bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial DNA replication is initiated at blastocyst formation in equine embryos
Authors: Hendriks W. Karin , Colleoni Silvia , Galli Cesare , Paris Damien B. B. P. , Colenbrander Ben , Stout Tom A. E.
Published: November 2018

Intracytoplasmic sperm injection is the technique of choice for equine IVF and, in a research setting, 18–36% of injected oocytes develop to blastocysts. However, blastocyst development in clinical programs is lower, presumably due to a combination of variable oocyte quality (e.g. from old mares), suboptimal culture conditions and marginal fertility of some stallions. Furthermore, mitochondrial constitution appears to be critical to developmental competence, and both maternal aging and invitro embryo production (IVEP) negatively affect mitochondrial number and function in murine and bovine embryos. The present study examined the onset of mitochondrial (mt) DNA replication in equine embryos and investigated whether IVEP affects the timing of this important event, or the expression of genes required for mtDNA replication (i.e. mitochondrial transcription factor (TFAM), mtDNA polymerase γ subunit B (mtPOLB) and single-stranded DNA binding protein (SSB)). We also investigated whether developmental arrest was associated with low mtDNA copy number. mtDNA copy number increased (P<0.01) between the early and expanded blastocyst stages both invivo and invitro, whereas the mtDNA:total DNA ratio was higher in invitro-produced embryos (P=0.041). Mitochondrial replication was preceded by an increase in TFAM but, unexpectedly, not mtPOLB or SSB expression. There was no association between embryonic arrest and lower mtDNA copy numbers.
Opossum milk IgG is from maternal circulation and timing of transfer correlates with neonatal immune development
Authors: Fehrenkamp Bethaney D. , Morrissey Kimberly A. , Miller Robert D.
Published: November 2018

Marsupials, with short gestation times, have more complex and changing patterns of milk composition than eutherians. Maternal immunoglobulins (Ig) that confer immunity on offspring are among the components that change during marsupial lactation. In the present study we quantified the abundance of mammary transcripts encoding Ig heavy chains and their corresponding transporters in the laboratory opossum Monodelphis domestica. IgA transcripts were the most abundant in opossum mammary and, with IgM, increased in abundance linearly from birth to weaning. Similarly, the Fc receptor for IgA, the poly-Ig receptor, also increased in abundance throughout lactation. There were few transcripts for IgG or IgE within the opossum mammaries. This is in contrast with reports for Australian marsupial species. Transcripts for the Neonatal Fc Receptor (FcRN), which transports IgG, were detected throughout lactation, and opossum milk is known to contain IgG. Therefore, milk IgG is likely to be taken from the maternal circulation, rather than resulting from local production. There is a parallel increase in FcRN in the newborn gut that declines around the time when neonates have matured to the point where they can make their own IgG. These results are consistent with a transfer of maternal Ig that is coordinated with the development of the neonatal immune system.
Expression and regulation of high mobility group AT-hook 1 (HMGA1) during ovulation and luteinisation in rat ovary
Authors: Li Hao-ran , Li Yan , Liu Yu , Yu Jiao-jiao , Li Fei-xue
Published: November 2018

High mobility group AT-hook 1 (HMGA1) is able to regulate gene expression and function as a tumour suppressor. The spatiotemporal expression pattern of HMGA1 was investigated in this study. Immature female rats (22–23 days old) were treated with 10IU, s.c., pregnant mare’s serum gonadotrophin to stimulate follicular development, followed 48h later by injection with 5IU, s.c., human chorionic gonadotrophin (hCG). Whole ovaries or granulosa cells were collected at various times after hCG administration (n=3 per time point). Real-time polymerase chain reaction and western blot analysis revealed that HMGA1 was highly stimulated in the ovary by 4–12h after hCG treatment. In situ hybridisation analysis demonstrated that Hmga1 mRNA expression was induced in granulosa cells between 8 and 12h after hCG treatment. There was negligible Hmga1 mRNA signal observed in newly forming corpora lutea. In addition, the data indicated that both the protein kinase (PK) A and PKC pathways regulated Hmga1 expression in rat granulosa cells. In rat granulosa cell cultures, upregulation of Hmga1 was dependent on new protein synthesis because Hmga1 was inhibited by cycloheximide. Furthermore, Hmga1 mRNA expression in rat granulosa cell cultures was inhibited by AG1478, whereas NS398 and RU486 had no effect, suggesting that Hmga1 expression was regulated, in part, by the epidermal growth factor pathway. In summary, the findings of this study suggest that induction of Hmga1 may be important for theca and granulosa cell differentiation into luteal cells.
Tropical summer induces DNA fragmentation in boar spermatozoa: implications for evaluating seasonal infertility
Authors: Peña Jr. Santiago T. , Stone Felicity , Gummow Bruce , Parker Anthony J. , Paris Damien B. B. P.
Published: November 2018

Summer infertility continues to undermine pig productivity, costing the pig industry millions in annual losses. The boar’s inefficient capacity to sweat, non-pendulous scrotum and the extensive use of European breeds in tropical conditions, can make the boar particularly vulnerable to the effects of heat stress; however, the link between summer heat stress and boar sperm DNA damage has not yet been demonstrated. Semen from five Large White boars was collected and evaluated during the early dry, late dry and peak wet seasons to determine the effect of seasonal heat stress on the quality and DNA integrity of boar spermatozoa. DNA damage in spermatozoa during the peak wet was 16-fold greater than during the early dry and nearly 9-fold greater than during the late dry season. Sperm concentration was 1.6-fold lower in the peak wet than early dry whereas no difference was found across several motility parameters as determined by computer-assisted sperm analysis. These results demonstrate that tropical summer (peak wet season) induces DNA damage and reduces concentration without depressing motility in boar spermatozoa, suggesting that traditional methods of evaluating sperm motility may not detect inherently compromised spermatozoa. Boar management strategies (such as antioxidant supplementation) need to be developed to specifically mitigate this problem.
Metrics for regulated biochemical pathway systems
Authors: Davis Jacob D , Voit Eberhard O
Published: November 2018

Motivation

The assessment of graphs through crisp numerical metrics has long been a hallmark of biological network analysis. However, typical graph metrics ignore regulatory signals that are crucially important for optimal pathway operation, for instance, in biochemical or metabolic studies. Here we introduce adjusted metrics that are applicable to both static networks and dynamic systems.

Results

The metrics permit quantitative characterizations of the importance of regulation in biochemical pathway systems, including systems designed for applications in synthetic biology or metabolic engineering. They may also become criteria for effective model reduction.

Availability and implementation

The source code is available at https://gitlab.com/tienbien44/metrics-bsa
Maternal L-proline supplementation enhances fetal survival, placental development, and nutrient transport in mice†
Authors: Liu Ning , Dai Zhaolai , Zhang Yunchang , Chen Jingqing , Yang Ying , Wu Guoyao , Tso Patrick , Wu Zhenlong
Published: November 2018

L-Proline (proline) in amniotic fluid was markedly increased during pregnancy in both pigs and sheep. However, in vivo data to support a beneficial effect of proline on fetal survival are not available. In this study, pregnant C57BL/6J mice were fed a purified diet supplemented with or without 0.50% proline from embryonic day 0.5 (E0.5) to E12.5 or term. Results indicated that dietary supplementation with proline to gestating mice enhanced fetal survival, reproductive performance, the concentrations of proline, arginine, aspartic acid, and tryptophan in plasma and amniotic fluid, while decreasing the concentrations of ammonia and urea in plasma and amniotic fluid. Placental mRNA levels for amino acid transporters, including Slc36a4, Slc38a2, Slc38a4, Slc6a14, and Na+/K+ ATPase subunit-1α (Atp1a1), fatty acid transporter Slc27a4, and glucose transporters Slc2a1 and Slc2a3, were augmented in proline-supplemented mice, compared with the control group. Histological analysis showed that proline supplementation enhanced labyrinth zone in the placenta of mice at E12.5, mRNA levels for Vegf, Vegfr, Nos2, and Nos3, compared with the controls. Western blot analysis showed that proline supplementation increased protein abundances of phosphorylated (p)-mTORC1, p-ribosomal protein S6 kinase (p70S6K), and p-eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), as well as the protein level of GCN2 (a negative regulator of mTORC1 signaling). Collectively, our results indicate a novel functional role of proline in improving placental development and fetal survival by enhancing placental nutrient transport, angiogenesis, and protein synthesis.
Dense deposit disease: a greatly increased biopsy incidence in India versus the USA
Authors: Prema K S Jansi , Kurien Anila A , Gopalakrishnan Natarajan , Walker Patrick D , Larsen Christopher P
Published: November 2018

Background

We present the largest clinicopathologic case series to date of dense deposit disease (DDD) in an Indian population and compare the renal biopsy incidence rate to that seen in a large renal laboratory in USA.

Methods

Cases of DDD were identified and evaluated from native kidney biopsies reported at Renopath, India and at Arkana Laboratories, in the USA. Renopath receives biopsies from four states, located in the South and Eastern part of India. Arkana Laboratories’ biopsies came from 37 states across the USA.

Results

During the study period, there were a total of 25 patients diagnosed with DDD among the 7335 native kidney biopsies at Renopath. Thus, the biopsy incidence rate (cases of DDD/total renal biopsies/year) is 0.0034. By comparison, there were 10 cases of DDD diagnosed among 26 319 native kidney biopsies at Arkana Laboratories during the same time period, with a renal biopsy incidence rate of 0.00038.

Conclusions

DDD in this Indian subpopulation has similar clinical and pathologic characteristics when compared to previously reported studies. However, the biopsy incidence rate is about 890% or 8.9 times more common in this subset of the Indian population when compared with a broad cross-section of the US population. In addition to potential genetic factors, environmental conditions and chronic infections likely contribute to the markedly higher biopsy incidence rate. Given the much greater number of patients with DDD in this population, further retrospective and prospective studies would allow more rapid progress in understanding the pathogenesis of DDD and thus potential treatment of patients with DDD.
Chlamydomonas WDR92 in association with R2TP-like complex and multiple DNAAFs to regulate ciliary dynein preassembly
Authors: Liu Guang , Wang Limei , Pan Junmin
Published: November 2018

The motility of cilia or eukaryotic flagella is powered by the axonemal dyneins, which are preassembled in the cytoplasm by proteins termed dynein arm assembly factors (DNAAFs) before being transported to and assembled on the ciliary axoneme. Here, we characterize the function of WDR92 in Chlamydomonas. Loss of WDR92, a cytoplasmic protein, in a mutant wdr92 generated by DNA insertional mutagenesis resulted in aflagellate cells or cells with stumpy or short flagella, disappearance of axonemal dynein arms, and diminishment of dynein arm heavy chains in the cytoplasm, suggesting that WDR92 is a DNAAF. Immunoprecipitation of WDR92 followed by mass spectrometry identified inner dynein arm heavy chains and multiple DNAAFs including RuvBL1, RPAP3, MOT48, ODA7, and DYX1C. The PIH1 domain-containing protein MOT48 formed a R2TP-like complex with RuvBL1/2 and RPAP3, while PF13, another PIH1 domain-containing protein with function in dynein preassembly, did not. Interestingly, the third PIH1 domain-containing protein TWI1 was not related to flagellar motility. WDR92 physically interacted with the R2TP-like complex and the other identified DNNAFs. Our data suggest that WDR92 functions in association with the HSP90 co-chaperone R2TP-like complex as well as linking other DNAAFs in dynein preassembly.
The Many Nuanced Evolutionary Consequences of Duplicated Genes
Authors: Teufel Ashley I , Johnson Mackenzie M , Laurent Jon M , Kachroo Aashiq H , Marcotte Edward M , Wilke Claus O
Published: November 2018

Gene duplication is seen as a major source of structural and functional divergence in genome evolution. Under the conventional models of sub or neofunctionalization, functional changes arise in one of the duplicates after duplication. However, we suggest here that the presence of a duplicated gene can result in functional changes to its interacting partners. We explore this hypothesis by in silico evolution of a heterodimer when one member of the interacting pair is duplicated. We examine how a range of selection pressures and protein structures leads to differential patterns of evolutionary divergence. We find that a surprising number of distinct evolutionary trajectories can be observed even in a simple three member system. Further, we observe that selection to correct dosage imbalance can affect the evolution of the initial function in several unexpected ways. For example, if a duplicate is under selective pressure to avoid binding its original binding partner, this can lead to changes in the binding interface of a nonduplicated interacting partner to exclude the duplicate. Hence, independent of the fate of the duplicate, its presence can impact how the original function operates. Additionally, we introduce a conceptual framework to describe how interacting partners cope with dosage imbalance after duplication. Contextualizing our results within this framework reveals that the evolutionary path taken by a duplicate’s interacting partners is highly stochastic in nature. Consequently, the fate of duplicate genes may not only be controlled by their own ability to accumulate mutations but also by how interacting partners cope with them.
Effectiveness of the Oral Human Attenuated Rotavirus Vaccine: A Systematic Review and Meta-analysis—2006–2016
Authors: Willame Corinne , Vonk Noordegraaf-Schouten Marije , Gvozdenović Emilia , Kochems Katrin , Oordt-Speets Anouk , Praet Nicolas , van Hoorn Rosa , Rosillon Dominique
Published: November 2018

Background

Gastroenteritis caused by rotavirus accounts for considerable morbidity in young children. We aimed to assess the vaccine effectiveness (VE) of the oral rotavirus vaccine Rotarix, as measured by laboratory-confirmed rotavirus infection after referral to hospital and/or emergency departments in children aged <5 years with gastroenteritis.

Methods

We performed a systematic search for peer-reviewed studies conducted in real-life settings published between 2006 and 2016 and a meta-analysis to calculate the overall Rotarix VE, which was further discriminated through stratified analyses.

Results

The overall VE estimate was 69% (95% confidence interval [CI], 62% to 75%); stratified analyses revealed a non-negligible impact of factors such as study design and socioeconomic status. Depending on the control group, VE ranged from 63% (95% CI, 52% to 72%) to 81% (95% CI, 69% to 88%) for unmatched and matched rotavirus test–negative controls. VE varied with socioeconomic status: 81% (95% CI, 74% to 86%) in high-income countries, 54% (95% CI, 39% to 65%) in upper-middle-income countries, and 63% (95% CI, 50% to 72%) in lower-middle-income countries. Age, rotavirus strain, and disease severity were also shown to impact VE, but to a lesser extent.

Conclusions

This meta-analysis of real-world studies showed that Rotarix is effective in helping to prevent hospitalizations and/or emergency department visits due to rotavirus infection.
Prediction of Severe Maternal Outcome Among Pregnant and Puerperal Women in Obstetric ICU
Authors: Oliveira-Neto Antonio Francisco , Parpinelli Mary Angela , Costa Maria Laura , Souza Renato Teixeira , Ribeiro do Valle Carolina , Sousa Maria Helena , Cecatti José Guilherme
Published: November 2018

Objective:

World Health Organization recommends the use of maternal near miss as a tool to monitor and improve quality of obstetric care. Severe maternal outcome corresponds to the sum of maternal near miss and maternal death cases. This study was aimed at validating Acute Physiology and Chronic Health Evaluation II and IV, Simplified Acute Physiology Score III, and Sequential Organ Failure Assessment in pregnant and postpartum women in predicting severe maternal outcome.

Design:

A retrospective cohort study.

Setting:

Obstetric ICU in a tertiary care hospital in Brazil.

Patients:

Pregnant and postpartum women admitted to the obstetric ICU during a 3-year period.

Interventions:

None.

Measurements and Main Results:

A total of 279 women were admitted to ICU, an admission rate of 34.6/1,000 live births, and the mortality index to severe maternal outcome (maternal death/maternal near miss + maternal death) was 7.7%. Total Sequential Organ Failure Assessment had a better overall performance than remaining scores for total hospitalizations (area under the curve, 0.86; standardized mortality ratio, 0.96; 95% CI, 0.74–1.22), for hypertensive direct causes (area under the curve, 0.81; standardized mortality ratio, 0.73; 95% CI, 0.31–1.43), and indirect causes (area under the curve, 0.89; standardized mortality ratio, 0.85; 95% CI, 0.59–1.19). The Acute Physiology and Chronic Health Evaluation II had a better overall performance than total Sequential Organ Failure Assessment for hemorrhagic causes (area under the curve, 0.75; standardized mortality ratio, 1.0; 95% CI, 0.61–1.54).

Conclusions:

Total Sequential Organ Failure Assessment may be used to predict severe maternal outcome in obstetric populations admitted to ICU. The Acute Physiology and Chronic Health Evaluation II may be applied to predict severe maternal outcome in hemorrhagic complications. We do not recommend Acute Physiology and Chronic Health Evaluation IV and Simplified Acute Physiology Score III for the prediction of severe maternal outcome.
Elucidating the End-of-Life Experience of Persons With Amyotrophic Lateral Sclerosis
Authors: Long Rachel , Havics Brianna , Zembillas Maria , Kelly Joannah , Amundson Mia
Published: November 2018

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease that occurs in 4 among 100 000 people in the United States. Individuals with ALS gradually lose their ability to control voluntary muscles, diminishing their ability to communicate. A comprehensive multidatabase search retrieved 31 qualitative research articles that addressed persons with end-of-life experiences with ALS. Inclusion/exclusion criteria were applied and a critical appraisal was applied for the final 8 included articles. First-person data extraction from the final articles represented emergence of 3 themes significant to persons with ALS: decisions for life-sustaining support, coping and fear of what is to come, and communication with providers. Tracheostomy and ventilation as a means of prolonging life were important considerations for individuals with ALS. Persons with ALS struggled emotionally with their sudden loss of control and facing their demise. Some facets in which they did exert control, such as living wills, were hindered by patient and health care provider communication. Effective communication in end-of-life circumstances is paramount to preserving patient autonomy and dignity. This can be achieved by the patients conveying their preferences with respect to end-of-life care in advance, as well the nurses and other health care providers supporting the patients emotionally as they cope with terminal illness. Understanding patients' views regarding end-of-life circumstances is pertinent to nurses and other health care providers as they plan for palliative care.
Prevalence and Correlates of the Use of Complementary and Alternative Medicine in Adults Living in a Rural Area
Authors: Cevik Celalettin , Tari Selcuk Kevser
Published: November 2018

There is growing interest in the use of complementary and alternative medicine (CAM) throughout the world; however, previous research performed in Turkey has not focused on CAM use in rural areas. The present study was aimed at determining CAM use among people aged 18 years or older living in Balikesir, a province in the western part of Turkey, and the correlates of CAM use. This cross-sectional study was conducted in Balikesir between January 2015 and April 2015. The sample group was reached with multistage cluster sampling method. The study included 410 people who agreed to participate. Data were collected with the questionnaire developed by the researchers from the households through face-to-face interviews. The data were analyzed using the descriptive statistics, chi-square test, and logistic regression analysis. Of the participants, 87.3% reported that they had used CAM in the past 12 months. While 39.4% of them preferred herbal products, 25.7% reported that they used CAM due to chronic pain. The results of the logistic regression model demonstrated that CAM use was 4.23 times higher in the age group of those 44 years of age and older, 7.32 times higher among the women, 11.11 times higher among those who had junior high school or lower education, 9.76 times higher among the employed participants and 15.12 times higher among those who had chronic diseases. The results of the study revealed that nearly 9 of every 10 participants used CAM methods and that the most commonly used method was the use of herbal products.
CORRELATION OF GENE EXPRESSION PROFILE STATUS AND AMERICAN JOINT COMMISSION ON CANCER STAGE IN UVEAL MELANOMA
Authors: Berry Duncan E. , Schefler Amy C. , Seider Michael I. , Materin Miguel , Stinnett Sandra , Mruthyunjaya Prithvi ,   the Ocular Oncology Study Consortium
Published: November 2018

Purpose:

To study the relationship between gene expression profile (GEP) subclass and American Joint Committee on Cancer (AJCC) stage in patients with uveal melanoma (UM).

Methods:

A retrospective, multicenter study was undertaken with patients entered from nine major ocular oncology centers from across the United States. Three hundred sixty eligible patients had UM and underwent I-125 plaque brachytherapy with concurrent tumor biopsy with GEP testing between January 1, 2010, and October 28, 2014. Patient demographics and UM features were analyzed by both GEP and AJCC status.

Results:

Gene expression profile class divided the cohort into three groups: Class 1a (n = 186), Class 1b (n = 77), and Class 2 (n = 113). When classified using AJCC staging criteria, we found the following: Stage I in 91 cases (25.3%), Stage IIA in 143 cases (39.7%), Stage IIB in 89 cases (24.7%), Stage IIIA in 36 cases (10%), and Stage IIIB in 1 case (0.3%). There were no Stage IV cases, as lymph node and metastatic data were not collected as a part of this study. Among Stage I tumors, both high tumor height and high largest basal diameter were associated with a higher frequency of Class 2 status (P < 0.05). As UMs progress to a larger AJCC tumor group (T1–T4), the odds ratio of having a worse prognosis based on GEP class was 1.75 (95% CI, 1.36–2.25; P < 0.001). Similarly, as UMs progress to a higher AJCC stage, the odds ratio of having a worse prognosis based on GEP class was 1.69 (95% CI, 1.36–2.10; P < 0.001).

Conclusion:

This report details the differences in clinical features between GEP subclasses and how they are distributed among the AJCC stages. When the tumors were grouped by AJCC staging criteria, both larger AJCC tumor (T) group and worsening AJCC stage were associated with worsening predicted prognosis, based on GEP subclass.
Preferred self-administered questionnaires to assess fear of movement, coping, self-efficacy, and catastrophizing in patients with musculoskeletal pain—A modified Delphi study
Authors: Sleijser-Koehorst Marije L.S. , Bijker Lisette , Cuijpers Pim , Scholten-Peeters Gwendolyne G.M. , Coppieters Michel W.
Published: November 2018

The way people with musculoskeletal disorders deal with pain influences their prognosis. Psychosocial factors that influence outcomes include fear of movement, coping, self-efficacy, and catastrophizing. A 3-round modified Delphi study was conducted with the aim to reach consensus on the most appropriate questionnaires to assess these 4 psychosocial factors in patients at risk of developing persistent musculoskeletal pain. The panel consisted of 36 experts, with track records in medicine, psychology, and allied health. To be considered an expert, a minimum number of authorships were required on research articles using self-administered questionnaires to assess these psychosocial factors in relevant patient populations. In round 1, the experts proposed 30 questionnaires to assess the 4 factors. In round 2, experts rated the questionnaires on suitability, considering clinimetric properties, content, feasibility, personal experiences, and expertise. The highest ranked questionnaires (maximally 5 per factor) were retained for round 3, in which the experts made a final assessment of the questionnaires and provided their positive and negative experiences with the questionnaires. Consensus was reached for the following questionnaires to assess (1) fear of movement: Fear Avoidance Beliefs Questionnaire and Tampa Scale (full version or 11-item version); (2) coping: Coping Strategies Questionnaire (initial or revised version) and Chronic Pain Coping Index; (3) self-efficacy: Pain Self-Efficacy Questionnaire (full version or 2-item version); and (4) catastrophizing: Pain Catastrophizing Scale and the revised version of the Coping Strategies Questionnaire. Although other questionnaires can be considered in specific circumstances, these questionnaires are recommended in people with musculoskeletal pain.
Biliary tract exploration through a common bile duct incision or left hepatic duct stump in laparoscopic left hemihepatectomy for left side hepatolithiasis: which is better?
Authors: Zeng Xintao , Yang Pei , Wang Wentao
Published: November 2018

Laparoscopic left hemihepatectomy (LLH) followed by biliary tract exploration is used to treat left-sided hepatolithiasis (LSH). The purpose of this study was to compare the efficacy of 2 methods of biliary tract exploration in LLH:biliary tract exploration through a common bile duct (CBD) incision (with T-tube drainage) or through the left hepatic duct (LHD) stump (without T-tube drainage).

LSH patients (113 patients) were recruited retrospectively in our hospital from December 2008 to January 2016. To compare different methods of biliary tract exploration during LLH, the patients were divided into 2 groups: 41 patients underwent biliary tract exploration through the LHD stump (LHD group), and 72 patients underwent biliary tract exploration through a CBD incision (CBD group). Baseline characteristics, surgical outcomes, surgery-related complications, postoperative hospital stay (PHS) and long-term results were compared between the 2 groups.

There was no unplanned reoperation in the 2 groups. One patient in the CBD group had a residual stone, which was removed by choledochoscopy 2 months postoperation. Two patients in the LHD group and 3 patients in the CBD group had bile leakage and were cured with abdominal drainage. There were no significant differences in the total operation time, incidence of residual stones and bile leakage between the 2 groups (P > .05). The PHS and the incidence of hypokalemia or hyponatremia in the LHD group were significantly lower than those in the CBD group (P < .05). T-tube-related complications occurred in 13.9% (10/72) of the CBD patients. The mean follow-up period was 37.2 ± 13.8 months. There were no significant differences in the incidence of recurrence stones or cholangitis (P > .05) between the 2 groups.

Exploration of the biliary tract through the LHD stump without T-tube drainage is safe with satisfactory short- and long-term results for selected LSH patients.
The International Multiple Sclerosis Visual System Consortium: Advancing Visual System Research in Multiple Sclerosis
Authors: Balcer Laura J. , Balk Lisanne J. , Brandt Alexander U. , Calabresi Peter A. , Martinez-Lapiscina Elena H. , Nolan Rachel C. , Paul Friedemann , Petzold Axel , Saidha Shiv ,   on behalf of the IMSVISUAL Consortium
Published: November 2018

Background:

The International Multiple Sclerosis Visual System Consortium (IMSVISUAL) was formed in November 2014 with the primary goal of improving research, care, and education regarding the role of the visual system in multiple sclerosis (MS) and related disorders.

Methods:

In this review, we describe the formation, goals, activities, and structure of IMSVISUAL, as well as the relationship of IMSVISUAL with the Americas Committee for Treatment and Research in MS (ACTRIMS). Finally, we provide an overview of the work IMSVISUAL has completed to date, as well as an outline of research projects ongoing under the auspices of IMSVISUAL.

Results:

IMSVISUAL has 140 members worldwide and continues to grow. Through IMSVISUAL-related research, optical coherence tomography (OCT)-derived peripapillary retinal nerve fiber layer (pRNFL) thinning has been established as a predictor of future disability in MS. IMSVISUAL has also developed guidelines for reporting OCT studies in MS. Moreover, a systematic review performed by IMSVISUAL found that not only are pRNFL and ganglion cell + inner plexiform layer (GCIPL) thicknesses reduced in patients with MS (particularly in eyes with prior optic neuritis [ON]), but that inner nuclear layer measures may be higher among MS ON eyes, relative to healthy control eyes. Currently, there are several ongoing IMSVISUAL projects that will establish a role for visual outcomes in diagnosing MS and quantifying the effects of emerging therapies in clinical trials.

Conclusions:

The development of IMSVISUAL represents a major collaborative commitment to defining the role of visual outcomes in high-quality, large-scale studies that generate definitive and instructive findings in the field of MS. As a consortium, IMSVISUAL has completed several international collaborative projects, is actively engaged in numerous ongoing research studies, and is committed to expanding the role of vision research in MS and related disorders.
Coordinated demethylation of H3K9 and H3K27 is required for rapid inflammatory responses of endothelial cells
Authors: Higashijima Yoshiki , Matsui Yusuke , Shimamura Teppei , Tsutsumi Shuichi , Nakaki Ryo , Abe Yohei , Link Verena M. , Osaka Mizuko , Yoshida Masayuki , Watanabe Ryo , Tanaka Toshihiro , Taguchi Akashi , Miura Mai , Inoue Tsuyoshi , Nangaku Masaomi , Kimura Hiroshi , Furukawa Tetsushi , Aburatani Hiroyuki , Wada Youichiro , Glass Christopher K. , Kanki Yasuharu
Published: November 2018

Lysine 9 di-methylation and lysine 27 tri-methylation of histone H3 (H3K9me2 and H3K27me3) are generally linked to gene repression. However, the functions of repressive histone methylation dynamics during inflammatory responses remain enigmatic. We found that tumor necrosis factor (TNF)-α rapidly induces the co-occupancy of lysine demethylases 7A (KDM7A) and 6A (UTX) with nuclear factor kappa-B (NF-κB) recruited elements in human endothelial cells. KDM7A and UTX demethylate H3K9me2 and H3K27me3, respectively, and both are required for activation of NF-κB-dependent inflammatory genes. Chromosome conformation capture-based methods demonstrated increased interactions between TNF-α-induced super enhancers at NF-κB-relevant loci, coinciding with KDM7A- and UTX-recruitment. Simultaneous inhibition of KDM7A and UTX significantly reduced leukocyte adhesion in mice, establishing the biological and potential translational relevance of this mechanism. Collectively, these findings suggest that rapid erasure of repressive histone marks by KDM7A and UTX is essential for NF-κB-dependent regulation of genes that control inflammatory responses of endothelial cells.

HIGHLIGHTS

KDM7A and UTX cooperatively control NF-κB-dependent transcription in vascular endothelial cells.

Demethylation of repressive histone marks by KDM7A and UTX is critical for early inflammatory responses.

KDM7A and UTX are associated with TNF-α-induced looping of super enhancers.

Pharmacological inhibition of KDM7A and UTX reduces leukocyte adhesive interactions with endothelial cells in mice.
Determinants of QTL mapping power in the realized Collaborative Cross
Authors: Keele Gregory R. , Crouse Wesley L. , Kelada Samir N. P. , Valdar William
Published: November 2018

The Collaborative Cross (CC) is a mouse genetic reference population whose range of applications includes quantitative trait loci (QTL) mapping. The design of a CC QTL mapping study involves multiple decisions, including which and how many strains to use, and how many replicates per strain to phenotype, all viewed within the context of hypothesized QTL architecture. Until now, these decisions have been informed largely by early power analyses that were based on simulated, hypothetical CC genomes. Now that more than 50 CC strains are available and more than 70 CC genomes have been observed, it is possible to characterize power based on realized CC genomes. We report power analyses based on extensive simulations and examine several key considerations: 1) the number of strains and biological replicates, 2) the QTL effect size, 3) the presence of population structure, and 4) the distribution of functionally distinct alleles among the founder strains at the QTL. We also provide general power estimates to aide in the design of future experiments. All analyses were conducted with our R package, SPARCC (Simulated Power Analysis in the Realized Collaborative Cross), developed for performing either large scale power analyses or those tailored to particular CC experiments.
Skin inflammation driven by differentiation of quiescent tissue-resident ILCs into a spectrum of pathogenic effectors
Authors: Bielecki Piotr , Riesenfeld Samantha J. , Kowalczyk Monika S. , Amezcua Vesely Maria C. , Kroehling Lina , Yaghoubi Parastou , Dionne Danielle , Jarret Abigail , Steach Holly R. , McGee Heather M. , Porter Caroline B. M. , Licona-Limon Paula , Bailis Will , Jackson Ruaidhri P. , Gagliani Nicola , Locksley Richard M. , Regev Aviv , Flavell Richard A.
Published: November 2018

Psoriasis pathology is driven by the type 3 cytokines IL-17 and Il-22, but little is understood about the dynamics that initiate alterations in tissue homeostasis. Here, we use mouse models, single-cell RNA-seq (scRNA-seq), computational inference and cell lineage mapping to show that psoriasis induction reconfigures the functionality of skin-resident ILCs to initiate disease. Tissue-resident ILCs amplified an initial IL-23 trigger and were sufficient, without circulatory ILCs, to drive pathology, indicating that ILC tissue remodeling initiates psoriasis. Skin ILCs expressed type 2 cytokines IL-5 and IL-13 in steady state, but were epigenetically poised to become ILC3-like cells. ScRNA-seq profiles of ILCs from psoriatic and naïve skin of wild type (WT) and Rag1-/- mice form a dense continuum, consistent with this model of fluid ILC states. We inferred biological “topics” underlying these states and their relative importance in each cell with a generative model of latent Dirichlet allocation, showing that ILCs from untreated skin span a spectrum of states, including a naïve/quiescent-like state and one expressing the Cd74 and Il13 but little Il5. Upon disease induction, this spectrum shifts, giving rise to a greater proportion of classical Il5- and Il13- expressing “ILC2s” and a new, mixed ILC2/ILC3-like subset, expressing Il13, Il17, and Il22. Using these key topics, we related the cells through transitions, revealing a quiescence-ILC2-ILC3s state trajectory. We demonstrated this plasticity in vivo, combining an IL-5 fate mouse with IL-17A and IL-22 reporters, validating the transition of IL-5–producing ILC2s to IL-22– and IL-17A–producing cells during disease initiation. Thus, steady-state skin ILCs are actively repressed and cued for a plastic, type 2 response, which, upon induction, morphs into a type 3 response that drives psoriasis. This suggests a general model where specific immune activities are primed in healthy tissue, dynamically adapt to provocations, and left unchecked, drive pathological remodeling.
The cyclic nitroxide antioxidant 4-methoxy-TEMPO decreases mycobacterial burden in vivo through host and bacterial targets
Authors: Black Harrison D , Xu Wenbo , Hortle Elinor , Robertson Sonia I , Britton Warwick J , Kaur Amandeep , New Elizabeth J , Witting Paul K , Chami Belal , Oehlers Stefan
Published: November 2018

Tuberculosis is a chronic inflammatory disease caused by persistent infection with Mycobacterium tuberculosis. The rise of antibiotic resistant strains necessitates the design of novel treatments. Recent evidence shows that not only is M. tuberculosis highly resistant to oxidative killing, it also co-opts host oxidant production to induce phagocyte death facilitating bacterial dissemination. We have targeted this redox environment with the cyclic nitroxide derivative 4-methoxy-TEMPO (MetT) in the zebrafish-M. marinum infection model. MetT inhibited the production of mitochondrial ROS and decreased infection-induced cell death to aid containment of infection. We identify a second mechanism of action whereby stress conditions, including hypoxia, found in the infection microenvironment appear to sensitise M. marinum to killing by MetT both in vitro and in vivo. Together, our study demonstrates MetT inhibited the growth and dissemination of M. marinum through host and bacterial targets.
Increased Interactivity and Improvements to the GigaScience Database, GigaDB.
Authors: Xiao Si Zhe , Armit Chris , Edmunds Scott , Goodman Laurie , Li Peter , Tuli Mary Ann , Hunter Christopher
Published: November 2018

With a large increase in the volume and type of data archived in GigaDB since its launch in 2011, we have studied the metrics and user patterns to assess the important aspects needed to best suit current and future use. This has led to new front-end developments and enhanced interactivity and functionality that greatly improves user experience. In this article, we present an overview of the current practices including the Biocurational role of the GigaDB staff, the broad usage metrics of GigaDB datasets, and an update on how the GigaDB platform has been overhauled and enhanced to improve the stability and functionality of the codebase. Finally, we report on future directions for the GigaDB resource.
High-resolution mapping of regulatory element interactions and genome architecture using ARC-C
Authors: Huang Ni , Seow Wei Qiang , Ahringer Julie
Published: November 2018

Interactions between cis-regulatory elements such as promoters and enhancers are important for transcription but global identification of these interactions remains a major challenge. Leveraging the chromatin accessiblity of regulatory elements, we developed ARC-C (accessible region chromosome conformation capture), which profiles chromatin regulatory interactions genome-wide at high resolution. Applying ARC-C to C. elegans, we identify ~15,000 significant interactions at 500bp resolution. Regions bound by transcription factors and chromatin regulators such as cohesin and condensin II are enriched for interactions, and we use ARC-C to show that the BLMP-1 transcription factor mediates interactions between its targets. Investigating domain level architecture, we find that C. elegans chromatin domains defined by either active or repressive modifications form topologically associating domains (TADs) and that these domains interact to form A/B (active/inactive) compartment structure. ARC-C is a powerful new tool to interrogate genome architecture and regulatory interactions at high resolution.
Rapid, seamless generation of recombinant poxviruses using host-range and visual selection
Authors: Vipat Sameera , Brennan Greg , Haller Sherry L. , Rothenburg Stefan
Published: November 2018

Vaccinia virus (VACV) was instrumental in eradicating variola virus (VARV), the causative agent of smallpox, from nature. Since this first use as a vaccine, VACV has been developed as a vector for therapeutic vaccines and as an oncolytic virus. These applications take advantage of VACV’s easily manipulated genetics and broad host range as an outstanding platform to generate recombinant therapeutics. Several methods have been developed to generate recombinant VACV, including marker selection methods and transient dominant selection. Here, we present a refinement of a host-range selection method coupled with visual identification. Our method takes advantage of selective pressure generated by the host antiviral protein kinase R (PKR) coupled with a fluorescent fusion gene expressing mCherry-tagged E3L, one of two VACV PKR antagonists. This method permits rapid, seamless generation of rVACV in a variety of cell types.
Potassium channel regulators are differentially expressed in hippocampi of Ts65Dn and Tc1 Down syndrome mouse models
Authors: Stern Shani , Keren Rinat , Kim Yongsung , Moses Elisha
Published: November 2018

Background:

Down syndrome remains the main genetic cause of intellectual disability, with an incidence rate of about 1 in 700 live births. The Ts65Dn mouse strain, with an extra murine chromosome that includes genes from chromosomes 10, 16 and 17 of the mouse and the Tc1 strain with an extra human chromosome 21, are currently accepted as informative and well-studied models for Down Syndrome. Using whole cell patch clamp we recently showed changes in several types of transmembrane currents in hippocampal neuronal cultures of Ts65Dn and Tc1 embryos. The associated genetic changes responsible for these changes in physiology were yet to be studied.

Methods:

We used qPCR to measure RNA expression level of a few of the channel genes that we suspect are implicated in the previously reported changes of measured currents, and performed statistical analysis using Matlab procedures for the standard t-test and ANOVA and for calculating correlations between the RNA expression levels of several channel genes.

Results:

We present differential gene expression levels measured using qPCR of the potassium channel regulators KCNE1 and KCNE2 in both Ts65Dn and Tc1 embryos and pups compared to controls. In Tc1, the human genes KCNJ6 and KCNJ15 are expressed in addition to a statistically insignificant increase of expression in the mouse genes KCNJ6 and KCNJ15. All channel genes that we have measured with large replication, have the same up-regulation or down-regulation in both mouse models, indicating that the transcription mechanism acts similarly in these two mouse models. The large dataset furthermore allows us to observe correlations between different channel genes. We find that, despite the significant changes in expression levels, channels that are known to interact have a high and significant correlation in expression both in controls and in the Down syndrome mouse model.

Conclusions:

We suggest the differential expression of KCNE1 and KCNE2 as a possible cause for our previously reported changes in potassium currents. We report a KCNJ6 and KCNJ15 overexpression, which plays a role in the increased input conductance and the reduced cell excitability that we previously reported in the Tc1 mouse model. The large and significant positive (KCNQ2-KCNQ3, KCNE1-KCNE2, KCNQ3-KCNE1, KCNQ2-KCNE1, KCNQ2-KCNE2, KCNQ3-KCNE2) and negative correlations (KCNE1-KCNJ15, KCNE2-KCNJ15) that we find between channel genes indicate that these genes probably work in a cooperative or in a mutually exclusive manner.
Spatiotemporal expression of FRIGIDA modulate flowering time in Arabidopsis thaliana
Authors: Kong Xiangxiang , Zhao Jinjie , Luo Landi , Chen Qian , Chang Guanxiao , Huang Jinling , Yang Yongping , Hu Xiangyang
Published: November 2018

FRIGIDA (FRI) as the major regulator of flowering time in Arabidopsis accessions can activate its target FLOWERING LOCUS C (FLC) to delay flowering before vernalization. Besides FLC, other FRI targets also exist in Arabidopsis. Although leaves sense environmental cues to modulate flowering time, it is not known if roots also regulate the floral transition. In this study, we investigated the spatiotemporal effect of FRI on flowering time. Local expression of FRI in the phloem and leaves activated FLC to delay flowering. Furthermore, we found that local expression of FRI in the roots also delayed flowering by activating other targets MADS AFFECTING FLOWERING4 (MAF4) and MAF5 in the roots. Graft and genetic experiments revealed that the spatial expression of FRI in the root might generate a mobile signal, which is transmitted from roots to shoot and antagonizes the FT signal to delay flowering. Specifically expressing FRI in the embryo efficiently delayed flowering, even expressing FRI as early as pro-embryo stage is enough to upregulate FLC expression to delay flowering. Together, our findings confirm the spatiotemporal effect of FRI on delaying flowering, and propose that root tissue also perceives the flowering signal to fine-tune the flowering time through MAF4/5 as novel targets of FRI.

Highlight

Root FRIDIGA activated the novel targets MAF4/5 to delay flowering; Temporal expressing FRIGIDA at as early as pro-embryo stage is efficient to delay flowering.
Transcription-factor centric genome mining strategy for discovery of diverse unprecedented RiPP gene clusters
Authors: Zhu Shaozhou , Zheng Guojun
Published: November 2018

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a rapidly emerging group of natural products with diverse biological activity. Most of their biosynthetic mechanisms are well studied and the “genome mining” strategy based on homology has led to the unearthing of many new ribosomal natural products, including lantipeptides, lasso peptides, cyanobactins. These precursor-centric or biosynthetic protein-centric genome mining strategies have encouraged the discovery of RiPPs natural products. However, a limitation of these strategies is that the newly identified natural products are similar to the known products and novel families of RiPP pathways were overlooked by these strategies. In this work, we applied a transcription-factor centric genome mining strategy and diverse unique crosslinked RiPP gene clusters were predicted in several sequenced microorganisms. Our research could significantly expand the category of biosynthetic pathways of RiPP natural products and predict new resources for novel RiPPs.
Boundary effects of expectation in human pain perception
Authors: Hird E.J. , Charalambous C. , El-Deredy W. , Jones A.K. , Talmi D.
Published: November 2018

Perception of sensory stimulation is influenced by numerous psychological variables. One example is placebo analgesia, where expecting low pain causes a painful stimulus to feel less painful. Yet, because pain evolved to signal threats to survival, it should be maladaptive for highly-erroneous expectations to yield unrealistic pain experiences. Therefore, we hypothesised that a cue followed by a highly discrepant stimulus intensity, which generates a large prediction error, will have a weaker influence on the perception of that stimulus. To test this hypothesis we collected two independent pain-cueing datasets. The second dataset and the analysis plan were preregistered (osf.io/5r6z7). Regression modelling revealed that reported pain intensities were best explained by a quartic polynomial model of the prediction error. The results indicated that the influence of cues on perceived pain decreased when stimulus intensity was very different from expectations, suggesting that prediction error size has an immediate functional role in pain perception.