the present study, we solved the crystal structure of EarP fromPseudomonas putida.The enzyme is composed of two opposing domains with Rossmann-folds, thus constituting a GT-B glycosyltransferase. While TDP-rhamnose is located within a highly conserved pocket of the C-domain, EarP recognizes the EF-P via its KOW-like N-domain. Based on our structural data combined with anin vitro /in vivoenzyme characterization, we propose a mechanism of inverting arginine glycosylation. As EarP is essential for pathogenicity inP. aeruginosaour study provides the basis for targeted inhibitor design.
Classification of RNA-Seq Data via Gaussian Copulas
Authors: Zhang Qingyang
Published: March 2017

RNA-sequencing (RNA-Seq) has become a preferred option to quantify gene expression, because it is more accurate and reliable than microarrays. In RNA-Seq experiments, the expression level of a gene is measured by the count of short reads that are mapped to the gene region. Although some normal-based statistical methods may also be applied to log-transformed read counts, they are not ideal for directly modeling RNA-Seq data. Two discrete distributions, Poisson distribution and negative binomial distribution, have been commonly used in the literature to model RNA-Seq data, where the latter is a natural extension of the former with allowance of overdispersion. Due to the technical difficulty in modeling correlated counts, most existing classifiers based on discrete distributions assume that genes are independent of each other. However, as we show in this paper, the independence assumption may cause non-ignorable bias in estimating the discriminant score, making the classification inaccurate. To this end, we drop the independence assumption and explicitly model the dependence between genes using Gaussian copula. We apply a Bayesian approach to estimate covariance matrix and the overdispersion parameter in negative binomial distribution. Both synthetic data and real data are used to demonstrate the advantages of our model.
Quantitative PCR assays for detection of five Arctic fish species:Lota lota, Cottus cognatus, Salvelinus alpinus, Salvelinus malma, andThymallus arcticusfrom environmental DNA
Authors: Rodgers Torrey W. , Olson John. R. , Klobucar Stephen L. , Mock Karen. E.
Published: March 2017

The North Slope of Alaska contains arctic fish populations that are important for subsistence of local human populations, and are under threat from natural resource extraction and climate change. We designed and evaluated four quantitative PCR assays for the detection of environmental DNA from five Alaskan fish species present on the North Slope of Alaska: burbot (Lota lota), arctic char (Salvelinus alpinus), Dolly Varden (Salvelinus malma), arctic grayling (Thymallus arcticus), and slimy sculpin (Cottus cognatus). All assays were designed and tested for species specificity and sensitivity, and all assays detected target species from filtered water samples collected from the field. These assays will enable efficient and economical detection and monitoring of these species in lakes and rivers. This in turn will provide managers with improved knowledge of current distributions and future range shifts associated with climate and development threats, enabling more timely management.
Unexpected recalcitrant course of drug‐induced erythema multiforme‐like eruption and interstitial pneumonia sequentially occurring after nivolumab therapy
Authors: Nomura Hisashi , Takahashi Hayato , Suzuki Satsuki , Kurihara Yuichi , Chubachi Shotaro , Kawada Ichiro , Yasuda Hiroyuki , Betsuyaku Tomoko , Amagai Masayuki , Funakoshi Takeru
Published: March 2017

Vemurafenib improves survival of melanoma patients. However, cutaneous side‐effects commonly occur in them. Nivolumab and ipilimumab are monoclonal antibodies against programmed death 1 and cytotoxic T‐lymphocyte‐associated antigen 4, both of which regulate excessive T‐cell activation. Although these agents induce antitumor immunity against melanoma, the modified immune condition may result in an unexpected adverse reaction which has not been observed previously. Herein, we report a case who manifested severe erythema multiforme‐like eruption with mucosal involvement associated with vemurafenib following nivolumab. The patient also subsequently suffered from ipilimumab‐induced interstitial pneumonia with refractory course. Such a case has never been reported. This case suggested that dermatologists should pay special attention to unexpected adverse events of these drugs, and carefully observe cutaneous and respiratory status of patients during the treatment of melanoma.
Case of harlequin ichthyosis with a favorable outcome: Early treatment and novel, differentially expressed, alternatively spliced transcripts of the ATP‐binding cassette subfamily A member 12 gene
Authors: Washio Ken , Sumi Mayuko , Nakata Kaori , Fukunaga Atsushi , Yamana Keiji , Koda Tsubasa , Morioka Ichiro , Nishigori Chikako , Yamanishi Kiyofumi
Published: March 2017

Harlequin ichthyosis (HI) is the most severe form of autosomal recessive congenital ichthyosis, with a high mortality rate. Recent advances in neonatal care and the early administration of retinoids have improved the survival rate of HI. Here, we present a case of HI who was successfully treated with early administration of etretinate and showed good prognosis. Next‐generation sequencing identified novel mutations of the ATP‐binding cassette subfamily A member 12 gene (ABCA12), c.5884+4_+5delAA and c.7239G>A, which caused skipping of exons 39 and 48, respectively. Transcripts with exon 48 skipping, which cause a deletion in the second ATP‐binding cassette of ABCA12, were dominantly expressed in the skin. Besides the early administration of etretinate, the differential expression of the mutant protein with limited segmental deletion of ABCA12 may be related to the favorable outcome of our patient.
Serum carcinoembryonic antigen specifically increases among various serum markers of adenocarcinoma in hypohidrosis or conditions related to hypohidrosis
Authors: Honma Masaru , Nozaki Hiroyoshi , Nagahata Hiroko , Fujii Mizue , Shibuya Takashi , Kanno Kyoko , Minami‐Hori Masako , Ishida‐Yamamoto Akemi
Published: March 2017

Anhidrosis/hypohidrosis are conditions presenting various level of sweating dysfunction. Among them, acquired idiopathic generalized anhidrosis (AIGA) presents inadequate decrease or loss of sweating without apparent neurological and dermatological symptoms except cholinergic urticaria. Recently, serum level of carcinoembryonic antigen (CEA), one of the most well‐known tumor markers, has been proposed as a clinical marker reflecting activity of AIGA. This study was performed to verify the specificity and independence of serum CEA level from the other serum tumor markers especially related to adenocarcinoma. The expression of various tumor markers in the serum collected from three healthy control subjects, four AIGA cases, and a cholinergic urticaria (CU) case with elevation of serum CEA level and history of hyperthermia was analyzed using a membrane‐based antibody array. In all AIGA and CU cases, the intensity of CEA was significantly increased (7.60–15.9 times compared with that of control), relatively well‐reflecting the serum CEA level, and the mean intensity of CEA was 11.8 times higher than the control subjects (P = 0.0011). On the other hand, the ratio of carbohydrate antigen (CA)125 and CA19‐9 was 1.93 and 0.23 times compared with the mean intensity of the control subjects, respectively, and there was no statistical significance. Immunohistochemistry on 10 AIGA cases showed increased expression of CEA but not CA19‐9 and CA125 in the eccrine sweat glands. In conclusion, the elevation of serum CEA level was independent from the other tumor markers in hypohidrotic condition represented by AIGA.
Neighbour effects on tree architecture: functional trade‐offs balancing crown competitiveness with wind resistance
Authors: MacFarlane David W. , Kane Brian
Published: March 2017

The architecture of trees is the result of constrained, morphologically plastic growth – constrained by an underlying architectural model embedded in their genome, the structure of which can be significantly altered during growth to match the changing environmental conditions to which the tree is exposed. Here, we examined the hypothesis that crowding from neighbours should cause trees to optimize traits for light competition at the expense of wind resistance, with the reverse being true for trees lacking neighbours. Previous studies have examined the influence of light competition or wind resistance on shaping tree architecture, but few, if any, have simultaneously addressed trade‐offs for optimizing these traits in response to crowding from neighbouring trees in forests, as compared to open‐grown conditions.

We studied the response of tree‐ and branch‐level architectural traits of temperate, broad‐leaved, deciduous tree species of differing shade tolerance and wood strength from multiple locations across the north‐eastern United States. Trees ranged in size (4–83 cm diameter at 1·3 m) and crowding conditions (open‐ and forest‐grown) and occupied different canopy positions. The open‐grown trees represented a null condition, where the lack of neighbouring trees to shape architectural traits could be contrasted with the influence of different levels of crowding in forests.

Our results show strong evidence for a tree neighbourhood‐induced convergence of architectural traits across species and conditions, even when trees are growing in urban rather than natural forest conditions. After accounting for crowding, the effects of species and sample location contributed very little to explaining variation in architectural traits. One exception was crown dimensions, for which species‐specific differences explained about 15% of the residual variation.

Under open‐grown conditions, alleviation of light competition caused trees to develop relatively large crowns and branches and a squat growth form suitable to resist greater wind exposure. By contrast, increasing shading from neighbouring trees caused forest‐grown trees to become increasingly more spindly in the main stem, with slender branches sparsely distributed over a disproportionately large crown volume – presumably to maximize light capture. Although the latter is an intrinsically less wind‐stable form, it can be adopted to increase light capture because neighbouring trees reduce exposure to the wind, which should greatly reduce the likelihood of stem breakage or uprooting under critical wind pressures.

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Restored tallgrass prairies have reduced phylogenetic diversity compared with remnants
Authors: Barak Rebecca S. , Williams Evelyn W. , Hipp Andrew L. , Bowles Marlin L. , Carr Gabriela M. , Sherman Robert , Larkin Daniel J.
Published: March 2017

Ecological restoration is critical for mitigating habitat loss and providing ecosystem services. However, restorations often have lower diversity than remnant, reference sites. Phylogenetic diversity is an important component of biodiversity and ecosystem function that has only recently been used to evaluate restoration outcomes. To move towards prediction in the restoration of biodiversity, it is necessary to understand how phylogenetic diversity of restorations compares with that of reference sites, and where deficits are found, to evaluate factors constraining phylogenetic diversity.

We quantified plant taxonomic and phylogenetic diversity in eastern tallgrass prairie, one of the most endangered ecosystems on earth. We measured diversity at large (site) and small (plot) scales in 19 restored prairies and compared patterns with those from 41 remnant prairies. To evaluate how environmental conditions and management actions influence outcomes, we tested the effects of soil properties and seed mix composition on diversity of restorations.

Restored prairies were less phylogenetically diverse than remnants at both spatial scales. On the other hand, the total species richness of remnant and restored prairies did not significantly differ, but remnants had higher native richness. Restored communities were taxonomically and phylogenetically distinct from remnants.

Soil properties (moisture andpH) influenced phylogenetic diversity and composition. There were positive relationships between the taxonomic and phylogenetic diversity of seed mixes and resulting diversity of planted assemblages (excluding volunteer species). Species in seed mixes were more closely related than expected by chance, and several clades found in remnant prairies were missing from seed mixes.

Synthesis and applications. Restored tallgrass prairies had lower phylogenetic diversity than remnant prairies, which may contribute to the widely observed phenomenon of restorations not being functionally equivalent to reference sites. It is encouraging for restoration efforts that seed mix phylogenetic diversity predicted phylogenetic diversity of planted assemblages. This indicates that designing phylogenetically diverse seed mixes for restoration is beneficial. In addition, clades found in reference sites that are missing from restoration seed mixes could be added to new or existing restorations to reduce gaps in phylogenetic diversity. Further work on the effects of management on phylogenetic diversity is needed to advance restoration of biodiversity.
Inventing Revivalist Millennialism: Edwards and the Scottish Connection
Authors: Friend Nathan
Published: March 2017

Revivalism and millennialism are important concepts that influence contemporary evangelicalism. However it was in the Great Awakening that Jonathan Edwards and select Scottish ministers first connected revivalism and millennialism together in a new evangelical print culture. Evangelical ministers used publications and personal correspondence to hypothesise that the current Atlantic revivals were signs pointing towards Christ’s millennial kingdom. The 1740s stands as a unique decade where evangelical ministers created an influential synthesis of revivalism, social progress, and millennialism. The revivalist and millennial synthesis was a harbinger of the evangelical future for religious movements in both the nineteenth and twentieth centuries.
Incorporating intraspecific trait variation into functional diversity: Impacts of selective logging on birds in Borneo
Authors: Ross Samuel R. P.‐J. , Hassall Christopher , Hoppitt William J. E. , Edwards Felicity A. , Edwards David P. , Hamer Keith C.
Published: March 2017

As conservation increasingly recognizes the importance of species’ functional roles in ecosystem processes, studies are shifting away from measuring species richness towards measures that account for the functional differences between species in a community. These functional diversity (FD) indices have received much recent attention and refinement, but their greatest limitation remains their inability to incorporate information about intraspecific trait variation (ITV).

We use an individual‐based model to account for ITV when calculating the functional diversity of two avian communities in Borneo; one in primary (unlogged) forest and one in selectively logged forest. We deal with the scarcity of trait data for individual species by developing a simulation approach, taking data from the literature where necessary. Using a bootstrapping procedure, we produce a range of ecologically feasible FD values taking account of ITV for five commonly used FD indices, and we quantify the confidence that can be placed in these values, using a newly developed bootstrapping method: btFD.

We find that incorporating ITV significantly alters the FD values of all indices used in our models. The rank order of FD for the two communities, indicating whether diversity was higher in primary or selectively logged forest, is largely unchanged by the inclusion of ITV. However, by accounting for ITV, we are able to reveal previously unrecognized impacts of selective logging on avian functional diversity through a narrower dispersion of individuals in functional trait space in logged forest.

Our results highlight the importance of incorporating ITV into measures of functional diversity, whilst our simulation approach addresses the frequently encountered difficulty of working with sparse trait data and quantifies the confidence that should be placed in such findings.
Long‐term future risk of severe exacerbations: Distinct 5‐year trajectories of problematic asthma
Authors: Yii A. C. A. , Tan J. H. Y. , Lapperre T. S. , Chan A. K. W. , Low S. Y. , Ong T. H. , Tan K. L. , Chotirmall S. H. , Sterk P. J. , Koh M. S.
Published: March 2017

Background

Assessing future risk of exacerbations is an important component of asthma management. Existing studies have investigated short‐ but not long‐term risk. Problematic asthma patients with unfavorable long‐term disease trajectory and persistently frequent severe exacerbations need to be identified early to guide treatment.

Aim

To identify distinct trajectories of severe exacerbation rates among “problematic asthma” patients and develop a risk score to predict the most unfavorable trajectory.

Methods

Severe exacerbation rates over five years for 177 “problematic asthma” patients presenting to a specialist asthma clinic were tracked. Distinct trajectories of severe exacerbation rates were identified using group‐based trajectory modeling. Baseline predictors of trajectory were identified and used to develop a clinical risk score for predicting the most unfavorable trajectory.

Results

Three distinct trajectories were found: 58.5% had rare intermittent severe exacerbations (“infrequent”), 32.0% had frequent severe exacerbations at baseline but improved subsequently (“nonpersistently frequent”), and 9.5% exhibited persistently frequent severe exacerbations, with the highest incidence of near‐fatal asthma (“persistently frequent”). A clinical risk score composed of ≥2 severe exacerbations in the past year (+2 points), history of near‐fatal asthma (+1 point), body mass index ≥25kg/m2 (+1 point), obstructive sleep apnea (+1 point), gastroesophageal reflux (+1 point), and depression (+1 point) was predictive of the “persistently frequent” trajectory (area under the receiver operating characteristic curve: 0.84, sensitivity 72.2%, specificity 81.1% using cutoff ≥3 points). The trajectories and clinical risk score had excellent performance in an independent validation cohort.

Conclusions

Patients with problematic asthma follow distinct illness trajectories over a period of five years. We have derived and validated a clinical risk score that accurately identifies patients who will have persistently frequent severe exacerbations in the future.
Identification of first‐stage labor arrest by electromyography in term nulliparous women after induction of labor
Authors: Vasak Blanka , Graatsma Elisabeth M. , Hekman‐Drost Elske , Eijkemans Marinus J. , Schagen van Leeuwen Jules H. , Visser Gerard H.A. , Jacod Benoit C.
Published: March 2017

Introduction

Worldwide induction and cesarean delivery rates have increased rapidly, with consequences for subsequent pregnancies. The majority of intrapartum cesarean deliveries are performed for failure to progress, typically in nulliparous women at term. Current uterine registration techniques fail to identify inefficient contractions leading to first‐stage labor arrest. An alternative technique, uterine electromyography has been shown to identify inefficient contractions leading to first‐stage arrest of labor in nulliparous women with spontaneous onset of labor at term. The objective of this study was to determine whether this finding can be reproduced in induction of labor.

Material and methods

Uterine activity was measured in 141 nulliparous women with singleton term pregnancies and a fetus in cephalic position during induced labor. Electrical activity of the myometrium during contractions was characterized by its power density spectrum.

Results

No significant differences were found in contraction characteristics between women with induced labor delivering vaginally with or without oxytocin and women with arrested labor with subsequent cesarean delivery.

Conclusion

Uterine electromyography shows no correlation with progression of labor in induced labor, which is in contrast to spontaneous labor.