bluuebunny/crossref_metadata_2025_split huggingface dataset:
The interaction between sex-specific selection and local adaptation in species without separate sexes
Authors: Olito Colin , Abbott Jessica K. , Jordan Crispin Y. 
Published: August 2018

Local adaptation in hermaphrodite species can be based on a variety of fitness components, including survival, as well as both female and male sex-functions within individuals. When selection via female and male fitness components varies spatially (e.g. due to environmental heterogeneity), local adaptation will depend, in part, on variation in selection through each fitness component, and the extent to which genetic trade-offs between sex-functions maintain genetic variation necessary for adaptation. Local adaptation will also depend on the hermaphrodite mating system because self-fertilization alters several key factors influencing selection and the maintenance of genetic variance underlying trade-offs between the sex-functions (sexually antagonistic polymorphism). As a first step to guide intuition regarding sex-specific adaptation in hermaphrodites, we develop a simple theoretical model incorporating the essential features of hermaphrodite mating and adaptation in a spatially heterogeneous environment, and explore the interaction between sex-specific selection, self-fertilization and local adaptation. Our results suggest that opportunities for sex-specific local adaptation in hermaphrodites depend strongly on the extent of self-fertilization and inbreeding depression. Using our model as a conceptual framework, we provide a broad overview of the literature on sex-specific selection and local adaptation in hermaphroditic plants and animals, emphasizing promising future directions in light of our theoretical predictions.This article is part of the theme issue ‘Linking local adaptation with the evolution of sex differences'.
Infection dynamics in L.major autophagic machinery is regulated by ATG9-PI3P negative feedback loop
Authors: Kosey Dipali , Soni Bhavnita , Nimsarkar Prajakta , Singh Shailza 
Published: August 2018

AbstractAutophagy is a self-destructing mechanism of cell via lysosomal degradation, which helps to degrade/ destroy hazardous substances, proteins, degenerating organelles and recycling nutrient. It plays an important role in cellular homeostasis and regulates internal environment of cell, moreover, when needed causes non-apoptotic programmed death of cell. It’s usually detailed with ageing and nutritional stress, but recent researches provide support for its role in innate as well as adaptive immunity. Autophagy has been observed as one of the major factors in parasite clearance in leishmaniasis. Due to intra-cellular pathogen, the cell mediated response is only alternative for adaptive immunity against Leishmania in host. T-cells have been observed as main component of cell mediated immunity in leishmaniasis. The differentiation of T-cells generates either destruction or proliferation of parasite as different kind of cytokine mediate different results. Pro-inflammatory cytokine IL12 and TNFα generate Th2 response which helps in active phagocytosis of parasite whereas an anti-inflammatory cytokine like IL10 mediate parasite promotion by blocking autophagic pathways and inhibiting phagocytic actions. TLR2/6 mediated signaling stimulated by LPG produces many pro-inflammatory cytokines like IL12, TNFα and IL6 etc. In macrophages, it is found that TNFα via autocrine signaling induce autophagy and help in parasite killing of Toxoplasma gondii via JNK phosphorylation in macrophages. The phosphorylated JNK induces Beclin by phosphorylating Bcl2, which inhibits Beclin action, thus releasing Beclin and promoting VpS34 which recruits PI3P for autophagosome formation. Recruitment of PI3P is controlled by ATG9 protein, autophagy related gene protein, which in normal condition is inhibited by mTOR via ULK/ ATG1. IL10 has been observed to inhibit autophagy via starvation induced AKT-PI3K pathway in macrophages and result in inducing mTOR. Thus, we can conclude that IL10 inhibits recruitment of PI3P via mTOR. Through systems aspect, here, we decipher that Atg9-PI3P acts as a negative feedback loop in autophagic machinery of leishmaniasis.
A CATH domain functional family based approach to identify putative cancer driver genes and driver mutations
Authors: Ashford Paul , Pang Camilla S.M. , Moya-García Aurelio A. , Adeyelu Tolulope , Orengo Christine A. 
Published: August 2018

Tumour sequencing identifies highly recurrent point mutations in cancer driver genes, but rare functional mutations are hard to distinguish from large numbers of passengers. We developed a novel computational platform applying a multi-modal approach to filter out passengers and more robustly identify putative driver genes. The primary filter identifies enrichment of cancer mutations in CATH functional families (CATH-FunFams) – structurally and functionally coherent sets of evolutionary related domains. Using structural representatives from CATH-FunFams, we subsequently seek enrichment of mutations in 3D and show that these mutation clusters have a very significant tendency to lie close to known functional sites or conserved sites predicted using CATH-FunFams. Our third filter identifies enrichment of putative driver genes in functionally coherent protein network modules confirmed by literature analysis to be cancer associated.Our approach is complementary to other domain enrichment approaches exploiting Pfam families, but benefits from more functionally coherent groupings of domains. Using a set of mutations from 22 cancers we detect 151 putative cancer drivers, of which 79 are not listed in cancer resources and include recently validated cancer genes EPHA7, DCC netrin-1 receptor and zinc-finger protein ZNF479.
Pharmacovigilance or patient safety: analysis from a patient safety program
Authors: Cortázar C Yira Constanza , Orozco D José Gilberto , López G José Julián 
Published: August 2018

AbstractPurposedrugs are the common point of pharmacovigilance and patient safety programs. Despite using a common language, the same epidemiological method and legislation that requires the operation of the two programs, there does not seem to be a clear relationship between them.Methodologyobservational descriptive cross sectional study of the reports database from an institutional patient safety program. Medication errors were classified according to the document The Conceptual Framework for the International Classification for Patient Safety (ICPS) WHO 2009. Adverse Reactions (ADR) were classified according to Uppsala Monitoring Center.Resultsthe omission of drugs or doses was the most frequent error with 42.8% followed by ADRs (20.9%). No harm incidents corresponded to 61.2% and the remaining 38.8% was represented in near missincidents and no harm incidents. There were included 41 ADR and 15 therapeutic failures corresponding to a point-prevalence of 57 ADR/10,000 patients-year and 28.6% (56/196) of reports related to drugs. Phlebitis is the most frequently reported with 23, 7% followed by hypersensitivity reactions with 18.4% and excessive neuromuscular blockade with 13.1%.Conclusionsconsidering time, level of care and number of bed, ADR prevalence seem low. A very important proportion of reports corresponding to near miss incidents or no harm incidents is not taken into account by the security managers, losing a valuable risk management opportunity in the patient safety programs.
Context dependent roles for RB-E2F transcriptional regulation in tumor suppression
Authors: Thwaites Michael J. , Cecchini Matthew J. , Passos Daniel T. , Dick Frederick A. 
Published: August 2018

AbstractRB-E2F transcriptional control plays a key role in regulating the timing of cell cycle progression from G1 to S-phase in response to growth factor stimulation. Despite this role, it is genetically dispensable for cell cycle exit in primary fibroblasts in response to growth arrest signals. Mice engineered to be defective for RB-E2F transcriptional control at cell cycle genes were also found to live a full lifespan with no susceptibility to cancer. Based on this background we sought to probe the vulnerabilities of RB-E2F transcriptional control defects found in Rb1R461E,K542E mutant mice (Rb1G) through genetic crosses with other mouse strains. We generated Rb1G/G mice in combination with Trp53 and Cdkn1a deficiencies, as well as in combination with KrasG12D. The Rb1G mutation enhanced Trp53 cancer susceptibility, but had no effect in combination with Cdkn1a deficiency or KrasG12D. Collectively, this study indicates that compromised RB-E2F transcriptional control is not uniformly cancer enabling, but rather has potent oncogenic effects when combined with specific vulnerabilities.
Trans-splicing of theC. elegans let-7primary transcript developmentally regulateslet-7microRNA biogenesis andlet-7family microRNA activity
Authors: Nelson Charles , Ambros Victor 
Published: August 2018

SUMMARYlet-7is a microRNA whose sequence and roles as a regulator of developmental progression are conserved throughout bilaterians. In most systems, transcription of thelet-7locus occurs relatively early in development, whilst processing oflet-7primary transcript into mature microRNA arises later and is associated with cellular differentiation. InC. elegansand other animals, the RNA binding protein LIN-28 post-transcriptionally inhibitslet-7biogenesis at early developmental stages. The mechanisms by which LIN-28 and other factors developmentally regulatelet-7biogenesis are not fully understood. Nor is it understood how the developmental regulation oflet-7might influence the expression or activities of other microRNAs of the same seed family. Here we show that inC. elegans, the primarylet-7transcript (pri-let-7) is trans-spliced to SL1 splice leader at a position downstream of thelet-7precursor stem-loop, producing a short, polyadenylated downstream mRNA. The trans-splicing event negatively impacts the biogenesis of maturelet-7microRNA incis, likely by destabilizing the upstreampri-let-7fragment. Moreover, the trans-spliced downstream mRNA contains complimentary sequences to multiple members of thelet-7seed family (let-7fam), and thereby serves as a sponge to negatively regulatelet-7famfunction intrans. Thus, this study provides evidence for a mechanism by which splicing of a microRNA primary transcript can negatively regulate said microRNA incisas well as other microRNAs intrans.HIGHLIGHTSThelet-7primary transcript is trans-spliced to produce an RNA that functions as a sponge that negatively regulates thelet-7-familymicroRNAs.Trans-splicing of this RNA negatively impactslet-7microRNA biogenesis.LIN-28 regulates this trans-splicing event
Mechanisms of a locally adaptive shift in allocation among growth, reproduction, and herbivore resistance inMimulus guttatus
Authors: Lowry David B. , Popovic Damian , Brennan Darlene J. , Holeski Liza M. 
Published: August 2018

ABSTRACTEnvironmental gradients can drive adaptive evolutionary shifts in plant resource allocation among growth, reproduction, and herbivore resistance. However, few studies have attempted to connect these adaptations to underlying physiological and genetic mechanisms. Here, we evaluate potential mechanisms responsible for a coordinated locally adaptive shift between growth, reproduction, and herbivore defense in the yellow monkeyflower,Mimulus guttatus.Through manipulative laboratory experiments we found that gibberellin (GA) growth hormones may play a role in the developmental divergence between perennial and annual ecotypes ofM. guttatus. Further, we detected an interaction between a locally adaptive chromosomal inversion,DIV1, and GA addition. This finding is consistent with the inversion contributing to the evolutionary divergence between inland annual and coastal perennial ecotypes by reducing GA biosynthesis/activity in perennials. Finally, we found evidence that theDIV1inversion is partially responsible for a coordinated shift in the divergence of growth, reproduction, and herbivore resistance traits between coastal perennial and inland annualM. guttatus. The inversion has already been established to have a substantial impact on the life-history shift between long-term growth and rapid reproduction. Here, we demonstrate that theDIV1inversion also has sizable impacts on both the total abundance and composition of phytochemical compounds involved in herbivore resistance.
DSCAM-AS1 promotes tumor growth of breast cancer by reducing miR-204-5p and upregulatingRRM2
Authors: Liang Wen-Hui , Li Na , Yuan Zhi-Qing , Qian Xin-Lai , Wang Zhi-Hui 
Published: August 2018

AbstractWe intended to analyze the effects of DSCAM-AS1, miR-204-5p andRRM2on breast cancer (BC) cells growth. Microarray analysis and qRT-PCR were employed to determine DSCAM-AS1 and miR-204-5p expression in BC. Luciferase reporter assay and cell transfection assay were applied to examine the target relationship between DSCAM-AS1, miR-204-5p and MMR2. CCK-8 assay, transwell assay and flow cytometry were used to detect cell proliferation, invasion and apoptosis of breast cancer cells. The expression of DSCAM-AS1, miR-204-5p and MMR2 were confirmed by Western Blot. We also conductedIn vivoassay to verify the effect of DSCAM-AS1 on tumor formation.DSCAM-AS1 was up-regulated, while miR-204-5p was down-regulated in BC tissues and cells. Meanwhile, DSCAM-AS1 directly targeted miR-204-5p. DSCAM-AS1 promoted the proliferation and invasion of BC cells and restrained cell apoptosis by reducing miR-204-5p and inhibiting miR-204-5p expression.RRM2was up-regulated in BC cells, and miR-204-5p inhibitedRRM2expression by targetingRRM2. Overexpression ofRRM2stimulated proliferation and cell invasion and impeded apoptosis of BC cells.In vivoexperiments showed that knockdown of DSCAM-AS1 decreased the tumorigenesis of BC cells, increased the expression of miR-204-5p while inhibitedRRM2expression.DSCAM-AS1 promoted proliferation and impaired apoptosis of BC cells by reducing miR-204-5p and enhancingRRM2expression. DSCAM-AS1/miR-204-5p/RRM2may serve as novel therapeutic targets for BC.Summary statementMicroarray analysis and qRT-PCR were employed to determine DSCAM-AS1 and miR-204-5p expression in BC. DSCAM-AS1 promoted proliferation and impaired apoptosis of BC cells by reducing miR-204-5p and enhancingRRM2expression.
Protect TUDCA stimulated CKD-derived hMSCs against the CKD-Ischemic disease via
upregulation of PrPC
Authors: Yoon Yeo Min , Kim SangMin , Han Yong-Seok , Yun Chul Won , Lee Jun Hee , Noh Hyunjin , Lee Sang Hun 
Published: August 2018

AbstractAlthough autologous human mesenchymal stem cells (hMSCs) are a promising source for regenerative stem cell therapy, the barriers associated with pathophysiological conditions in this disease limit therapeutic applicability to patients. We proved treatment of CKD-hMSCs with TUDCA enhanced the mitochondrial function of these cells and increased complex I & IV enzymatic activity, increasing PINK1 expression and decreasing mitochondrial O2•− and mitochondrial fusion in a PrPC-dependent pathway. Moreover, TH-1 cells enhanced viability when co-cultured in vitro with TUDCA-treated CKD-hMSC. In vivo, tail vein injection of TUDCA-treated CKD-hMSCs into the mouse model of CKD associated with hindlimb ischemia enhanced kidney recovery, the blood perfusion ratio, vessel formation, and prevented limb loss, and foot necrosis along with restored expression of PrPC in the blood serum of the mice. These data suggest that TUDCA-treated CKD-hMSCs are a promising new autologous stem cell therapeutic intervention that dually treats cardiovascular problems and CKD in patients.
The Signaling Pathways Project: an integrated ‘omics knowledgebase for mammalian cellular signaling pathways
Authors: Ochsner Scott , Abraham David , Martin Kirt , Ding Wei , McOwiti Apollo , Kankanamge Wasula , Wang Zichen , Andreano Kaitlyn , Hamilton Ross A. , Chen Yue , Hamilton Angelica , Gantner Marin L. , Dehart Michael , Qu Shijing , Hilsenbeck Susan G. , Becnel Lauren B. , Bridges Dave , Ma’ayan Avi , Huss Janice M. , Stossi Fabio , Foulds Charles E. , Kralli Anastasia , McDonnell Donald P. , McKenna Neil J. 
Published: August 2018

AbstractIntegrated mining of public transcriptomic and ChIP-Seq datasets has the potential to illuminate facets of mammalian cellular signaling pathways not yet explored in the research literature. Here, we designed a web knowledgebase, the Signaling Pathways Project (SPP), which incorporates stable community classifications of the four major categories of signaling pathway node (receptors, enzymes, transcription factors and co-nodes) and their cognate bioactive small molecules (BSMs). We then mapped over 10,000 public transcriptomic or cistromic experiments to their relevant signaling pathway node, BSM or biosample of study. To provide for prediction of pathway node-target transcriptional regulatory relationships, we generated consensus ‘omics signatures, or consensomes, based on measures of significant differential expression of genomic targets across all underlying transcriptomic experiments. To expose the SPP knowledgebase to researchers, a web browser interface accommodates a variety of routine data mining strategies. Consensomes were validated using alignment with literature-based knowledge, gene target-level integration of transcriptomic and ChIP-Seq data points, and in bench experiments that confirmed previously uncharacterized node-gene target regulatory relationships. SPP is freely accessible at https://beta.signalingpathways.org.
Ocular findings and blood flow in patients with Takayasu arteritis: a cross-sectional study
Authors: Esen Fehim , Ergelen Rabia , Alibaz-Öner Fatma , Çelik Gülce , Direskeneli Haner , Kazokoğlu Haluk 
Published: August 2018

Background/aimsTakayasu arteritis (TAK) is a chronic granulomatous vasculitis that can lead to ischaemic ocular complications. We aimed to document ocular complications, ocular blood flow and the association of them with systemic clinical findings in TAK.Material and methodsWe included 65 patients with TAK (60 female, 5 male, mean age: 41.8±12.9 years) and 30 healthy subjects (30 female, mean age: 39.0±7.5 years) in this study. All of the patients had a detailed rheumatological and ophthalmological evaluation. Ocular blood flow in ophthalmic artery (OA) and central retinal artery (CRA) was evaluated with colour Doppler ultrasonography.ResultsHypertensive retinopathy was observed in 33.9%, and Takayasu retinopathy was observed in 6.2% of patients. Posterior subcapsular cataracts or a history of cataract surgery was seen in 15.4% of the cases. None of the patients experienced visual loss due to ischaemic or neovascular complications. Patients with TAK had increased resistivity index (RI) in ophthalmic artery (0.75 vs 0.66, p=0.002) and CRA (0.75 vs 0.67, p=0.001). Patients with hypertensive retinopathy had significantly longer disease duration (p=0.016). Ophthalmic artery RI was significantly higher in patients with ipsilateral radial artery pulselessness compared with patients without (0.77 vs 0.68, p=0.031).ConclusionThis study reported the lowest prevalence of Takayasu retinopathy and is the only series without permanent visual loss. We documented for the first time that radial artery pulselessness can predict reduction of ipsilateral ocular perfusion. We believe that better management of TAK with current medications reduced ocular complication rates.
Effects and costs of real-time cardiac telerehabilitation: randomised controlled non-inferiority trial
Authors: Maddison Ralph , Rawstorn Jonathan Charles , Stewart Ralph A H , Benatar Jocelyne , Whittaker Robyn , Rolleston Anna , Jiang Yannan , Gao Lan , Moodie Marj , Warren Ian , Meads Andrew , Gant Nicholas 
Published: August 2018

ObjectiveCompare the effects and costs of remotely monitored exercise-based cardiac telerehabilitation (REMOTE-CR) with centre-based programmes (CBexCR) in adults with coronary heart disease (CHD).MethodsParticipants were randomised to receive 12 weeks of telerehabilitation or centre-based rehabilitation. REMOTE-CR provided individualised exercise prescription, real-time exercise monitoring/coaching and theory-based behavioural strategies via a bespoke telerehabilitation platform; CBexCR provided individualised exercise prescription and coaching via established rehabilitation clinics. Outcomes assessed at baseline, 12 and/or 24 weeks included maximal oxygen uptake (V̇O2max, primary) modifiable cardiovascular risk factors, exercise adherence, motivation, health-related quality of life and programme delivery, hospital service utilisation and medication costs. The primary hypothesis was a non-inferior between-group difference in V̇O2max at 12 weeks (inferiority margin=−1.25 mL/kg/min); inferiority margins were not set for secondary outcomes.Results162 participants (mean 61±12.7 years, 86% men) were randomised. V̇O2 max was comparable in both groups at 12 weeks and REMOTE-CR was non-inferior to CBexCR (REMOTE-CR-CBexCR adjusted mean difference (AMD)=0.51 (95% CI −0.97 to 1.98) mL/kg/min, p=0.48). REMOTE-CR participants were less sedentary at 24 weeks (AMD=−61.5 (95% CI −117.8 to −5.3) min/day, p=0.03), while CBexCR participants had smaller waist (AMD=1.71 (95% CI 0.09 to 3.34) cm, p=0.04) and hip circumferences (AMD=1.16 (95% CI 0.06 to 2.27) cm, p=0.04) at 12 weeks. No other between-group differences were detected. Per capita programme delivery (NZD1130/GBP573 vs NZD3466/GBP1758) and medication costs (NZD331/GBP168 vs NZD605/GBP307, p=0.02) were lower for REMOTE-CR. Hospital service utilisation costs were not statistically significantly different (NZD3459/GBP1754 vs NZD5464/GBP2771, p=0.20).ConclusionREMOTE-CR is an effective, cost-efficient alternative delivery model that could—as a complement to existing services—improve overall utilisation rates by increasing reach and satisfying unique participant preferences.
Fecal Calprotectin Pretreatment and Induction Infliximab Levels for Prediction of Primary Nonresponse to Infliximab Therapy in Crohn’s Disease
Authors: Beltrán Belén , Iborra Marisa , Sáez-González Esteban , Marqués-Miñana Maria R. , Moret Inés , Cerrillo Elena , Tortosa Luis , Bastida Guillermo , Hinojosa Joaquín , Poveda-Andrés Jose Luis , Nos Pilar 
Published: August 2018

<b><i>Introduction:</i></b> The association between infliximab (IFX) and fecal calprotectin (FC) levels on one hand, and the clinical and endoscopic response of patients with inflammatory bowel disease on the other, is well established. <b><i>Objective and Methods:</i></b> To investigate the association between inflammatory biochemical parameters and serum concentrations of IFX during induction treatment with a primary nonresponse in a prospective cohort of Crohn’s disease (CD) patients. <b><i>Results:</i></b> Of the 35 patients included, 8 (22.8%) had primary nonresponse at the end of induction. Induction IFX levels were lower among primary nonresponders at weeks 6 and 14 (week 6: median IFX level 7.3 vs. 11.2 μg/mL, respectively, <i>p</i> = 0.090; week 14: median IFX level 1.5 vs. 4.7 μg/mL, respectively, <i>p</i> = 0.020). FC levels were higher in patients with primary nonresponse versus primary response at weeks 0, 6, and 14 (week 0: median FC level 1,830 vs. 410 μg/g, ­respectively, <i>p</i> = 0.030; week 6: median FC level 1,150 vs. 230 μg/g, respectively, <i>p</i> = 0.074; week 14: median FC level 1,210 vs. 208 μg/g, respectively, <i>p</i> = 0.060). For the multivariate analysis, the median IFX level at week 14 and median FC level at week 0 were independently associated with primary nonresponse. A significant inverse correlation was determined between FC level at week 0 and IFX level at week 14 (Spearman’s rho correlation, 0.440; <i>p</i> &#x3c; 0.05). <b><i>Conclusions:</i></b> IFX levels (at week 14) and baseline FC levels could predict primary nonresponse after induction IFX therapy in patients with CD. A high baseline inflammatory load might modify the pharmacokinetic processes of anti-tumor necrosis factor drugs. Drug level monitoring and measurement of baseline inflammatory parameters could improve the efficacy of IFX in the induction therapy of patients with active CD.